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Objectives To examine the impact of the COVID-19 pandemic on deprivation-related inequalities in hospitalisations for cardiovascular disease (CVD) conditions in Denmark and England between March 2018 and December 2021.Design Time-series studies in England and Denmark.Setting With the approval of National Health Service England, we used English primary care electronic health records, linked to secondary care and death registry data through the OpenSAFELY platform and nationwide Danish health registry data.Participants We included adults aged 18 and over without missing age, sex or deprivation information. On 1 March 2020, 16 234 700 people in England and 4 491 336 people in Denmark met the inclusion criteria.Primary outcome measures Hospital admissions with the primary reason for myocardial infarction (MI), ischaemic or haemorrhagic stroke, heart failure and venous thromboembolism (VTE).Results We saw deprivation gradients in monthly CVD hospitalisations in both countries, with differences more pronounced in Denmark. Based on pre-pandemic trends, in England, there were an estimated 2608 fewer admissions than expected for heart failure in the most deprived quintile during the pandemic compared with an estimated 979 fewer admissions in the least deprived quintile. For all other outcomes, there was little variation by deprivation quintile. In Denmark, there were an estimated 1013 fewer admissions than expected over the pandemic for MI in the most deprived quintile compared with 619 in the least deprived quintile. Similar trends were seen for stroke and VTE, though absolute numbers were smaller. Heart failure admissions were similar to pre-pandemic levels with little variation by deprivation quintile.Conclusions Overall, we did not find that the pandemic substantially worsened pre-existing deprivation-related differences in CVD hospitalisations, though there were exceptions in both countries.

Objective: The aim was to examine the association between hospital-diagnosed overweight/obesity and incident CVD according to the time period of the overweight/obesity diagnosis. Design: This is a cohort study. Methods: From Danish national health registries, we identified all residents with a first-time hospital-based overweight/obesity diagnosis code, 1977–2018 (n = 195,221), and an age and sex-matched general population comparison cohort (n = 1,952,210). We computed adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox regression. We adjusted for comorbidities and educational level and applied 10 years of follow-up. Results: The overall incidence rate was 10.1 (95% CI 10.0–10.1) per 1000 person-years for the comparison cohort and 25.1 (95% CI 24.8–25.4) per 1000 person-years for the overweight/obesity cohort, corresponding to an aHR of 2.5 (95% CI 2.4–2.5). The aHR was elevated for all subtypes of CVD: heart failure: 3.9 (95% CI 3.7–4.1), bradyarrhythmia: 2.9 (95% CI 2.7–3.1), angina pectoris: 2.7 (95% CI 2.7–2.8), atrial fibrillation or flutter: 2.6 (95% CI 2.5–2.6), acute myocardial infarction: 2.4 (95% CI 2.3–2.4), revascularization procedure: 2.4 (95% CI 2.2–2.5), valvular heart disease: 1.7 (95% CI 1.6–1.8), ischemic stroke: 1.6 (95% CI 1.4–1.7), transient ischemic attack: 1.6 (95% CI 1.5–1.7), and cardiovascular death: 1.6 (95% CI 1.5–1.6). The 1–10-year aHR of any CVD associated with an overweight/obesity diagnosis decreased from 2.8 (95% CI 2.7–2.9) in 1977–1987 to 1.8 (95% CI 1.8–1.9) in 2008–2018. Conclusion: Patients with hospital-diagnosed overweight/obesity had high rates of ischemic heart disease, heart failure, structural heart disease, arrhythmia, stroke, and death, although the strength of the association decreased in recent years.

Abstract Importance The burden of caring for children with complex medical problems such as major congenital anomalies falls principally on mothers, who in turn suffer a variety of potentially severe economic consequences. As well, health consequences of caregiving often further impact the social and economic prospects of mothers of children with major congenital anomalies (MCMCAs). Evaluating the long-term economic consequences of extensive in-home caregiving among MCMCAs can inform strategies to mitigate these effects. Objective To assess whether MCMCAs face reduced employment and increased need for disability benefits over a 20-year period. Design A population-based matched cohort study. Setting Denmark. Participants All women who gave birth to a singleton child with a major congenital anomaly in Denmark between January 1, 1997 and December 31, 2017 (n = 23,637) and a comparison cohort of mothers matched by maternal age, parity, and infant’s year of birth (n = 234,586). Exposures Liveborn infant with a major congenital anomaly. Main outcomes and measures The primary outcome was mothers’ employment status, stratified by their child’s age. Employment status was categorized as employed, outside the workforce (on temporary leave, holding a flexible job, or pursuing education), or unemployed; the number of weeks in each category was measured over time. The secondary outcome was time to receipt of a disability pension, which in Denmark implies permanent exit from the labor market. We used a negative binomial regression model to estimate the number of weeks in each employment category, stratified by the child’s age (i.e., 0–1 year, > 1–6 years, 7–13 years, 14–18 years). A Cox proportional hazards regression model was used to compute hazard ratios as a measure of the relative risk of receiving a disability pension. Rate ratios and hazard ratios were adjusted for maternal demographics, pregnancy history, health, and infant’s year of birth. Results During 1–6 years after delivery, MCMCAs were outside the workforce for a median of 50 weeks (IQR, 6–107 weeks), while members of the comparison cohort were outside the workforce for a median of 48 weeks (IQR, 4–98 weeks), corresponding to an adjusted rate ratio [ARR] of 1.05 (95% confidence interval [CI], 1.04–1.07). During the first year after delivery, MCMCAs were more likely to be employed than mothers in the comparison cohort (ARR, 1.08; 95% CI, 1.06–1.10). At all timepoints thereafter, MCMCAs had a lower rate of workforce participation. The rate of being outside the workforce was 5% higher than mothers in the comparison cohort during 1–6 years after delivery (ARR, 1.05; 95% CI, 1.04–1.07), 9% higher during 7–13 years after delivery (ARR, 1.09; 95% CI, 1.06–1.12), and 12% higher during 14–18 years after delivery (ARR, 1.12; 95% CI, 1.07–1.18). Overall, MCMCAs had a 20% increased risk of receiving a disability pension during follow-up than mothers in the matched comparison cohort [incidence rates 3.10 per 1000 person-years (95% CI, 2.89–3.32) vs. 2.34 per 1000 person-years (95% CI, 2.29–2.40), adjusted hazard ratio, 1.20; 95% CI, 1.11–1.29]. Conclusion and relevance MCMCAs were less likely to participate in the Danish workforce, less likely to be employed, and more likely to receive disability pensions than mothers of unaffected children. The rate of leaving the workforce intensified as their affected children grew older. The high demands of caregiving among MCMCAs may have long-term employment consequences even in nations with comprehensive and heavily tax-supported childcare systems, such as Denmark.

Background and purpose: Revisions due to periprosthetic joint infection (PJI) are underestimated in national arthroplasty registries. Our primary objective was to assess the validity in the Danish Knee Arthroplasty Register (DKR) of revisions performed due to PJI against the Healthcare-Associated Infections Database (HAIBA). The secondary aim was to describe the cumulative incidences of revision due to PJI within 1 year of primary total knee arthroplasty (TKA) according to the DKR, HAIBA, and DKR/HAIBA combined. Methods: This longitudinal observational cohort study included 56,305 primary TKAs (2010–2018), reported in both the DKR and HAIBA. In the DKR, revision performed due to PJI was based on pre- and intraoperative assessment disclosed by the surgeon immediately after surgery. In HAIBA, PJI was identified from knee-related revision procedures coinciding with 2 biopsies with identical microbiological pathogens. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of revision due to PJI in the DKR (vs. HAIBA, within 1 year of TKA) with 95% confidence intervals (CI). Cumulative incidences were calculated using the Kaplan–Meier method. Results: The DKR‘s sensitivity for PJI revision was 58% (CI 53–62) and varied by TKA year (41%–68%) and prosthetic type (31% for monoblock; 63% for modular). The specificity was 99.8% (CI 99.7–99.8), PPV 64% (CI 62–72), and NPV 99.6% (CI 99.6–99.7). 80% of PJI cases not captured by the DKR were caused by non-reporting rather than misclassification. 33% of PJI cases in the DKR or HAIBA were culture-negative. Considering potential misclassifications, the best-case sensitivity was 64%. The cumulative incidences of PJI were 0.8% in the DKR, 0.9% in HAIBA, and 1.1% when combining data. Conclusion: The sensitivity of revision due to PJI in the DKR was 58%. The cumulative incidence of PJI within 1 year after TKA was highest (1.1%) when combining the DKR and HAIBA, showing that incorporating microbiology data into arthroplasty registries can enhance PJI validity.

