Do sex, age, and comorbidities modify the association of socioeconomic status and opioid use after total hip arthroplasty?: a population-based study from the Danish Hip Arthroplasty Register.

BACKGROUND AND PURPOSE: We aimed to examine the association between socioeconomic status (SES) markers and opioid use after primary total hip arthroplasty (THA) due to osteoarthritis, and whether sex, age, or comorbidities modify any association. METHODS: Using Danish databases, we included 80,038 patients undergoing primary THA (2001-2018). We calculated prevalences and prevalence ratios (PRs with 95% confidence intervals [CIs]) of immediate post-THA opioid use (≥ 1 prescription within 1 month) and continued opioid use (≥ 1 prescription in 1-12 months) among immediate opioid users. Exposures were individual-based education, cohabitation, and wealth. RESULTS: The prevalence of immediate opioid use was ~45% in preoperative non-users and ~60% in preoperative users (≥ 1 opioid 0-6 months before THA). Among non-users, the prevalences and PRs of continued opioid use were: 28% for low vs. 21% for high education (PR 1.28, CI 1.20-1.37), 27% for living alone vs. 23% for cohabiting (PR 1.09, CI 1.04-1.15), and 30% for low vs. 20% for high wealth (PR 1.43, CI 1.35-1.51). Among users, prevalences were 67% for low vs. 55% for high education (1.22, CI 1.17-1.27), 68% for living alone vs. 60% for cohabiting (PR 1.10, CI 1.07-1.12), and 73% for low wealth vs. 54% for high wealth (PR 1.32, CI 1.28-1.36). Based on testing for interaction, sex, age, and comorbidity did not statistically significant modify the associations. Nevertheless, associations were stronger in younger patients for all SES markers (mainly for non-users). CONCLUSION: Markers of low SES were associated with a higher prevalence of continued post-THA opioid use. Age modified the magnitude of the associations, but it was not statistically significant.

Organic food consumption and fecundability in a preconception cohort study of Danish couples trying to conceive.

BACKGROUND: Little is known about potential health effects of eating organic food in relation to reproduction. OBJECTIVE: We examined associations between organic food consumption and fecundability. METHODS: Data were derived from a preconception cohort study of Danish couples trying to conceive (SnartForaeldre.dk, SF). Participants completed a baseline questionnaire on socio-demographics, anthropometrics and lifestyle and a validated food-frequency questionnaire, which included questions on proportions of organic food consumed within six food groups. Participants were followed up with bimonthly questionnaires for up to 12 months or until pregnancy. Analyses were restricted to 2061 participants attempting pregnancy for ≤6 cycles at enrollment and 1303 with <3 cycles. Fecundability ratios (FRs) and 95% confidence intervals (CI) were estimated by proportional probabilities regression models adjusted for potential confounders including age, lifestyle and socioeconomic factors. Associations were examined for vegetables, fruits, cereals, dairy products, eggs and meat, separately, and for the overall pattern of organic food consumption (organic sum score). RESULTS: The final analytic sample comprised 2069 participants. In the full cohort, organic food consumption was not meaningfully associated with fecundability. Among participants <3 cycles of pregnancy attempt at study entry (n = 1303), the FR was 1.11 (95% CI 0.93, 1.33) for the category 'less than half', for 'more than half' the FR was 1.17 (95% CI 0.99, 1.38) and for 'almost everything' the FR was 1.12 (95% CI 0.97, 1.28). CONCLUSION: Higher consumption of organic foods was not meaningfully associated with fecundability, although slightly greater fecundability was seen among participants with <3 cycles of pregnancy attempt time.

Healthcare Resource Utilization and Costs for Empagliflozin Versus Glucagon-Like Peptide-1 Receptor Agonists in Routine Clinical Care in Denmark.

