Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): individual management based on artificial intelligence - a secondary analysis.

BACKGROUND: Current guidelines regarding oxytocin stimulation are not tailored to individuals as they are based on randomised controlled trials. The objective of the study was to develop an artificial intelligence (AI) model for individual prediction of the risk of caesarean delivery (CD) in women with a cervical dilatation of 6 cm after oxytocin stimulation for induced labour. The model included not only variables known when labour induction was initiated but also variables describing the course of the labour induction. METHODS: Secondary analysis of data from the CONDISOX randomised controlled trial of discontinued vs. continued oxytocin infusion in the active phase of induced labour. Extreme gradient boosting (XGBoost) software was used to build the prediction model. To explain the impact of the predictors, we calculated Shapley additive explanation (SHAP) values and present a summary SHAP plot. A force plot was used to explain specifics about an individual's predictors that result in a change of the individual's risk output value from the population-based risk. RESULTS: Among 1060 included women, 160 (15.1%) were delivered by CD. The XGBoost model found women who delivered vaginally were more likely to be parous, taller, to have a lower estimated birth weight, and to be stimulated with a lower amount of oxytocin. In 108 women (10% of 1060) the model favoured either continuation or discontinuation of oxytocin. For the remaining 90% of the women, the model found that continuation or discontinuation of oxytocin stimulation affected the risk difference of CD by less than 5% points. CONCLUSION: In women undergoing labour induction, this AI model based on a secondary analysis of data from the CONDISOX trial may help predict the risk of CD and assist the mother and clinician in individual tailored management of oxytocin stimulation after reaching 6 cm of cervical dilation.

Using Explainable Artificial Intelligence to Predict Potentially Preventable Hospitalizations: A Population-Based Cohort Study in Denmark.

BACKGROUND: The increasing aging population and limited health care resources have placed new demands on the healthcare sector. Reducing the number of hospitalizations has become a political priority in many countries, and special focus has been directed at potentially preventable hospitalizations. OBJECTIVES: We aimed to develop an artificial intelligence (AI) prediction model for potentially preventable hospitalizations in the coming year, and to apply explainable AI to identify predictors of hospitalization and their interaction. METHODS: We used the Danish CROSS-TRACKS cohort and included citizens in 2016-2017. We predicted potentially preventable hospitalizations within the following year using the citizens' sociodemographic characteristics, clinical characteristics, and health care utilization as predictors. Extreme gradient boosting was used to predict potentially preventable hospitalizations with Shapley additive explanations values serving to explain the impact of each predictor. We reported the area under the receiver operating characteristic curve, the area under the precision-recall curve, and 95% confidence intervals (CI) based on five-fold cross-validation. RESULTS: The best performing prediction model showed an area under the receiver operating characteristic curve of 0.789 (CI: 0.782-0.795) and an area under the precision-recall curve of 0.232 (CI: 0.219-0.246). The predictors with the highest impact on the prediction model were age, prescription drugs for obstructive airway diseases, antibiotics, and use of municipality services. We found an interaction between age and use of municipality services, suggesting that citizens aged 75+ years receiving municipality services had a lower risk of potentially preventable hospitalization. CONCLUSION: AI is suitable for predicting potentially preventable hospitalizations. The municipality-based health services seem to have a preventive effect on potentially preventable hospitalizations.

Effects of a transitional care intervention on readmission among older medical inpatients: a quasi-experimental study.