Abstract Background Elevated triglyceride levels are a clinically useful marker of remnant cholesterol. It is unknown whether triglycerides are associated with residual cardiovascular risk in CVD-naïve patients with newly diagnosed type 2 diabetes mellitus (T2DM), who are already on statin therapy. We aimed to assess the association between triglyceride levels and risk of major cardiovascular events (MACE) in statin-treated patients with newly diagnosed T2DM managed in routine clinical care. Methods This cohort study included newly diagnosed T2DM patients without a previous diagnosis of cardiovascular disease in Northern Denmark during 2005–2017. Individual triglyceride levels while on statin treatment were assessed within 1 year after T2DM diagnosis. The primary outcome was a composite of myocardial infarction, ischemic stroke, or cardiac death (MACE). Patients were followed from one year after T2DM diagnosis until 30 April 2021, MACE, emigration, or death. We used Cox regression to compute hazard ratios (HRs) controlling for confounding factors. Results Among 27,080 statin-treated patients with T2DM (median age 63 years; 53% males), triglyceride levels were

[This corrects the article DOI: 10.1371/journal.pmed.1004238.].

Background Bleeding and venous thromboembolism (VTE) are adverse outcomes after colorectal cancer (CRC) surgery. Type 2 diabetes (T2D) clusters with bleeding and VTE risk factors. We examined the bleeding and VTE risk in patients with T2D undergoing CRC surgery and the prognosis after these adverse outcomes.

BackgroundThe association between assisted reproductive technologies (ARTs) and the body mass index (BMI) of children remains controversial. Confounding by morbidity and other factors associated with parental infertility may have biased studies comparing children born after ART with children born after no treatment. We investigated the associations between different fertility treatments and BMI in children at age 5 to 8 years, adjusting for and stratifying by causes of parental infertility.Methods and findingsThis Danish cohort study included 327,301 children born between 2007 and 2012 (51% males, median age at follow-up 7 years). Of these, 13,675 were born after ART, 7,728 were born after ovulation induction with or without intrauterine insemination [OI/IUI], and 305,898 were born after no fertility treatments. Using the International Obesity Task Force (IOTF) standards, we defined overweight (BMI ≥ IOTF-25) and obesity (BMI ≥ IOTF-30). We compared children born after ART versus OI/IUI; intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilization (IVF); and frozen-thawed versus fresh embryo transfer and estimated crude and adjusted prevalences of children with overweight or obesity at age 5 to 8 years, prevalence odds ratios (PORs), and differences in mean BMI z-scores. Adjustment was performed using stabilized inverse probability of treatment weights, including parity, year of conception, parental causes of infertility, age, educational level, comorbidities, maternal country of origin, BMI, and smoking as covariates. The crude prevalence of obesity was 1.9% in children born after ART, 2.0% in those born after OI/IUI, and 2.7% in those born after no fertility treatment. After adjustment, children born after ART and OI/IUI had the same prevalence of being overweight (11%; POR 1.00, 95% confidence interval [CI] 0.91 to 1.11; p = 0.95) or obese (1.9%; POR 1.01, 95% CI 0.79 to 1.29; p = 0.94). Comparison of ICSI with conventional IVF yielded similar pattern (POR 0.95, 95% CI 0.83 to 1.07; p = 0.39 for overweight and POR 1.16, 95% CI 0.84 to 1.61; p = 0.36 for obesity). Obesity was more prevalent after frozen-thawed (2.7%) than fresh embryo transfer (1.8%) (POR 1.54, 95% CI 1.09 to 2.17; p = 0.01). The associations between fertility treatments and BMI were only modestly different in subgroups defined by the cause of infertility. Study limitations include potential residual confounding, restriction to live births, and lack of detailed technical information about the IVF procedures.ConclusionsWe found no association with BMI at age 5 to 8 years when comparing ART versus OI/IUI or when comparing ICSI versus conventional IVF. However, use of frozen-thawed embryo transfer was associated with a 1.5-fold increased risk of obesity compared to fresh embryo transfer. Despite an elevated relative risk, the absolute risk difference was low.

Introduction Comorbidities are common in patients with chronic obstructive pulmonary disease (COPD). Estimates of prevalence, incidence and prognostic impact of comorbidities provide foundational knowledge of COPD epidemiology. We examined the prevalence, incidence and prognostic impact of 21 comorbidities among patients with COPD compared with the Danish general population.Methods We conducted a nationwide, population-based cohort study based on longitudinal Danish registry data, covering all Danish hospitals (2010–2021). The cohorts comprised 142 973 patients with a first-time hospital-based diagnosis of COPD and 428 917 age-matched and sex-matched comparators from the general population. During follow-up, we estimated the 5-year risk and risk difference, using competing risk methods when applicable.Results At time of diagnosis, the comorbidities with the highest prevalence were mood, stress-related or anxiety disorders (25.2% for patients with COPD vs 13.1% for comparators), osteoporosis/hip fractures (17.4% vs 9.9%), diabetes (15.6% vs 10.5%), peripheral arterial disease (13.5% vs 4.9%) and heart failure (13.3% vs 4.0%). During follow-up, the risk of most incident comorbidities was markedly elevated among patients with COPD. The five comorbidities associated with the highest 5-year absolute risk difference with respect to the risk in the general population were mood, stress-related or anxiety disorders (5.7%), osteoporosis/hip fractures (5.6%), heart failure (4.2%), smoking-related cancers (2.8%) and peripheral arterial disease (2.7%). The 5-year mortality risk was 43% vs 17.7%. Among patients with COPD, the 5-year mortality risk markedly increased with the number of comorbidities present.Conclusions Our population-based findings underscore the importance of considering comorbidities in the management of COPD.

Summary: Background: Despite recent improvements in the treatment of cancer, little is known about the long-term survival in patients with cancer and venous thromboembolism. We aimed to examine the five-year mortality of venous thromboembolism in cancer patients in a large population-based cohort study. Methods: Using Danish healthcare registries from 1995 to 2020, we obtained data on cancer patients with venous thromboembolism and comparison cohorts of cancer patients without venous thromboembolism, matched in terms of cancer type, age, sex, and year of cancer diagnosis, and adjusted for level of comorbidity and frailty using the Charlson Comorbidity Index Score and Hospital Frailty Risk Score, marital status, use of selected medications, and recent surgery (

Abstract Background Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the ‘$10 Challenge’. Methods We conducted a cross-sectional study of DARE alumni over five consecutive years (2015–2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software. Results DARE Medical students were 31.2 years (range 24–35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p

IntroductionWhile inhaled corticosteroids (ICS) may increase pneumonia risk in patients with chronic obstructive pulmonary disease (COPD), the impact of ICS on pneumonia outcomes is debated. We examined whether ICS use is associated with adverse outcomes among COPD patients with community-acquired pneumonia (CAP).Materials and methodsPopulation-based cohort study of all COPD patients with an incident hospitalization for CAP between 1997 and 2013 in Northern Denmark. Information on medications, COPD severity, comorbidities, complications, and death was obtained from medical databases. Adjusted risk ratios (aRRs) for pleuropulmonary complications, intensive care unit (ICU) admissions, and 30-day mortality in current and former ICS users were compared with those in non-users, using regression analyzes to handle confounding.ResultsOf 11,368 COPD patients with CAP, 6,073 (53.4%) were current ICS users and 1,733 (15.2%) were former users. Current users had a non-significantly decreased risk of pleuropulmonary complications [2.6%; aRR = 0.82 (0.59–1.12)] compared to non-users (3.2%). This was also observed among former users [2.5%; aRR = 0.77 (0.53–1.12)]. Similarly, decreased risks of ICU admission were observed among current users [aRR = 0.77 (0.57–1.04)] and among former users [aRR = 0.81 (0.58–1.13)]. Current ICS users had significantly decreased 30-day mortality [9.1%; aRR = 0.72 (0.62–0.85)] compared to non-users (12.6%), with a stronger association observed among patients with frequent exacerbations [0.58 (0.39–0.86)]. No significant association was observed among former ICS users [0.89 (0.75–1.05)].ConclusionOur results suggest a decreased risk of death with ICS use among COPD patients admitted for CAP.