INTRODUCTION: The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin has shown reductions in major adverse cardiac events similar to glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, evidence is limited about how these therapies compare regarding overall healthcare resource utilization and costs in routine clinical care. METHODS: We conducted a comparative cohort study based on linked prospective healthcare databases for the entire population of Denmark during 2015-2018. We included 13,747 new users of empagliflozin and 13,249 new users of GLP-1RAs. Propensity scores were applied to balance potential confounders across the two treatment groups through inverse probability treatment weighting (IPTW). We assessed directly referable costs per person-year associated with healthcare resource utilization (inpatient, emergency room, and outpatient clinic hospital care, primary care health services, and prescription medication costs at pharmacies) among drug initiators while on-treatment. RESULTS: The two IPTW cohorts were well balanced at baseline (median age 61 years, 60% men, diabetes duration 6.7 years, 19% with pre-existing ischemic heart disease, 8% with pre-existing cerebrovascular disease), with similar healthcare costs in the previous year. During follow-up, average on-treatment costs per person-year were very similar among empagliflozin and GLP-1 RA initiators for the following services: inpatient hospitalizations (13,565 DKK versus 13,275 DKK), hospital outpatient clinic visits (12,007 DKK versus 12,152 DKK), emergency room visits (370 DKK versus 399 DKK), and primary care services (4108 DKK versus 4302 DKK). Total costs for any prescription drugs were clearly lower for empagliflozin initiators than for GLP-1 RA initiators (8946 DKK versus 14,029 DKK). In sum, overall healthcare costs on-treatment were lower for empagliflozin initiators (38,995 DKK per person-year) than for GLP-1RA initiators (44,157 DKK per person-year). CONCLUSIONS: In this nationwide population-based cohort study, average healthcare costs after drug initiation and while on treatment were lower for empagliflozin initiators than for GLP-1RAs initiators, driven by lower drug costs. REGISTRATION: The study protocol and analysis plan have been registered on the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) ( http://www.encepp.eu/encepp/viewResource.htm?id=37726 , first protocol registration 4 June 2019), and on clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT03993132 , first posted 20 June 2019).

Mortality, neurodevelopmental impairments, and economic outcomes after invasive group B streptococcal disease in early infancy in Denmark and the Netherlands: a national matched cohort study.

BACKGROUND: Group B Streptococcus (GBS) disease is a leading cause of neonatal death, but its long-term effects have not been studied after early childhood. The aim of this study was to assess long-term mortality, neurodevelopmental impairments (NDIs), and economic outcomes after infant invasive GBS (iGBS) disease up to adolescence in Denmark and the Netherlands. METHODS: For this cohort study, children with iGBS disease were identified in Denmark and the Netherlands using national medical and administrative databases and culture results that confirmed their diagnoses. Exposed children were defined as having a history of iGBS disease (sepsis, meningitis, or pneumonia) by the age of 89 days. For each exposed child, ten unexposed children were randomly selected and matched by sex, year and month of birth, and gestational age. Mortality data were analysed with the use of Cox proportional hazards models. NDI data up to adolescence were captured from discharge diagnoses in the National Patient Registry (Denmark) and special educational support records (the Netherlands). Health care use and household income were also compared between the exposed and unexposed cohorts. FINDINGS: 2258 children-1561 in Denmark (born from Jan 1, 1997 to Dec 31, 2017) and 697 in the Netherlands (born from Jan 1, 2000 to Dec 31, 2017)-were identified to have iGBS disease and followed up for a median of 14 years (IQR 7-18) in Denmark and 9 years (6-11) in the Netherlands. 366 children had meningitis, 1763 had sepsis, and 129 had pneumonia (in Denmark only). These children were matched with 22 462 children with no history of iGBS disease. iGBS meningitis was associated with an increased mortality at age 5 years (adjusted hazard ratio 4·08 [95% CI 1·78-9·35] for Denmark and 6·73 [3·76-12·06] for the Netherlands). Any iGBS disease was associated with an increased risk of NDI at 10 years of age, both in Denmark (risk ratio 1·77 [95% CI 1·44-2·18]) and the Netherlands (2·28 [1·64-3·17]). A history of iGBS disease was associated with more frequent outpatient clinic visits (incidence rate ratio 1·93 [95% CI 1·79-2·09], p<0·0001) and hospital admissions (1·33 [1·27-1·38], p<0·0001) in children 5 years or younger. No differences in household income were observed between the exposed and unexposed cohorts. INTERPRETATION: iGBS disease, especially meningitis, was associated with increased mortality and a higher risk of NDIs in later childhood. This previously unquantified burden underlines the case for a maternal GBS vaccine, and the need to track and provide care for affected survivors of iGBS disease. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATIONS: For the Dutch and Danish translations of the abstract see Supplementary Materials section.

Prediction of Sex-Specific Suicide Risk Using Machine Learning and Single-Payer Health Care Registry Data From Denmark.