PURPOSE: To evaluate the effect of a transitional care intervention (TCI) on readmission among older medical inpatients. METHODS: This non-randomised quasi-experimental study was conducted at Horsens Regional Hospital in Denmark from 1 February 2017 to 31 December 2018. Inclusion criteria were patients ≥ 75 years old admitted for at least 48 h. First, patients were screened for eligibility. Then, the allocation to the intervention or control group was performed according to the municipality of residence. Patients living in three municipalities were offered the hospital-based intervention, and patients living in a fourth municipality were allocated to the control group. The intervention components were (1) discharge transportation with a home visit, (2) a post-discharge cross-sectorial video conference and (3) seven-day telephone consultation. The primary outcome was 30-day unplanned readmission. Secondary outcomes were 30- and 90-day mortality and days alive and out of hospital (DAOH). RESULTS: The study included 1205 patients (intervention: n = 615; usual care: n = 590). In the intervention group, the median age was 84.3 years and 53.7% were females. In the control group, the median age was 84.9 years and 57.5% were females. The 30-day readmission rates were 20.8% in the intervention group and 20.2% in the control group. Adjusted relative risk was 1.00 (95% confidence interval: 0.80, 1.26; p = 0.99). No significant difference was found between the groups for the secondary outcomes. CONCLUSION: The TCI did not impact readmission, mortality or DAOH. Future research should conduct a pilot test, address intervention fidelity and consider real-world challenges. TRIAL REGISTRATION: Clinical trial number: NCT04796701. Registration date: 24 February 2021.

Interventions to Prevent Potentially Avoidable Hospitalizations: A Mixed Methods Systematic Review.

Background: The demand for healthcare is increasing due to an aging population, more people living with chronic diseases and medical comorbidities. To manage this demand, political institutions call for action to reduce the potentially avoidable hospitalizations. Quantitative and qualitative aspects should be considered to understand how and why interventions work, and for whom. The aim of this mixed methods systematic review was to identify and synthesize evidence on interventions targeting avoidable hospitalizations from the perspectives of the citizens and the healthcare professionals to improve the preventive healthcare services. Methods and Results: A mixed methods systematic review was conducted following the JBI methodology using a convergent integrated approach to synthesis. The review protocol was registered in PROSPERO, reg. no. CRD42020134652. A systematic search was undertaken in six databases. In total, 45 articles matched the eligibility criteria, and 25 of these (five qualitative studies and 20 quantitative studies) were found to be of acceptable methodological quality. From the 25 articles, 99 meaning units were extracted. The combined evidence revealed four categories, which were synthesized into two integrated findings: (1) Addressing individual needs through care continuity and coordination prevent avoidable hospitalizations and (2) Recognizing preventive care as an integrated part of the healthcare work to prevent avoidable hospitalizations. Conclusions: The syntheses highlight the importance of addressing individual needs through continuous and coordinated care practices to prevent avoidable hospitalizations. Engaging healthcare professionals in preventive care work and considering implications for patient safety may be given higher priority. Healthcare administers and policy-makers could support the delivery of preventive care through targeted educational material aimed at healthcare professionals and simple web-based IT platforms for information-sharing across healthcare settings. The findings are an important resource in the development and implementation of interventions to prevent avoidable hospitalizations, and may serve to improve patient safety and quality in preventive healthcare services.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=134652, identifier: CRD42020134652.

Healthcare Use in the Five Years Before a First Infertility Diagnosis: A Danish Register-Based Case-Control Study in the CROSS-TRACKS Cohort.

Purpose: Infertility may affect somatic and mental health later in life. Nevertheless, health status before diagnosed infertility is sparsely studied in women. We aimed to describe healthcare use in primary and secondary care before a first infertility diagnosis and compare use between cases and controls. Materials and Methods: The case-control study was based on register data and used incidence density sampling. From the CROSS-TRACKS Cohort, we included women residing in the Horsens area in Denmark in 2012-2018 (n = 54,175). Eligible women were aged 18-40 years, nulliparous, and living in heterosexual relationships. Cases were women with a first infertility diagnosis in the Danish National Patient Registry (index date). Five controls were matched on age, birth year, and calendar time. Through linkage to Danish national health registries, we identified general practitioner (GP) attendance, paraclinical examinations, hospital contacts, diagnoses, and redeemed prescriptions. Healthcare use from one year to five years before index date was compared with conditional logistic regression. Results: We identified 711 cases and 3555 controls. At one year before index date, cases consulted their GP (odds ratio (OR) = 5.2, 95% confidence interval (CI): 3.2, 8.3) and visited hospital (OR = 1.2, 95% CI: 1.0, 1.4) and redeemed prescriptions (OR = 2.3 95% CI: 1.9, 2.7) more often compared to controls. Cases more often had blood and hemoglobin tests performed, redeemed more drugs related to genitourinary and hormonal diseases, and were more often diagnosed with endocrine and genitourinary diseases in the year before a first infertility diagnosis compared to controls. Cases and controls had comparable healthcare use from five years to one year before a first infertility diagnosis. Conclusion: Cases and controls had similar healthcare use from five years to one year before a first infertility diagnosis. However, cases had a higher healthcare use in the year preceding a first infertility diagnosis compared to controls.