Abstract Background Type 2 diabetes and obesity may be inversely associated with amyotrophic lateral sclerosis (ALS), but the evidence is controversial. Methods Using Danish, nationwide registries (1980‐2016), we identified patients with a diagnosis of type 2 diabetes (N = 295,653) and patients with a diagnosis of obesity (N = 312,108). Patients were matched (1:3) to persons from the general population on birth year and sex. We computed incidence rates and Cox regression derived hazard ratios (HRs) of a diagnosis of ALS. In multivariable analyses, HRs were controlled for sex, birth year, calendar year, and comorbidities. Results We observed 168 incident cases of ALS (0.7 [95% confidence interval (CI): 0.6–0.8] per 10,000 person‐years) among patients with type 2 diabetes and 859 incident cases of ALS (0.9 [95% CI: 0.9–1.0] per 10,000 person‐years) among matched comparators. The adjusted HR was 0.87 (95% CI: 0.72–1.04). The association was present among men (adjusted HR: 0.78 [95% CI: 0.62–0.99]) but not women (adjusted HR: 1.03 [95% CI: 0.78–1.37]), and among those aged ≥60 years (adjusted HR: 0.75 [95% CI: 0.59–0.96]) but not younger. We observed 111 ALS events (0.4 [95% CI: 0.4–0.5] per 10,000 person‐years) among obesity patients and 431 ALS events (0.5 [95% CI: 0.5–0.6] per 10,000 person‐years) among comparators. The adjusted HR was 0.88 (95% CI: 0.70–1.11). Conclusions Diagnoses of type 2 diabetes and obesity were associated with a reduced rate of ALS compared with general population comparators, particularly among men and patients aged 60 years or above. However, absolute rate differences were small.

BackgroundMigraine carries risk of myocardial infarction (MI) and stroke. The risk of premature MI (i.e., among young adults) and stroke differs between men and women; previous studies indicate that migraine is mainly associated with an increased risk of stroke among young women. The aim of this study was to examine impact of migraine on the risk of premature (age ≤60 years) MI and ischemic/hemorrhagic stroke among men and women.Methods and findingsUsing Danish medical registries, we conducted a nationwide population-based cohort study (1996 to 2018). Redeemed prescriptions for migraine-specific medication were used to identify women with migraine (n = 179,680) and men with migraine (n = 40,757). These individuals were matched on sex, index year, and birth year 1:5 with a random sample of the general population who did not use migraine-specific medication. All individuals were required to be between 18 and 60 years old. Median age was 41.5 years for women and 40.3 years for men. The main outcome measures to assess impact of migraine were absolute risk differences (RDs) and hazard ratios (HRs) with 95% confidence intervals (CIs) of premature MI, ischemic, and hemorrhagic stroke, comparing individuals with migraine to migraine-free individuals of the same sex. HRs were adjusted for age, index year, and comorbidities. The RD of premature MI for those with migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.3% (95% CI [-0.1%, 0.6%]; p = 0.061) for men. The adjusted HR was 1.22 (95% CI [1.14, 1.31]; p < 0.001) for women and 1.07 (95% CI [0.97, 1.17]; p = 0.164) for men. The RD of premature ischemic stroke for migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.5% (95% CI [0.1%, 0.8%]; p < 0.001) for men. The adjusted HR was 1.21 (95% CI [1.13, 1.30]; p < 0.001) for women and 1.23 (95% CI [1.10, 1.38]; p < 0.001) for men. The RD of premature hemorrhagic stroke for migraine versus no migraine was 0.1% (95% CI [0.0%, 0.2%]; p = 0.011) for women and -0.1% (95% CI [-0.3%, 0.0%]; p = 0.176) for men. The adjusted HR was 1.13 (95% CI [1.02, 1.24]; p = 0.014) for women and 0.85 (95% CI [0.69, 1.05]; p = 0.131) for men. The main limitation of this study was the risk of misclassification of migraine, which could lead to underestimation of the impact of migraine on each outcome.ConclusionsIn this study, we observed that migraine was associated with similarly increased risk of premature ischemic stroke among men and women. For premature MI and hemorrhagic stroke, there may be an increased risk associated with migraine only among women.

Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes. Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal. Results: Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes. Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria.

Background Opioid use has been linked to an increased risk of myocardial infarction and cardiovascular mortality, but the prognostic impact of opioid use before an incident myocardial infarction is largely unknown. Methods and Results We conducted a nationwide population‐based cohort study including all patients hospitalized for an incident myocardial infarction in Denmark (1997–2016). Based on their last redeemed opioid prescription before admission, patients were categorized as current users (0–30 days), recent users (31–365 days), former users (>365 days), and nonusers. One‐year all‐cause mortality was calculated using the Kaplan–Meier method. Hazard ratios (HRs) were computed using Cox proportional hazards regression analyses, adjusting for age, sex, comorbidity, any preceding surgery within 6 months before the myocardial infarction admission, and medication use before the myocardial infarction admission. We identified 162 861 patients with an incident myocardial infarction. Of these, 8% were current opioid users, 10% were recent opioid users, 24% were former opioid users, and 58% were nonusers of opioids. One‐year mortality was highest among current users (42.5% [95% CI, 41.7%–43.3%]) and lowest among nonusers (20.5% [95% CI, 20.2%–20.7%]). Compared with nonusers, current users had an elevated 1‐year all‐cause mortality risk (adjusted HR, 1.26 [95% CI, 1.22–1.30]). Following adjustment, neither recent users nor former users of opioids were at elevated risk. Conclusions Preadmission opioid use was associated with an increased 1‐year all‐cause mortality risk following an incident myocardial infarction. Opioid users thus represent a high‐risk subgroup of patients with myocardial infarction.

Objective To estimate the prevalence of diagnosed alpha-1 antitrypsin deficiency (dAATD) in Denmark as of 31 December 2018, and dAATD incidence and mortality from 1 January 2000 to 31 December 2018.Study design and setting We used the Danish National Patient Registry to identify patients with dAATD based on the International Classification of Diseases, 10th Revision (ICD-10) code E88.0A and the Danish Civil Registration System (CRS) for population counts and vital status. We estimated dAATD prevalence, incidence and mortality. We compared mortality among patients with dAATD and an age-matched and sex-matched cohort extracted from the Danish CRS. We conducted a sensitivity analysis to examine whether coding changes during 2000–2018, from a general to a more specific ICD-10 code for AATD, and left truncation affected results appreciably.Results The prevalence of dAATD was 12.9 (95% CI 11.9 to 13.8) per 100 000 persons. The age distribution was bimodal, with peaks at ages ≤12 and ≥45 years. The incidence rate per 100 000 person-years was 0.90 (95% CI 0.85 to 0.96), again with a bimodal age distribution. Mortality was higher for patients with dAATD than for the general population (mortality rate ratio (mRR) 4.7, 95% CI 4.1 to 5.3), especially for children (mRR 33.8, 95% CI 6.8 to 167.4). The sensitivity analysis indicated that dAATD prevalence might have been as high as 19.7 per 100 000 persons due to less specific ICD-10 coding for AATD early in the study period or 21.4 per 100 000 persons correcting for left truncation.Conclusion Diagnosed AATD was associated with increased mortality, especially for children. The finding for children was based on few deaths and had very wide 95% CIs.

Abstract Background Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence. Methods In this population-based case-control study, we included women diagnosed with stage I–III breast cancer between 1985 and 2001, aged 35–69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER−/TAM−). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence. Results HIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER−/TAM− stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER−/TAM− OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER−/TAM− stratum. Conclusion In this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER− breast cancer.