Importance: Suicide is a public health problem, with multiple causes that are poorly understood. The increased focus on combining health care data with machine-learning approaches in psychiatry may help advance the understanding of suicide risk. Objective: To examine sex-specific risk profiles for death from suicide using machine-learning methods and data from the population of Denmark. Design, Setting, and Participants: A case-cohort study nested within 8 national Danish health and social registries was conducted from January 1, 1995, through December 31, 2015. The source population was all persons born or residing in Denmark as of January 1, 1995. Data were analyzed from November 5, 2018, through May 13, 2019. Exposures: Exposures included 1339 variables spanning domains of suicide risk factors. Main Outcomes and Measures: Death from suicide from the Danish cause of death registry. Results: A total of 14 103 individuals died by suicide between 1995 and 2015 (10 152 men [72.0%]; mean [SD] age, 43.5 [18.8] years and 3951 women [28.0%]; age, 47.6 [18.8] years). The comparison subcohort was a 5% random sample (n = 265 183) of living individuals in Denmark on January 1, 1995 (130 591 men [49.2%]; age, 37.4 [21.8] years and 134 592 women [50.8%]; age, 39.9 [23.4] years). With use of classification trees and random forests, sex-specific differences were noted in risk for suicide, with physical health more important to men's suicide risk than women's suicide risk. Psychiatric disorders and possibly associated medications were important to suicide risk, with specific results that may increase clarity in the literature. Generally, diagnoses and medications measured 48 months before suicide were more important indicators of suicide risk than when measured 6 months earlier. Individuals in the top 5% of predicted suicide risk appeared to account for 32.0% of all suicide cases in men and 53.4% of all cases in women. Conclusions and Relevance: Despite decades of research on suicide risk factors, understanding of suicide remains poor. In this study, the first to date to develop risk profiles for suicide based on data from a full population, apparent consistency with what is known about suicide risk was noted, as well as potentially important, understudied risk factors with evidence of unique suicide risk profiles among specific subpopulations.

Risk stratification by assessment of coronary artery disease using coronary computed tomography angiography in diabetes and non-diabetes patients: a study from the Western Denmark Cardiac Computed Tomography Registry.

AIMS: We examined whether severity of coronary artery disease (CAD) measured by coronary computed tomography angiography can be used to predict rates of myocardial infarction (MI) and death in patients with and without diabetes. METHODS AND RESULTS: A cohort study of consecutive patients (n = 48 731) registered in the Western Denmark Cardiac Computed Tomography Registry from 2008 to 2016. Patients were stratified by diabetes status and CAD severity (no, non-obstructive, or obstructive). Endpoints were MI and death. Event rates per 1000 person-years, unadjusted and adjusted incidence rate ratios were computed. Median follow-up was 3.6 years. Among non-diabetes patients, MI event rates per 1000 person-years were 1.4 for no CAD, 4.1 for non-obstructive CAD, and 9.1 for obstructive CAD. Among diabetes patients, the corresponding rates were 2.1 for no CAD, 4.8 for non-obstructive CAD, and 12.6 for obstructive CAD. Non-diabetes and diabetes patients without CAD had similar low rates of MI [adjusted incidence rate ratio 1.40, 95% confidence interval (CI): 0.71-2.78]. Among diabetes patients, the adjusted risk of MI increased with severity of CAD (no CAD: reference; non-obstructive CAD: adjusted incidence rate ratio 1.71, 95% CI: 0.79-3.68; obstructive CAD: adjusted incidence rate ratio 4.42, 95% CI: 2.14-9.17). Diabetes patients had higher death rates than non-diabetes patients, irrespective of CAD severity. CONCLUSION: In patients without CAD, diabetes patients have a low risk of MI similar to non-diabetes patients. Further, MI rates increase with CAD severity in both diabetes and non-diabetes patients; with diabetes patients with obstructive CAD having the highest risk of MI.

Prognostic assessment of stable coronary artery disease as determined by coronary computed tomography angiography: a Danish multicentre cohort study.