Dietary folate intake and fecundability in two preconception cohorts.

STUDY QUESTION: To what extent is dietary folate intake and total folate intake (dietary and supplemental intakes) associated with fecundability, the per cycle probability of conception? SUMMARY ANSWER: Preconception dietary folate intake was positively associated with fecundability in a monotonic pattern. WHAT IS KNOWN ALREADY: Supplemental folic acid has been associated with improved fertility, but little is known about the relation between dietary folate and fecundability. STUDY DESIGN, SIZE, DURATION: A prospective cohort study including 9559 women trying to conceive without fertility treatment and enrolled in the period 2013-2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used data from two internet-based prospective cohort studies of pregnancy planners from Denmark, where folic acid fortification is not performed (SnartForældre.dk (SF); n = 3755) and North America, where the food supply is fortified with folic acid (Pregnancy Study Online (PRESTO); n = 5804). Women contributed menstrual cycles at risk until they reported conception or experienced a censoring event. We used proportional probabilities regression models to compute fecundability ratios (FRs) and 95% CI, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with a dietary folate intake ≥400 µg/day, the adjusted FRs for women in SF were 0.92 (95% CI: 0.85-0.99) for intake 250-399 µg/day, and 0.80 (95% CI: 0.68-0.94) for intake of <250 µg/day. The corresponding FRs in PRESTO were 0.95 (95% CI: 0.89-1.01) and 0.81 (95% CI: 0.65-1.00). Compared with the highest level of total folate intake (diet folate ≥400 µg/day plus folic acid supplementation), in both cohorts fecundability was lowest among women with the lowest dietary intake <250 µg/day dietary folate and no supplementation (FR: 0.76, 95% CI: 0.59-0.98 [SF] and 0.49, 95% CI: 0.31-0.77 [PRESTO]). Further, total intake dietary folate <250 µg/day plus supplementation was associated with reduced fecundability for SF participants (FR; 0.79, 95% CI: 0.65-0.98) and for PRESTO participants (FR; 0.92, 95% CI: 0.72-1.16). LIMITATIONS, REASONS FOR CAUTION: It is unknown whether dietary folate and folic acid intake affect fecundability on its own or if there is an interaction with other micronutrients provided in healthy diet. Thus, the observed associations may not reflect dietary folate intake alone, but overall healthy diet. WIDER IMPLICATIONS OF THE FINDINGS: Recommendations for preconception dietary folate intake and folic acid supplementation are of importance not only to prevent neural tube defects but also to enhance fecundability. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the National Institute of Child Health and Human Development (R01-HD086742). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Risk of asbestosis, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study.