Abstract Background To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality. Methods We conducted a cohort study nested in the ProBeCaRe (Predictors of Breast Cancer Recurrence) cohort (n = 5959). We identified all premenopausal women aged 18–55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007–2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate, or high), income (low, medium, or high), and employment status (employed, unemployed, or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs), and used Poisson regression to compute incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of recurrence and death. We stratified on estrogen receptor (ER) status/tamoxifen to evaluate interaction. Results Our study cohort included 2616 women; 286 (CIP 13%) experienced recurrence and 223 (CIP 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased 5-year risks of recurrence (IRR 1.45, 95% CI 1.11–1.89) and mortality (IRR 1.83, 95% CI 1.32–2.52). Furthermore, we observed increased 5-year mortality in women with low education (IRR 1.49, 95% CI 0.95–2.33), low income (IRR 1.37, 95% CI 0.83–2.28), unemployment (IRR 1.61, 95% CI 0.83–3.13), or health-related work absenteeism (IRR 1.80, 95% CI 1.14–2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen. Overall analyses (follow-up max. 10 years) provided similar results. Conclusions Low SEP in premenopausal women with non-metastatic breast cancer was associated with increased mortality, but not always recurrence. This suggests underdetection of recurrences in certain groups. Poor prognosis in women with low SEP, especially single women, may partly be explained by tamoxifen adherence.

Introduction Since disseminated intravascular coagulation (DIC) was first described, it has been considered a serious disease of the coagulation system and a major challenge to clinicians. Currently, several important knowledge gaps remain. The DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study will aim to answer questions regarding the incidence and mortality of patients with DIC including time trends. The study will also identify prognostic factors that may guide personalised prevention and treatment. Furthermore, the study will describe treatment patterns and the safety and effectiveness of various treatment modalities.Methods and analysis We will establish the DANDIC Cohort using data collected in daily clinical practice from the Central Denmark Region, which covers approximately 1.3 million residents. The study period will encompass 1 January 2011 through 1 July 2021. Potential DIC cases will be identified from the hospital laboratory database, based on coagulation biomarkers, and diagnoses will be adjudicated by medical experts. The dataset will be enriched with detailed clinical data from electronic medical charts on aetiologies, bleeding, microthrombus formation, organ failure, thrombosis, treatments and comorbidities. The dataset will also take advantage of in-hospital data with longitudinal information on laboratory records, transfusions, microbiology and treatments. It will be possible to merge this dataset with other unique Danish health registries with more than 10 years of virtually complete follow-up. The project will use state-of-the-art epidemiological and biostatistical methods.Ethics and dissemination The project has been approved by the Danish Patient Safety Authority (31-1521-452), the Central Denmark Region (1-45-70-83-21), the Danish Data Protection Agency (1-16-02-258-21) and all the hospital chairs. Register-based studies require no ethical approval in Denmark. The results will be disseminated in international peer-reviewed journals.

Abstract Background Diabetes patients without obstructive coronary artery disease as assessed by coronary angiography have a low risk of myocardial infarction, but their myocardial infarction risk may still be higher than the general population. We examined the 10-year risks of myocardial infarction, ischemic stroke, and death in diabetes patients without obstructive coronary artery disease according to coronary angiography, compared to risks in a matched general population cohort. Methods We included all diabetes patients without obstructive coronary artery disease examined by coronary angiography from 2003 to 2016 in Western Denmark. Patients were matched by age and sex with a cohort from the Western Denmark general population without a previous myocardial infarction or coronary revascularization. Outcomes were myocardial infarction, ischemic stroke, and death. Ten-year cumulative incidences were computed. Adjusted hazard ratios (HR) then were computed using stratified Cox regression with the general population as reference. Results We identified 5734 diabetes patients without obstructive coronary artery disease and 28,670 matched individuals from the general population. Median follow-up was 7 years. Diabetes patients without obstructive coronary artery disease had an almost similar 10-year risk of myocardial infarction (3.2% vs 2.9%, adjusted HR 0.93, 95% CI 0.72–1.20) compared to the general population, but had an increased risk of ischemic stroke (5.2% vs 2.2%, adjusted HR 1.87, 95% CI 1.47-2.38) and death (29.6% vs 17.8%, adjusted HR 1.24, 95% CI 1.13–1.36). Conclusions Patients with diabetes and no obstructive coronary artery disease have a 10-year risk of myocardial infarction that is similar to that found in the general population. However, they still remain at increased risk of ischemic stroke and death.

Background In addition to primary neurodegenerative processes, vascular disorders, such as stroke, can lead to parkinsonism. However, some cardiovascular risk factors, such as smoking and elevated cholesterol levels, are associated with reduced risk of Parkinson disease. We examined the risk of Parkinson disease and secondary parkinsonism in 1‐year survivors of myocardial infarction (MI). Methods and Results We conducted a nationwide population‐based matched cohort study using Danish medical registries from 1995 to 2016. We identified all patients with a first‐time MI diagnosis and sampled a sex‐, age‐, and calendar year–matched general population comparison cohort without MI. Cox regression analysis was used to compute adjusted hazard ratios (aHRs) for Parkinson disease and secondary parkinsonism, controlled for matching factors and adjusted for relevant comorbidities and socioeconomic factors. We identified 181 994 patients with MI and 909 970 matched comparison cohort members (median age, 71 years; 62% men). After 21 years of follow‐up, the cumulative incidence was 0.9% for Parkinson disease and 0.1% for secondary parkinsonism in the MI cohort. Compared with the general population cohort, MI was associated with a decreased risk of Parkinson disease (aHR, 0.80; 95% CI, 0.73–0.87) and secondary parkinsonism (aHR, 0.72; 95% CI, 0.54–0.94). Conclusions MI was associated with a 20% decreased risk of Parkinson disease and 28% decreased risk of secondary parkinsonism. Reduced risk may reflect an inverse relationship between cardiovascular risk factors and Parkinson disease.

Summary: Background: Ticagrelor was introduced in Denmark in 2011 after randomised data showed its superiority over clopidogrel for patients with acute coronary syndrome (ACS). We assessed the effectiveness and safety of ticagrelor implementation in ACS patients undergoing percutaneous coronary intervention (PCI). Methods: We identified PCI-treated ACS patients in Western Denmark who redeemed a P2Y12 inhibitor prescription within 14 days. Using Danish health registries, 1-year outcomes were compared before (2007-2010) and after (2012-2015) introduction of ticagrelor. Outcomes were MACE (death, myocardial infarction, and ischaemic stroke) and hospitalisation for bleeding. Inverse probability of treatment weights were used to estimate weighted incidence rate ratios (wIRRs). Findings: We included 14,450 patients; 7,102 were treated in the earlier time period (99·9% clopidogrel) and 7,348 in the later time period (87·8% ticagrelor). Ticagrelor implementation was not associated with a clinically relevant difference in 1-year risk of MACE with 413 events in the ticagrelor period vs. 424 events in the clopidogrel period (cumulative incidence percentage [CIP] 5·6% vs. 6·0%; wIRR 1·06, 95% CI 0·92-1·22). The 1-year risk of bleeding was also similar between groups with 335 bleedings requiring hospitalisation in the ticagrelor period vs. 309 events in the clopidogrel period (CIP 4·6% vs. 4·4%; wIRR 1·05, 95% CI 0·89-1·23). Results were robust in patients above and below 70 years of age. Interpretation: Implementation of ticagrelor was not associated with changes in risks of ischaemic or bleeding events in Danish PCI-treated ACS patients.

BackgroundLong-term complications of venous thromboembolism (VTE) hamper physical function and impair quality of life; still, it remains unclear whether VTE is associated with risk of permanent work-related disability. We aimed to assess the association between VTE and the risk of receiving a permanent work-related disability pension and to assess whether this association was explained by comorbidities such as cancer and arterial cardiovascular disease.Methods and findingsA Danish nationwide population-based cohort study consisting of 43,769 individuals aged 25 to 66 years with incident VTE during 1995 to 2016 and 218,845 birth year-, sex-, and calendar year-matched individuals from the general population, among whom 45.9% (N = 120,540) were women, was established using Danish national registries. The cohorts were followed throughout 2016, with permanent work-related disability pension as the outcome. Hazard ratios (HRs) with 95% confidence intervals (CIs) for disability pension were computed and stratified by sex and age groups (25 to 34, 35 to 44, 45 to 54, and 55 to 66 years of age) and adjusted for comorbidities and socioeconomic variables. Permanent work-related disability pensions were granted to 4,415 individuals with VTE and 9,237 comparison cohort members (incidence rates = 17.8 and 6.2 per 1,000 person-years, respectively). VTE was associated with a 3-fold (HR 3.0, 95% CI: 2.8 to 3.1) higher risk of receiving a disability pension. Adjustments for socioeconomic status and comorbidities such as cancer and cardiovascular diseases reduced the estimate (HR 2.3, 95% CI: 2.2 to 2.4). The risk of disability pension receipt was slightly higher in men than in women (HR 2.5, 95% CI: 2.3 to 2.6 versus HR 2.1, 95% CI: 2.0 to 2.3). As this study is based on medical and administrative registers, information on post-VTE care, individual health behavior, and workplace factors linked to disability pension in the general population are lacking. Furthermore, as disability pension schemes vary, our results might not be directly generalizable to other countries or time periods.ConclusionsIn this study, incident VTE was associated with increased risk of subsequent permanent work-related disability, and this association was still observed after accounting for comorbidities such as cancer and cardiovascular diseases. Our results emphasize the social consequences of VTE and may help occupational and healthcare professionals to identify vulnerable individuals at risk of permanent exclusion from the labor market after a VTE event.