Aims: To examine the 3.5 year prognosis of stable coronary artery disease (CAD) as assessed by coronary computed tomography angiography (CCTA) in real-world clinical practice, overall and within subgroups of patients according to age, sex, and comorbidity. Methods and results: This cohort study included 16,949 patients (median age 57 years; 57% women) with new-onset symptoms suggestive of CAD, who underwent CCTA between January 2008 and December 2012. The endpoint was a composite of late coronary revascularization procedure >90 days after CCTA, myocardial infarction, and all-cause death. The Kaplan-Meier estimator was used to compute 91 day to 3.5 year risk according to the CAD severity. Comparisons between patients with and without CAD were based on Cox-regression adjusted for age, sex, comorbidity, cardiovascular risk factors, concomitant cardiac medications, and post-CCTA treatment within 90 days. The composite endpoint occurred in 486 patients. Risk of the composite endpoint was 1.5% for patients without CAD, 6.8% for obstructive CAD, and 15% for three-vessel/left main disease. Compared with patients without CAD, higher relative risk of the composite endpoint was observed for non-obstructive CAD [hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.01-1.63], obstructive one-vessel CAD (HR: 1.83; 95% CI: 1.37-2.44), two-vessel CAD (HR: 2.97; 95% CI: 2.09-4.22), and three-vessel/left main CAD (HR: 4.41; 95% CI :2.90-6.69). The results were consistent in strata of age, sex, and comorbidity. Conclusion: Coronary artery disease determined by CCTA in real-world practice predicts the 3.5 year composite risk of late revascularization, myocardial infarction, and all-cause death across different groups of age, sex, or comorbidity burden.

Cost-effectiveness of remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction.

AIMS: Remote ischaemic conditioning seems to improve long-term clinical outcomes in patients undergoing primary percutaneous coronary intervention. Remote ischaemic conditioning can be applied with cycles of alternating inflation and deflation of a blood-pressure cuff. We evaluated the cost-effectiveness of remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction from the perspective of the Danish healthcare system. METHODS AND RESULTS: Between February 2007 and November 2008, 251 patients with ST-elevation myocardial infarction were randomly assigned to remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention (n=126) or to primary percutaneous coronary intervention alone (n=125). During a 4-year follow-up period, we used data from Danish medical registries and medical records to estimate within-trial cardiovascular medical care costs and major adverse cardiac and cerebrovascular event-free survival. After 4 years of follow-up, mean cumulative cardiovascular medical care costs were €2763 (95% confidence interval 207-5318, P=0.034) lower in the remote ischaemic conditioning group than in the control group (€12,065 vs. €14,828), while mean major adverse cardiac and cerebrovascular event-free survival time was 0.30 years (95% confidence interval 0.03-0.57, P=0.032) higher in the remote ischaemic conditioning group than in the control group (3.51 vs. 3.21 years). In the cost-effectiveness plane, remote ischaemic conditioning therapy was economically dominant (less costly and more effective) in 97.26% of 10,000 bootstrap replications. CONCLUSION: Remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention appears to be a cost-effective treatment strategy in patients with ST-elevation myocardial infarction.

Maternal Recall Error in Retrospectively Reported Time-to-Pregnancy: an Assessment and Bias Analysis.

BACKGROUND: Epidemiologic studies of fecundability often use retrospectively measured time-to-pregnancy (TTP), thereby introducing potential for recall error. Little is known about how recall error affects the bias and precision of the fecundability odds ratio (FOR) in such studies. METHODS: Using data from the Danish Snart-Gravid Study (2007-12), we quantified error for TTP recalled in the first trimester of pregnancy relative to prospectively measured TTP among 421 women who enrolled at the start of their pregnancy attempt and became pregnant within 12 months. We defined recall error as retrospectively measured TTP minus prospectively measured TTP. Using linear regression, we assessed mean differences in recall error by maternal characteristics. We evaluated the resulting bias in the FOR and 95% confidence interval (CI) using simulation analyses that compared corrected and uncorrected retrospectively measured TTP values. RESULTS: Recall error (mean = -0.11 months, 95% CI -0.25, 0.04) was not appreciably associated with maternal age, gravidity, or recent oral contraceptive use. Women with TTP > 2 months were more likely to underestimate their TTP than women with TTP ≤ 2 months (unadjusted mean difference in error: -0.40 months, 95% CI -0.71, -0.09). FORs of recent oral contraceptive use calculated from prospectively measured, retrospectively measured, and corrected TTPs were 0.82 (95% CI 0.67, 0.99), 0.74 (95% CI 0.61, 0.90), and 0.77 (95% CI 0.62, 0.96), respectively. CONCLUSIONS: Recall error was small on average among pregnancy planners who became pregnant within 12 months. Recall error biased the FOR of recent oral contraceptive use away from the null by 10%. Quantitative bias analysis of the FOR can help researchers quantify the bias from recall error.

Folic acid supplement use and menstrual cycle characteristics: a cross-sectional study of Danish pregnancy planners.