INTRODUCTION: The risk of asbestosis, malignant mesothelioma and lung cancer among motor vehicle mechanics is of concern because of potential exposure to chrysotile asbestos during brake, clutch and gasket repair and maintenance. Asbestos has also been used in insulation and exhaust systems. METHODS: We examined the long-term risk of incident mesothelioma, lung cancer, asbestosis and other lung diseases and mortality due to mesothelioma, lung cancer, asbestosis and other lung diseases in a nationwide cohort of all men registered as motor vehicle mechanics since 1970 in Denmark. This was compared with the corresponding risk in a cohort of male workers matched 10:1 by age and calendar year, with similar socioeconomic status (instrument makers, dairymen, upholsterers, glaziers, butchers, bakers, drivers, farmers and workers in the food industry, trade or public services). RESULTS: Our study included 138 559 motor vehicle mechanics (median age 24 years; median follow-up 20 years (maximum 45 years)) and 1 385 590 comparison workers (median age 25 years; median follow-up 19 years (maximum 45 years)). Compared with other workers, vehicle mechanics had a lower risk of morbidity due to mesothelioma/pleural cancer (n=47 cases) (age-adjusted and calendar-year-adjusted HR=0.74 (95% CI 0.55 to 0.99)), a slightly increased risk of lung cancer (HR=1.09 (95% CI 1.03 to 1.14)), increased risk of asbestosis (HR=1.50 (95% CI 1.10 to 2.03)) and a chronic obstructive pulmonary disease risk close to unity (HR=1.02 (95% CI 0.99 to 1.05)). Corresponding HRs for mortality were 0.86 (95% CI 0.64 to 1.15) for mesothelioma/pleural cancer, 1.06 (95% CI 1.01 to 1.12) for lung cancer, 1.79 (95% CI 1.10 to 2.92) for asbestosis, 1.06 (95% CI 0.86 to 1.30) for other lung diseases caused by external agents and 1.00 (95% CI 0.98 to 1.01) for death due to all causes. CONCLUSIONS: We found that the risk of asbestosis was increased among vehicle mechanics. The risk of malignant mesothelioma/pleural cancers was not increased among vehicle mechanics.

The Framing of machine learning risk prediction models illustrated by evaluation of sepsis in general wards.

Problem framing is critical to developing risk prediction models because all subsequent development work and evaluation takes place within the context of how a problem has been framed and explicit documentation of framing choices makes it easier to compare evaluation metrics between published studies. In this work, we introduce the basic concepts of framing, including prediction windows, observation windows, window shifts and event-triggers for a prediction that strongly affects the risk of clinician fatigue caused by false positives. Building on this, we apply four different framing structures to the same generic dataset, using a sepsis risk prediction model as an example, and evaluate how framing affects model performance and learning. Our results show that an apparently good model with strong evaluation results in both discrimination and calibration is not necessarily clinically usable. Therefore, it is important to assess the results of objective evaluations within the context of more subjective evaluations of how a model is framed.

Reduction of Myocardial Infarction and All-Cause Mortality Associated to Statins in Patients Without Obstructive CAD.

OBJECTIVES: The aim of this work was to evaluate the prognostic impact of statin therapy in symptomatic patients without obstructive CAD. BACKGROUND: Information on the prognostic impact of post-coronary computed tomographic angiography (CTA) statin use in patients with no or nonobstructive coronary artery disease (CAD) is sparse. METHODS: Patients undergoing CTA with suspected CAD in western Denmark from 2008 to 2017 with <50% coronary stenoses were identified. Information on post-CTA use of statin therapy and cardiovascular events were obtained from national registries. RESULTS: The study included 33,552 patients, median aged 56 years, 58% female, with no (n = 19,669) or nonobstructive (n = 13,883) CAD and a median follow-up of 3.5 years. The absolute risk of the combined end point of myocardial infarction (MI) or all-cause mortality was directly associated with the CAD burden with an event rate/1,000 patient-years of 4.13 (95% CI: 3.69-4.61) in no, 7.74 (95% CI: 6.88-8.71) in mild (coronary artery calcium score [CACS] 0-99), 13.72 (95% CI: 11.61-16.23) in moderate (CACS 100-399), and 32.47 (95% CI: 26.25-40.16) in severe (CACS ≥400) nonobstructive CAD. Statin therapy was associated with a multivariable adjusted HR for MI and death of 0.52 (95% CI: 0.36-0.75) in no, 0.44 (95% CI: 0.32-0.62) in mild, 0.51 (95% CI: 0.34-0.75) in moderate, and 0.52 (95% CI: 0.32-0.86) in severe nonobstructive CAD. The estimated numbers needed to treat to prevent the primary end point were 92 (95% CI: 61-182) in no, 36 (95% CI: 26-58) in mild, 24 (95% CI: 15-61) in moderate, and 13 (95% CI: 7-86) in severe nonobstructive CAD. Residual confounding may persist, but not to an extent explaining all of the observed risk reduction associated with statin treatment. CONCLUSIONS: The risk of MI and all-cause mortality in patients without obstructive CAD is directly associated with the CAD burden. Statin therapy is associated with a reduction of MI and all-cause death across the spectrum of CAD, however, the absolute benefit of treatment is directionally proportional with the CAD burden.