Abstract Background Fecal incontinence may be an early symptom of cancer, but its association with cancer remains unclear. We examined the risk of selected cancers, including colorectal cancer, other gastrointestinal cancers, hormone‐related cancers, and lymphoma, in patients with fecal incontinence. Methods Using Danish population‐based registries, all patients with hospital‐based diagnoses of fecal incontinence during 1995‐2013 were identified. We calculated cumulative incidences of cancers. As a measure of relative risks, we computed standardized incidence ratios (SIRs), that is, the observed number of cancers relative to the expected number based on national incidence rates by sex, age, and calendar year. Results Among 16 556 patients with fecal incontinence, the cumulative incidence of colorectal cancers, other gastrointestinal cancers, hormone‐related cancers, and lymphoma each was less than 0.4% after 1 year. It increased to under 3% after 10 years. The SIR for any cancer during 19 years of follow‐up was 1.12 [95% confidence interval (CI), 1.06‐1.19]. The SIRs during the first year were 2.31 (95% CI, 1.65‐3.13) for colorectal cancer, 1.56 (95% CI, 0.89‐2.54) for other gastrointestinal cancers, 1.00 (95% CI, 0.72‐1.35) for hormone‐related cancers, and 2.02 (95% CI, 1.01‐3.61) for lymphoma. Beyond 1 year, the SIR reached unity for other gastrointestinal cancers, hormone‐related cancers, and lymphoma, while a reduced risk was observed for colorectal cancer (SIR = 0.77, 95% CI, 0.59‐0.98). Conclusions Fecal incontinence was a marker of cancer, especially gastrointestinal cancers and lymphoma within 1 year, which presumably is driven partly by reverse causation. However, the absolute risks were low. Heightened diagnostic efforts may explain in part the increased short‐term risk of colorectal cancers.

Background: Population-based cohorts of immune thrombocytopenia (ITP) are useful for understanding occurrence, clinical characteristics and long-term clinical course. This paper describes the content of the Nordic Country Patient Registry for Romiplostim (NCPRR) and provides prevalence and incidence estimates of chronic ITP (cITP). Methods: The NCPRR, a cohort study established in 2009, includes all adult (≥18 years) patients in Denmark, Sweden and Norway with cITP (defined as ITP lasting >12 months and platelet count

Background: Sleep disturbances may increase risks of Alzheimer's disease (AD) and other dementias. Benign prostatic hyperplasia (BPH) is usually associated with lower urinary tract symptoms, including nocturia, and thereby disturbed sleep. We examined if men with BPH are at increased risk of AD and all-cause dementia. Methods: In a Danish nationwide cohort (1996–2016), we identified 297,026 men with BPH, defined by inpatient or outpatient hospital diagnosis or by BPH-related surgical or medical treatment, and 1,107,176 men from the general population matched by birth year. We computed rates, cumulative incidences, and adjusted hazard ratios (HRs) of AD and all-cause dementia. Follow-up started 1 year after BPH diagnosis date/index date. Findings: Median follow-up was 6·9 years (Interquartile range (IQR), 3·6 – 11·6 years] in the BPH cohort and 6·4 years (IQR: 3·4 – 10·8 years) in the comparison cohort. The cumulative 1–10 year risk of AD was 1·15% [95% confidence interval (CI), 1·11–1·20], in the BPH cohort and 1·00% (95% CI, 0·98 – 1·02) in the comparison cohort. The adjusted 1–10–year hazard ratios were 1·16 (95% CI: 1·10–1·21) for AD and 1·21 (95% CI: 1·17–1·25) for all-cause dementia. From >10 years up to 21 years of follow-up, BPH remained associated with 10%- 20% increased risk of AD and all-cause dementia. Interpretation: During up to 21 years of follow-up, men with BPH had persistently higher risk of AD and all-cause dementia compared with men in the general population. Our results identify BPH as a common, potentially remediable disorder associated with dementia risk. Funding: Lundbeckfonden, Aarhus University Research Foundation, and the National Institutes of Health.

Objective This population-based, matched cohort study aimed to evaluate utilization of health care services by mothers of children with major congenital anomalies (MCAs), compared to mothers of children without MCAs over a 20-year post-birth time horizon in Denmark. Methods Our analytic sample included mothers who gave birth to an infant with a MCA (n = 23,927) and a cohort of mothers matched to them by maternal age, parity and infant’s year of birth (n = 239,076). Primary outcomes were period prevalence and mothers’ quantity of health care utilization (primary, inpatient, outpatient, surgical, and psychiatric services) stratified by their child’s age (i.e., ages 0–6 = before school, ages 7–13 = pre-school + primary education, and ages 14–18 = secondary education or higher). The secondary outcome measure was length of hospital stays. Outcome measures were adjusted for maternal age at delivery, parity, marital status, income quartile, level of education in the year prior to the index birth, previous spontaneous abortions, maternal pregnancy complications, maternal diabetes, hypertension, alcohol-related diseases, and maternal smoking. Results In both cohorts the majority of mothers were between 26 and 35 years of age, married, and employed, and 47% were primiparous. Mothers of infants with anomalies had greater utilization of outpatient, inpatient, surgical, and psychiatric services, compared with mothers in the matched cohort. Inpatient service utilization was greater in the exposed cohort up to 13 years after a child’s birth, with the highest risk in the first six years after birth [adjusted risk ratio, 1.13; 95% confidence interval (CI), 1.12–1.14], with a decrease over time. Regarding the quantity of health care utilization, the greatest difference between the two groups was in inpatient service utilization, with a 39% increased rate in the exposed cohort during the first six years after birth (adjusted rate ratio, 1.39; 95% CI, 1.37–1.42). During the first 6 years after birth, mothers of children with anomalies stayed a median of 6 days (interquartile range [IQR], 3–13) in hospital overall, while the comparison cohort stayed a median of 4 days (IQR, 2–7) in hospital overall. Rates of utilization of outpatient clinics (adjusted rate ratio, 1.36; 95% CI, 1.29–1.42), as well as inpatient (adjusted rate ratio, 1.77; 95% CI, 1.68–1.87), and surgical services (adjusted rate ratio, 1.33; 95% CI, 1.26–1.41) was higher in mothers of children with multiple-organ MCAs during 0 to 6 years after birth. Among mothers at the lowest income levels, utilization of psychiatric clinic services increased to 59% and when their child was 7 to 13 years of age (adjusted rate ratio, 1.59; 95% CI, 1.24–2.03). Conclusion Mothers of infants with a major congenital anomaly had greater health care utilization across services. Health care utilization decreased over time or remained stable for outpatient, inpatient, and surgical care services, whereas psychiatric utilization increased for up to 13 years after an affected child’s birth. Healthcare utilization was significantly elevated among mothers of children with multiple MCAs and among those at the lowest income levels.