PURPOSE: To examine the association between folic acid (FA) supplementation obtained through either single FA tablets or multivitamins (MVs) and menstrual cycle characteristics among 5386 women aged 18-40 years, enrolled in an Internet-based study of Danish women attempting pregnancy during 2007-2011. METHODS: In a cross-sectional study, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of FA supplementation with menstrual cycle regularity; short (<27 days), long (30-33 days), and very long (≥34 days) cycle lengths; and duration and intensity of menstrual bleeding. RESULTS: Compared with nonuse, FA supplementation was associated with reduced odds of short cycle length (OR = 0.80, 95% CI: 0.68-0.94) and a trend toward increased odds of very long cycle length (OR = 1.21, 95% CI: 0.87-1.68) compared with cycle length of 27-29 days. The inverse association with short cycle length was stronger among 18- to 30-year-old women (OR = 0.68, 95% CI: 0.53-0.87), nulliparous women (OR = 0.66, 95% CI: 0.52-0.84), and women who used both FA and MVs (OR = 0.75, 95% CI: 0.60-0.95). We found no clear association between FA supplementation and cycle regularity and duration and intensity of menstrual bleeding. CONCLUSIONS: FA supplementation was inversely associated with short menstrual cycle length. This association was strongest among women aged 18-30 years, nulliparous women, and women who used both FA and MVs.

SSRIs and upper gastrointestinal bleeding: what is known and how should it influence prescribing?

SSRIs have achieved a high usage rate in the treatment of depression because of a similar efficacy to TCAs and a favourable safety and tolerability profile. However, SSRI use has been associated with bleeding. We reviewed the epidemiological evidence on the association between SSRI use alone and the risk of upper gastrointestinal bleeding, and on synergistic effects reported with other commonly used drugs that can also cause bleeding.A literature search identified four studies of SSRI use and risk for upper gastrointestinal bleeding and a further two studies of SSRI use and bleeding in general, including upper gastrointestinal bleeding. The available evidence indicates quite convincingly that SSRI use may play a causal role in upper gastrointestinal bleeding and that these drugs may act synergistically with other bleeding risk-increasing medications such as NSAIDs or low-dose aspirin. Assuming a causal role of SSRIs, reported excess gastrointestinal bleedings attributable to SSRI use was reported to be 3.1 per 1000 treatment years, 4.1 per 1000 treatment years among octogenarians and 11.7 per 1000 treatment years among persons with prior upper gastrointestinal bleeding. These non-negligible risks warrant that prescribing doctors consider strategies on the individual level to reduce the likelihood of an upper gastrointestinal adverse event. Patients at particular risk include those with previous ulcers or gastrointestinal bleeding, the elderly and those with certain concurrent illnesses and/or high-risk comedications. Suggested strategies include alternatives to SSRI use, prescribing of less gastrotoxic NSAIDs or co-prescribing of gastroprotective drugs. Patients should be informed about the likelihood of possible upper gastrointestinal bleeding and high-risk patients should be followed closely.

Variation in proportion of frequent attenders between Danish general practices.

AIM: The authors examined the inter-practice variation in the proportion of adult frequent attenders and whether practice factors may explain some of this variation. METHODS: A population-based cross-sectional study was performed on the basis of registers including 262 active general practices and their 419,072 registered adults aged 20 and over in the County of Aarhus, Denmark (630,000 inhabitants) from November 1997 to October 1998. The number of face-to-face daytime contacts with general practitioners was counted for each individual on the basis of data drawn from the files of the National Health Service. Frequent attenders were defined as the 10% most frequent attenders in the county over 12 months for each sex, and four age groups. Both the crude and standardized proportions of frequent attenders in each practice were calculated. Associations between practice factors and the frequent attender proportions were assessed from the squared partial correlation coefficients. RESULTS: The proportion of frequent attenders ranged from 1.9 to 26.2% (factor 13.8) (standardized: 1.6 to 27.8% (factor 17.4)) with 10th to 90th percentiles of 4.4 to 12.9% (factor 2.9) (standardized: 4.3 to 13.2% (factor 3.1)). A low standardized proportion of frequent attenders was statistically significantly associated with a high degree of urbanization, a large number of registered individuals per GP and female GP (multiple R(2) > 0.16 for all practices and 0.22 for solo practices). CONCLUSIONS: Variation in the proportion of frequent attenders was considerable between practices and about one-fifth of this variation could be explained by practice factors.