Cohort profile: CROSS-TRACKS: a population-based open cohort across healthcare sectors in Denmark.

PURPOSE: This paper describes the open cohort CROSS-TRACKS, which comprises population-based data from primary care, secondary care and national registries to study patient pathways and transitions across sectors while adjusting for sociodemographic characteristics. PARTICIPANTS: A total of 221 283 individuals resided in the four Danish municipalities that constituted the catchment area of Horsens Regional Hospital in 2012-2018. A total of 96% of the population used primary care, 35% received at least one transfer payment and 66% was in contact with a hospital at least once in the period. Additional clinical information is available for hospital contacts (eg, alcohol intake, smoking status, body mass index and blood pressure). A total of 23% (n=8191) of individuals aged ≥65 years had at least one potentially preventable hospital admission, and 73% (n=5941) of these individuals had more than one. FINDINGS TO DATE: The cohort is currently used for research projects in epidemiology and artificial intelligence. These projects comprise a prediction model for potentially preventable hospital admissions, a clinical decision support system based on artificial intelligence, prevention of medication errors in the transition between sectors, health behaviour and sociodemographic characteristics of men and women prior to fertility treatment, and a recently published study applying machine learning methods for early detection of sepsis. FUTURE PLANS: The CROSS-TRACKS cohort will be expanded to comprise the entire Central Denmark Region consisting of 1.3 million residents. The cohort can provide new knowledge on how to best organise interventions across healthcare sectors and prevent potentially preventable hospital admissions. Such knowledge would benefit both the individual citizen and society as a whole.

Rheumatoid Arthritis as a Risk Factor for Coronary Artery Calcification and Obstructive Coronary Artery Disease in Patients with Chest Pain: A Registry Based Cross-Sectional Study.

PURPOSE: To examine the occurrence and severity of coronary artery disease (CAD) in patients with rheumatoid arthritis (RA) compared to non-RA patients in a population referred for coronary computed tomography angiography (CTA) due to chest pain. PATIENTS AND METHODS: In this cross-sectional study, 46,210 patients from a national CTA database were included. Patients with RA were stratified on serology, treatment with conventional synthetic or biological disease-modifying antirheumatic drugs (DMARDs), and the need for relapse or flare treatment with intraarticular or -muscular glucocorticoid injections (GCIs). Primary outcomes were coronary artery calcium score (CACS) >0 and CACS ≥400, and secondary outcome was obstructive CAD. Associations between RA and outcomes were examined using logistic regression and results were adjusted for age, sex, cardiovascular risk factors and comorbidities. RESULTS: A total of 395 (0.9%) RA patients were identified. In overall RA, crude odds ratio (OR) for having CACS >0 was 1.48 (1.21-1.82) and 1.52 (1.15-2.01) for CACS ≥400, whereas adjusted ORs were 1.08 (0.86-1.36) and 1.21 (0.89-1.65), respectively. Seropositive RA patients had adjusted OR of 1.16 (0.89-1.50) for CACS >0 and 1.37 (0.98-1.90) for CACS ≥400. Patients who had received ≥1 GCI in the period of 3 years prior to the CTA had an adjusted OR of 1.37 (0.94-2.00) for having CACS >0 and 1.46 (0.92-2.31) for CACS ≥400. CONCLUSION: This is the first large-scale, CTA-based study examining the occurrence and severity of CAD in RA patients with symptoms suggestive of cardiovascular disease. A higher prevalence of coronary artery calcification was found in RA patients. After adjusting for age, sex, cardiovascular risk factors and comorbidities, the tendency was less pronounced. We found a trend for increased coronary calcification in RA patients being seropositive or needing treatment with GCI for a relapse or flare.

The association of serum lipid levels with colorectal cancer recurrence.