Background Angiotensin‐converting enzyme inhibitors (ACE‐Is) and angiotensin receptor blockers (ARBs) may worsen the prognosis of coronavirus disease 2019, but any association could be confounded by the cardiometabolic conditions indicating ACE‐I/ARB use. We therefore examined the impact of ACE‐Is/ARBs on respiratory tract infection outcomes. Methods and Results This cohort study included all adult patients hospitalized with influenza or pneumonia from 2005 to 2018 in Denmark using population‐based medical databases. Thirty‐day mortality and risk of admission to the intensive care unit in ACE‐Is/ARBs users was compared with nonusers and with users of calcium channel blockers. We used propensity scores to handle confounding and computed propensity score‐weighted risks, risk differences (RDs), and risk ratios (RRs). Of 568 019 patients hospitalized with influenza or pneumonia, 100 278 were ACE‐I/ARB users and 37 961 were users of calcium channel blockers. In propensity score‐weighted analyses, ACE‐I/ARB users had marginally lower 30‐day mortality than users of calcium channel blockers (13.9% versus 14.5%; RD, −0.6%; 95% CI, −1.0 to −0.1; RR, 0.96; 95% CI, 0.93–0.99), and a lower risk of admission to the intensive care unit (8.0% versus 9.6%; RD, −1.6%; 95% CI, −2.0 to −1.2; RR, 0.83; 95% CI, 0.80–0.87). Compared with nonusers, current ACE‐I/ARB users had lower mortality (RD, −2.4%; 95% CI, −2.8 to −2.0; RR, 0.85; 95% CI, 0.83–0.87), but similar risk of admission to the intensive care unit (RD, 0.4%; 95% CI, 0.0–0.7; RR, 1.04; 95% CI, 1.00–1.09). Conclusions Among patients with influenza or pneumonia, ACE‐I/ARB users had no increased risk of admission to the intensive care unit and slightly reduced mortality after controlling for confounding.

Abstract Background Retinal vein thrombosis has in case reports been reported a clinical sign of cancer, especially hematological cancer. However, it is unclear whether retinal vein thrombosis is a marker of underlying cancer, as is the case for deep venous thrombosis and pulmonary embolism. We investigated the risk of occult cancer in patients with retinal vein thrombosis. Methods A nationwide population‐based cohort study in Denmark on all patients diagnosed with a retinal vein thrombosis during 1994 and 2013. The main outcome measures were any cancer and site‐specific cancers

Abstract Background Prenatal exposure to influenza or fever is associated with risk of congenital malformations. Oseltamivir is used to treat influenza and to provide post-exposure prophylaxis. We examined the association between oseltamivir use during pregnancy and birth outcomes. Methods This was a nationwide registry-based prevalence study with individual level data linkage, in a setting of universal health care access. We included all recorded pregnancies in Denmark in 2002–2013, and used data from population registries to examine associations between dispensings for oseltamivir during pregnancy (first trimester, second/third trimester, none) and congenital malformations, foetal death, preterm birth, foetal growth, and low 5-min Apgar score. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using propensity score matching. Results The study included 946,176 pregnancies. Of these, 449 had first-trimester exposure and 1449 had second/third-trimester exposure to oseltamivir. Adjusted ORs following first-trimester exposure were 0.94 (95% CI 0.49 to 1.83) for any major congenital malformation and 1.75 (95% CI 0.51 to 5.98) for congenital heart defects, based on 7 exposed cases. The association with congenital heart defects was present for etiologically implausible exposure periods and for known safe exposures. There was no evidence of an association between prenatal exposure to oseltamivir and any of the other birth outcomes assessed. Conclusions The study does not provide evidence of risk associated with oseltamivir treatment additional to that associated with influenza infection.

Abstract Background Many cardiovascular conditions exhibit seasonality in occurrence and mortality, but little is known about the seasonality of venous thromboembolism. Methods Using Danish registries, we identified all patients with deep vein thrombosis, pulmonary embolism, splanchnic vein thrombosis, cerebral vein thrombosis, and retinal vein thrombosis during 1977–2016. We tallied monthly deaths occurring within 90 days of the venous thromboembolism diagnosis. We estimated peak-to-trough ratios and timing of the peak of both diagnoses and deaths summed over all years of the study period. The departure from 1.0 of the peak-to-trough ratio measures the intensity of any seasonal pattern. Results We estimated a peak-to-trough ratio of 1.09 (95% confidence interval: 1.07–1.11) for deep vein thrombosis and 1.22 (1.19–1.24) for pulmonary embolism occurrence. The peak-to-trough ratios for splanchnic vein thrombosis, cerebral vein thrombosis, and retinal vein thrombosis occurrence were 1.10 (1.01–1.20), 1.19 (1.00–1.40), and 1.12 (1.07–1.17), respectively. The occurrence of all conditions peaked during winter or fall. In time trend analyses, the peak-to-trough ratio increased considerably for splanchnic vein thrombosis, cerebral vein thrombosis, and retinal vein thrombosis occurrence. In associated mortality, the peak-to-trough ratio for deep vein thrombosis was larger (1.15, 1.07–1.23) than that for pulmonary embolism (1.04, 1.01–1.08). Discussion Excess winter risks were modest, but more marked for pulmonary embolism occurrence than for deep vein thrombosis occurrence. The seasonal pattern intensified throughout the study period for splanchnic vein thrombosis, cerebral vein thrombosis, and retinal vein thrombosis. The winter peak in mortality following pulmonary embolism was smaller than that for deep vein thrombosis.

Background Childhood weight trajectories may influence cardiometabolic traits and thereby the risk of venous thromboembolism (VTE) later in life. We examined whether overweight and changes in weight status during childhood were associated with risk of VTE in adulthood. Methods and Results We used Danish medical registries to conduct a population‐based cohort study of Danish schoolchildren aged 7 to 13 years and born during 1930‐1989. We calculated body‐mass index (BMI) z‐scores based on weight and height measurements. We estimated hazard ratios using Cox regressions to examine associations between changes in BMI z‐scores from 7 to 13 years of age and the subsequent risk of VTE. Among 313 998 children, 5007 girls and 5397 boys were diagnosed with VTE as adults. Compared with children with a normal BMI (25th to 75th percentile category) at both ages, children with a BMI persistently above the 75th percentile had a 1.30‐ to 1.50‐fold increased risk of VTE in adulthood. Children who experienced a BMI increase from the 25th to 75th or >75th to 90th percentile to a higher percentile category had a 1.35‐ to 1.70‐fold increased risk of adulthood VTE. Children whose BMI percentile category decreased between 7 and 13 years of age had a VTE risk similar to that of children with a persistently normal BMI. Conclusions Risk of VTE in adulthood was higher in children with a persistently above‐average BMI. Whereas weight gain from 7 to 13 years of age additionally increased VTE risk, remission from overweight by 13 years of age completely reverted the risk.

BackgroundBiochemical adrenal insufficiency induced by glucocorticoid treatment is prevalent, but data on the clinical implications are sparse. We investigated clinical consequences of glucocorticoid-induced adrenal insufficiency after oral glucocorticoid cessation.MethodsWe conducted a Danish population-based self-controlled case series utilizing medical registries. In this design each individual serves as their own control allowing event rates to be compared as a function of time and treatment. Clinical indicators of adrenal insufficiency were defined as diagnoses of gastrointestinal symptoms, hypotension, cardiovascular collapse, syncope, hyponatremia, and hypoglycaemia. We included 286,680 persons who discontinued long-term (≥ 3 months) oral glucocorticoid treatment. We defined five risk periods and a reference period (before treatment): period 0 (on treatment), withdrawal period (1 month before and after cessation), followed by three consecutive 2 month-risk periods after withdrawal (periods 2-4).ResultsMedian age at cessation was 69 years and 57% were female. Median treatment duration was 297 days and median cumulative dose was 3000 mg prednisolone equivalents. The incidence rates of hypotension, gastrointestinal symptoms, hypoglycemia and hyponatremia were increased in the withdrawal period compared to before treatment started (reference period). Incidence rate ratios comparing the withdrawal period with the reference period were 2.5 [95% confidence interval (CI): 1.4-4.3] for hypotension, 1.7 (95% CI: 1.6-1.9) for gastrointestinal symptoms, 2.2 (95% CI: 0.7-7.3) for hypoglycemia, and 1.5 (95% CI: 1.1-2.0) for hyponatremia. During 7 months of follow up, the rates of hypotension and gastrointestinal symptoms remained elevated compared to the reference period. Risk factors included use of antibiotics, increasing average daily dose of glucocorticoids, cumulative dose, and age.ConclusionOral glucocorticoid withdrawal was associated with adverse outcomes attributable to adrenal insufficiency. Our study underscores the need for future research to establish evidence-based clinical guidance on management of patients who discontinue oral glucocorticoids.

Background: Seafood is an important source of omega-3 fatty acids, which have been associated with improved oocyte quality and embryo morphology in some studies. However, seafood is also a source of persistent organic pollutants and heavy metals, which may adversely affect fecundity. Previous studies of seafood intake and fecundity have generated inconsistent results. Methods: In two prospective cohort studies of 7836 female pregnancy planners from Denmark (Snart Foraeldre, n = 2709) and North America (PRESTO, n = 5127), we evaluated the association of dietary intake of total seafood and marine-sourced long-chain omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid) with fecundability. Participants completed a baseline questionnaire on sociodemographics, behavioral factors, anthropometrics, and medical history, and a food frequency questionnaire. Pregnancy status was updated bimonthly for up to 12 months or until reported conception. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) using proportional probabilities regression models, adjusted for energy intake and other potential confounders. We restricted analyses to women with ≤6 menstrual cycles of attempt time at enrollment. Results: Intake of total seafood or marine-sourced long-chain omega-3 fatty acids was not appreciably associated with fecundability in either cohort (≥200 vs.

Background We aimed to examine whether acute pericarditis is an indicator of undetected cancer and identify patient‐level factors associated with high cancer risk among patients presenting with pericarditis. Methods and Results A population‐based matched cohort study was conducted using primary care data from the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics. Patients with acute pericarditis (n=6530) were matched to a comparison cohort (n=26 111) on age, sex, calendar time, and general practice. We estimated cumulative cancer incidences, and calculated hazard ratios using Cox regression. Effect modification by patients' characteristics and lifestyle factors was examined, and we fitted a parsimonious model to evaluate absolute excess risk of later cancer among pericarditis patients by key patient‐level factors. We identified 728 and 1379 incidents of cancer among pericarditis patients and the comparison cohort (median follow‐up, 2.8 and 3.5 years). Pericarditis was associated with an elevated subsequent risk of any cancer (hazard ratio=3.03; 95% confidence interval, 2.74–3.36). The association was particularly pronounced 0 to 3 months after pericarditis (hazard ratio=23.56; 95% confidence interval, 18.00–30.83), but a more‐modest association remained thereafter (hazard ratio=1.95; 95% confidence interval, 1.48–2.57 after 3–12 months, and hazard ratio=1.40; 95% confidence interval, 1.21–1.62 after >12 month). Older individuals hospitalized with pericarditis and with combinations of obesity and smoking were at the highest excess risk of having a cancer diagnosis 3 to 12 months later, reaching 4.8%. Conclusions Occult cancers may be going undiagnosed during the acute episode of pericarditis. Patients presenting with pericarditis and combinations of older age, obesity, smoking, and a need for hospitalization might warrant targeted investigations for cancer.

BackgroundData on the true burden of hyperkalemia in patients with heart failure (HF) in a real‐world setting are limited. Methods and ResultsIncidence rates of hyperkalemia (first blood test with a potassium level >5.0 mmol/L) in primary or hospital care were assessed in a population‐based cohort of patients with incident HF diagnoses in northern Denmark from 2000 to 2012. Risk factors and clinical outcomes were compared in patients with HF with versus without hyperkalemia. Of 31 649 patients with HF, 39% experienced hyperkalemia (mean follow‐up, 2.2 years). Risks of experiencing a second, third, or fourth event were 43%, 54%, and 60%, respectively. Among patients with HF with stage 3A, 3B, 4, or 5 kidney dysfunction, 26%, 35%, 44%, and 48% experienced hyperkalemia within the first year. Important hyperkalemia risk factors included chronic kidney disease (prevalence ratio, 1.46; 95% confidence interval [CI], 1.43−1.49), diabetes mellitus (prevalence ratio, 1.38; 95% CI, 1.32−1.45), and spironolactone use (prevalence ratio, 1.48; 95% CI, 1.42−1.54). In patients with HF who developed hyperkalemia, 53% had any acute‐care hospitalization 6 months before the hyperkalemia event, increasing to 74% 6 months after hyperkalemia (before‐after risk ratio, 1.41; 95% CI, 1.38−1.44). Compared with matched patients with HF without hyperkalemia, adjusted 6‐month hazard ratios in patients with hyperkalemia were 2.75‐fold (95% CI, 2.65–2.85) higher for acute‐care hospitalization and 3.39‐fold (95% CI, 3.19–3.61) higher for death. ConclusionsAlmost 4 in 10 patients with HF develop hyperkalemia, and many patients have recurrent hyperkalemia episodes. Hyperkalemia risk is strongly associated with degree of reduced kidney function and use of spironolactone. Hyperkalemia is associated with severe clinical outcomes and death in HF.

Little is known about the occurrence and distribution of types of paraneoplastic syndromes (PNS) in patients with lung cancer. Identification of autoimmune PNS is particularly important for discerning them from immune-related adverse events of novel immunotherapies. We estimated the occurrence of PNS among patients with lung cancer and compared it with that in the general population.In this registry-based cohort study in Denmark, we identified all patients with incident primary lung cancer between 1997 and 2010, and in a general-population comparison cohort matched on calendar time, sex, age, and residence. Among patients with non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), we estimated prevalence of potential PNS and selected autoimmune conditions and compared their incidence rates with those of equivalent conditions in the general population cohort, using hazard ratios (HRs) adjusted for baseline comorbidity.There were 35,319 patients with NSCLC and 6,711 patients with SCLC. The incidence rates per 1000 person-years (95% confidence interval) of any potential PNS or selected autoimmune disorders were 135.4 (131.9-139.1) among NSCLC patients and 237.3 (224.4-250.5) among SCLC patients. Adjusted HRs for any potential PNS or selected autoimmune disorders were 4.8 (4.7-5.0) for NSCLC and 8.2 (7.6-8.8) for SCLC.Incidence rate of any potential PNS or selected autoimmune disorders among patients with lung cancer was greater than that in the general population and was greater after SCLC than after NSCLC.These results provide context to discerning PNS from adverse effects of novel immunotherapies during the clinical course of NSCLC and SCLC.

Apolipoprotein D (ApoD) has been proposed as a predictor of breast cancer recurrence among estrogen receptor-positive (ER+), tamoxifen-treated patients.We conducted a population-based case-control study nested in a population of 11,251 women aged 35-69 years at diagnosis with Stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers cases among women with ER+ disease treated with tamoxifen for at least 1 year and 300 cases in women with ER- disease never treated with tamoxifen. We matched one control subject per case and assessed ApoD expression in the tumor cell nucleus and cytoplasm using tissue microarray immunohistochemistry. We computed the odds ratio (OR) associating ApoD expression with recurrence and adjusted for potential confounding using logistic regression.Cytoplasmic ApoD expression was seen in 68% of ER+ tumors, in 66% of ER- tumors, and in 66% of controls across both groups. In women with ER+ tumors, the associations of cytoplasmic ApoD expression with recurrence (OR = 1.0; 95% CI = 0.7 to 1.4) and increasing cytoplasmic expression with recurrence (OR = 1.0; 95% CI = 0.996 to 1.003) were null, as were those for women with ER- tumors. Associations for nuclear ApoD expression and combined nuclear and cytoplasmic expression were similarly near-null.ApoD expression is likely not a predictor of recurrence in tamoxifen-treated patients.This study eliminates the previously suggested marker ApoD as a predictor of recurrence among tamoxifen-treated women.

Background The prevalence of depression is 4‐ to 5‐fold higher in heart failure patients than in the general population. We examined the influence of depression on all‐cause mortality in patients with heart failure. Methods and Results Using Danish medical registries, this nationwide population‐based cohort study included all patients with a first‐time hospitalization for heart failure (1995–2014). All‐cause mortality risks and 19‐year mortality rate ratios were estimated based on Cox regression analysis, adjusting for age, sex, time period, comorbidity, and socioeconomic status. The analysis included 9636 patients with and 194 887 patients without a diagnosis of depression. Compared with patients without a history of depression, those with depression had higher 1‐year (36% versus 33%) and 5‐year (68% versus 63%) mortality risks. Overall, the adjusted mortality rate ratio was 1.03 (95% CI 1.01–1.06). Compared with no depression, the adjusted mortality rate ratios for mild, moderate, and severe depression, as defined by diagnostic codes, were 1.06 (95% CI 1.00–1.13), 1.03 (95% CI 0.99–1.08), and 1.02 (95% CI 0.96–1.09), respectively. In a subcohort of patients, the mortality rate ratios were modified by left ventricular ejection fraction, with adjusted mortality rate ratios of 1.17 (95% CI, 1.05–1.31) for ≤35%, 0.98 (95% CI 0.81–1.18) for 36% to 49%, and 0.96 (95% CI 0.74–1.25) for ≥50%. Results were consistent after adjustment for alcohol abuse and smoking. Conclusions A history of depression was an adverse prognostic factor for all‐cause mortality in heart failure patients with left ventricular ejection fraction ≤35% but not for other heart failure patients.