BACKGROUND: Biologic and epidemiologic evidence suggests that tumor cells depend on reprogrammed lipid metabolic function for survival and growth. Lipids may promote tumor recurrence by providing energy needed for proliferation. Studies have found associations of serum lipids with cancer incidence, mortality, and disease-free mortality, though they have yet to evaluate the prognostic potential of serum lipids for colorectal cancer (CRC) recurrence. METHODS: 341 Danish CRC patients who underwent surgical resection were actively followed between 2003-2011 from date of surgery until December 31, 2012, or death. Serum lipids including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), were collected at regular intervals. Lipids were assigned as time-varying exposures evaluated with a one-year lag. Cox proportional hazards models were used to assess recurrence rate, adjusting for clinically relevant covariates. A restricted analysis was performed in a group of non-statin users (n = 236). RESULTS: Among 341 CRC patients, increased HDL-C appeared to have a beneficial impact on recurrence-free survival (RFS) for CRC patients, especially among statin users (hazard ratio [HR] for 0.1 mmol/L increase = 0.58; 95 % confidence interval [CI]: 0.43, 0.78). Increased LDL-C and TG were not associated with RFS. Increased lipids showed a near-null effect on CRC recurrence [e.g. HR (95 % CI) for 0.1 mmol/L increase LDL = 1.01 (0.97, 1.19)] among non-statin users. CONCLUSION: Serum lipid levels of LDL-C and TG do not appear to be associated with CRC recurrence. Further investigation of the role of HDL-C in CRC recurrence may be of interest based on the suggestive inverse association observed here.

Application of the Adaptive Validation Substudy Design to Colorectal Cancer Recurrence.

BACKGROUND: Among men and women diagnosed with colorectal cancer (CRC), 20-50% will develop a cancer recurrence. Cancer recurrences are not routinely captured by most population-based registries; however, linkage across Danish registries allows for the development of predictive models to detect recurrence. Successful application of such models in population-based settings requires validation against a gold standard to ensure the accuracy of recurrence identification. OBJECTIVE: We apply a recently developed validation study design for prospectively collected validation data to validate predicted CRC recurrences against gold standard diagnoses from medical records in an actively followed cohort of CRC patients in Denmark. METHODS: We use a Bayesian monitoring framework, traditionally used in clinical trials, to iteratively update classification parameters (positive and negative predictive values, and sensitivity and specificity) in an adaptive validation substudy design. This design allows determination of the sample size necessary to estimate the corresponding parameters and to identify when validation efforts can cease based on predefined criteria for parameter values and levels of precision. RESULTS: Among 355 men and women diagnosed with CRC in Denmark and actively followed semi-annually, there were 63 recurrences diagnosed by active follow-up and 70 recurrences identified by a predictive algorithm. The adaptive validation design met stopping criteria for the classification parameters after 120 patients had their recurrence information validated. This stopping point yielded parameter estimates for the classification parameters similar to those obtained when the entire cohort was validated, with 66% less patients needed for the validation study. CONCLUSION: In this proof of concept application of the adaptive validation study design for outcome misclassification, we demonstrated the ability of the method to accurately determine when sufficient validation data have been collected. This method serves as a novel validation substudy design for prospectively collected data with simultaneous implementation of a validation study.

Seasonal patterns in fecundability in North America and Denmark: a preconception cohort study.