Background and study aims: Dual antiplatelet therapy (DAPT) is recommended following percutaneous coronary intervention (PCI) with drug-eluting stent (DES). DAPT is a risk factor for gastrointestinal bleeding. We aimed to quantify (1) the rate of gastroscopy within 12 months after PCI, (2) the rate of adverse cardiac events and gastroscopy-related bleeding complications within 30 days of gastroscopy, and (3) the association between antiplatelet therapy and these events. Patients and methods: Patients receiving gastroscopy within 12 months of PCI were identified and two nested case-control analyses were performed within the PCI cohort by linking Danish medical registries. Cases were patients with adverse cardiac events (cardiac death, myocardial infarction, or stent thrombosis) or hemostatic intervention. In both studies, controls were patients with gastroscopy including biopsy without adverse cardiac events and hemostatic intervention, respectively. Medical records were reviewed to obtain information on exposure to DAPT. Results: We identified 22 654 PCI patients of whom 1497 patients (6.6 %) underwent gastroscopy. Twenty-two patients (1.5 %) suffered an adverse cardiac event, 93 patients (6.2 %) received hemostatic intervention during or within 30 days of the index gastroscopy. Interrupting DAPT was associated with a 3.46 times higher risk of adverse cardiac events (95 %CI 0.49 – 24.7). Discontinuation of one antiplatelet agent did not increase the risk (OR 0.65, 95 %CI 0.17 – 2.47). No hemostatic interventions were caused by endoscopic complications. Conclusion: Gastroscopy can be safely performed in PCI patients treated with DES and single antiplatelet therapy while interruption of DAPT may be associated with an increased risk of adverse cardiac events.

Rune Erichsen1, Lisa Strate2, Henrik Toft Sørensen1, John A Baron31Department of Clinical Epidemiology, Aarhus University Hospital, Denmark; 2Division of Gastroenterology, University of Washington, Seattle, WA, USA; 3Departments of Medicine and of Community and Family Medicine, Dartmouth Medical School, NH, USAObjective: To investigate the accuracy of diagnostic coding for diverticular disease in the Danish National Registry of Patients (NRP).Study design and setting: At Aalborg Hospital, Denmark, with a catchment area of 640,000 inhabitants, we identified 100 patients recorded in the NRP with a diagnosis of diverticular disease (International Classification of Disease codes, 10th revision [ICD-10] K572–K579) during the 1999–2008 period. We assessed the positive predictive value (PPV) as a measure of the accuracy of discharge codes for diverticular disease using information from discharge abstracts and outpatient notes as the reference standard.Results: Of the 100 patients coded with diverticular disease, 49 had complicated diverticular disease, whereas 51 had uncomplicated diverticulosis. For the overall diagnosis of diverticular disease (K57), the PPV was 0.98 (95% confidence intervals [CIs]: 0.93, 0.99). For the more detailed subgroups of diagnosis indicating the presence or absence of complications (K573–K579) the PPVs ranged from 0.67 (95% CI: 0.09, 0.99) to 0.92 (95% CI: 0.52, 1.00). The diagnosis codes did not allow accurate identification of uncomplicated disease or any specific complication. However, the combined ICD-10 codes K572, K574, and K578 had a PPV of 0.91 (95% CI: 0.71, 0.99) for any complication.Conclusion: The diagnosis codes in the NRP can be used to identify patients with diverticular disease in general; however, they do not accurately discern patients with uncomplicated diverticulosis or with specific diverticular complications.Keywords: diverticulum, colon, diverticulitis, validation studies

Niels Christian Bjerregaard1, Anders Tøttrup1, Henrik Toft Sørensen2, Søren Laurberg11Department of Surgery P, Aarhus Sygehus, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus C, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, DenmarkBackground: In 2002, a new diagnostic strategy in symptomatic outpatients without known established colorectal cancer risk factors aged 40 years or older was implemented in Denmark. Fecal occult blood test (Hemoccult Sensa®) was a part of that strategy in patients without visible rectal bleeding.Aims: The aim was to assess the validity of the Hemoccult Sensa® test in detecting colorectal cancer in the above-mentioned outpatients.Patients: Symptomatic outpatients without known established colorectal cancer risk factors and without visible rectal bleeding.Methods: Hemoccult Sensa® was performed before endoscopic examination. Colorectal cancer was identified at histopathological examination. Patients completed a questionnaire about their symptoms before their first hospital appointment.Results: Eight of 256 patients were found to have colorectal cancer. Median patient age was 63 years. The positive predictive value, negative predictive value, sensitivity, and specificity of Hemoccult Sensa® for colorectal cancer were 10.5% (95% confidence interval [CI]: 6.8–14.3), 99.0% (95% CI: 97.8–100.0), 75.0% (95% CI: 69.7–80.3), and 79.4% (95% CI: 74.5–84.4).Conclusions: Hemoccult Sensa® as the initial examination in symptomatic outpatients without known established colorectal cancer risk factors presenting without rectal bleeding has to be used with caution. We did not find Hemoccult Sensa® test to be an acceptable alternative to flexible sigmoidoscopy.Keywords: colorectal neoplasms, occult blood, diagnostic tests, sensitivity, specificity

Anna K Jönsson1, Erzsebet Horváth-Puhó2, Staffan Hägg3, Lars Pedersen4, Henrik Toft Sørensen41Nordic School of Public Health, Gothenburg, Sweden; 2Centre for Registry Research, Aarhus C, Denmark; 3Division of Clinical Pharmacology, Linköping University, Linköping, Sweden; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus C, DenmarkAbstract: During the last decade, the risk of venous thromboembolism (VTE) has been reported in users of antipsychotic drugs. However, the reports have been inconclusive. This study aimed to determine the relative risk of VTE in antipsychotic drug users. Using data from medical databases in North Jutland and Aarhus Counties, Denmark, and the Danish Civil Registration System, we identified 5,999 cases with a first-time diagnosis of VTE and, based on risk set sampling, 59,990 sex- and age-matched population controls during 1997–2005. Users of antipsychotic drugs were identified from population-based prescription databases and categorized based on filled prescriptions prior to admission date for VTE or index date for controls as current (at least one prescription within 90 days), recent (at least one prescription within 91–180 days), former (at least one prescription within 181–365 days) or nonusers (no recorded prescription within 365 days). Compared with nonusers, current users of any antipsychotic drugs had an increased risk of VTE (adjusted relative risk [ARR]: 1.99, 95% confidence interval [CI]: 1.69–2.34). Former users of any antipsychotic drugs had a nonsignificant elevated risk of VTE compared with nonusers (ARR: 1.54, 95% CI: 0.99–2.40, p-value: 0.056). In conclusion, users of antipsychotic drugs have an increased risk of VTE, compared with nonusers, which might be due to the treatment itself, to lifestyle factors, to the underlying disease, or to residual confounding. Keywords: antipsychotic agents, venous thromboembolism, adverse effects, case-control study

To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.

BACKGROUND: Survival of breast cancer patients with comorbidity, compared to those without comorbidity, has been well characterized. The interaction between comorbid diseases and breast cancer, however, has not been well-studied. METHODS: From Danish nationwide medical registries, we identified all breast cancer patients between 45 and 85 years of age diagnosed from 1994 to 2008. Women without breast cancer were matched to the breast cancer patients on specific comorbid diseases included in the Charlson comorbidity Index (CCI). Interaction contrasts were calculated as a measure of synergistic effect on mortality between comorbidity and breast cancer. RESULTS: The study included 47,904 breast cancer patients and 237,938 matched comparison women. In the first year, the strongest interaction between comorbidity and breast cancer was observed in breast cancer patients with a CCI score of ≥4, which accounted for 29 deaths per 1000 person-years. Among individual comorbidities, dementia interacted strongly with breast cancer and accounted for 148 deaths per 1000 person-years within one year of follow-up. There was little interaction between comorbidity and breast cancer during one to five years of follow-up. CONCLUSIONS: There was substantial interaction between comorbid diseases and breast cancer, affecting mortality. Successful treatment of the comorbid diseases or the breast cancer can delay mortality caused by this interaction in breast cancer patients.