STUDY QUESTION: To what extent does fecundability vary across seasons? SUMMARY ANSWER: After accounting for seasonal patterns in pregnancy planning, we observed higher fecundability in the fall and lower fecundability in the spring, particularly at lower latitudes. WHAT IS KNOWN ALREADY: In human populations, there are strong seasonal patterns of births that vary across geographic regions and time periods. However, previous studies of seasonality and fecundity are limited because they examine season of birth rather than season of conception and therefore neglect to account for seasonal variation in initiating attempts to conceive or pregnancy loss or differences in gestational length. STUDY DESIGN, SIZE, DURATION: We conducted a preconception cohort study of 14 331 women residing in North America (June 2013-May 2018: n = 5827) and Denmark (June 2007-May 2018: n = 8504). Participants were attempting to conceive without fertility treatment and had been attempting pregnancy for ≤6 menstrual cycles at enrolment. PARTICIPANTS/MATERIAL, SETTING, METHODS: We collected information on season of each pregnancy attempt using last menstrual period dates over the study period. Pregnancy was reported on female bi-monthly follow-up questionnaires. We fit log-binomial models with trigonometric regression to examine periodic variation in fecundability. We accounted for seasonal variation in initiation of pregnancy attempts by including indicator variables for menstrual cycle of attempt in the regression models. MAIN RESULTS AND THE ROLE OF CHANCE: Initiation of pregnancy attempts peaked in September, with stronger seasonality in North America than in Denmark (48 vs. 16% higher probability initiating attempts in September compared with March). After accounting for seasonal variation in initiation of pregnancy attempts, we observed modest seasonal variation in fecundability, with a peak in the late fall and early winter in both cohorts, but stronger peak/low ratios in North America (1.16; 95% confidence interval [CI]: 1.05, 1.28) than in Denmark (1.08; 95% CI: 1.00, 1.16). When we stratified the North American data by latitude, we observed the strongest seasonal variation in the southern USA (peak/low ratio of 1.45 [95% CI: 1.14, 1.84]), with peak fecundability in late November. LIMITATIONS, REASONS FOR CAUTION: We estimated menstrual cycle dates between follow-up questionnaires, which may have introduced exposure misclassification, particularly when women skipped follow-up questionnaires. We were unable to measure seasonally varying factors that may have influenced fecundability, including ambient temperature, vitamin D levels or infectious disease. WIDER IMPLICATIONS OF THE FINDINGS: An understanding of how fecundability varies across seasons could help identify factors that can impair reproductive function. Neglecting to account for seasonal variation in initiation of pregnancy attempts could bias estimates of seasonal patterns in fecundability. This is the first preconception cohort study to examine seasonal variation in fecundability after accounting for seasonality in initiation of pregnancy attempts. Fecundability was highest in the fall and lowest in the spring, with stronger effects in southern latitudes of North America, suggesting that seasonal exposures may affect fecundity. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Eunice K. Shriver National Institute of Child Health and Human Development (R21-050264, R01-HD060680, R21-HD072326 and R01-HD086742) and the Danish Medical Research Council (271-07-0338). The authors declare no conflicts of interest.

​Risk of major adverse cardiovascular events among patients with rheumatoid arthritis after initial CT-based diagnosis and treatment.

OBJECTIVE: Rheumatoid arthritis (RA) is a known risk factor for developing coronary artery disease (CAD). The influence of RA on the prognosis after initial CAD diagnosis and treatment is however largely unknown. We examined the risk of major cardiovascular events among RA and non-RA patients with chest pain referred to cardiac CT. METHODS: This was a follow-up study, using data from the Western Denmark Heart Registry, containing data on CT angiography examinations (Cardiac CT). Information on RA diagnosis and covariates were identified through nationwide administrative registers. The primary outcome was a combined outcome including, myocardial infarction, ischaemic or unspecified stroke, coronary artery bypass grafting, percutaneous coronary intervention, and all-cause mortality. Median time until events or censoring was 3.5 years (min/max: 0.0: 9.2). Cox proportional hazard models were used to examine the association between RA/non-RA patients and outcomes. RESULTS: Among 42 257 patients, referred between 2008 and 2016, we identified 358 (0.8%) with RA. An increased risk was seen in RA compared with non-RA (adjusted HR 1.35, 95% CI 0.93 to 1.96). Among patients who had received flare treatment more than once prior to cardiac CT the adjusted HR 1.80 (95% CI 1.08 to 3.00), and among patients with seropositive RA the adjusted HR 1.42 (95% CI 0.93 to 2.16). CONCLUSION: In patients referred to cardiac CT due to chest pain, we found a trend of an association between RA and the combined primary outcome, supporting that RA per se, but in particular seropositive and active RA, may increase the risk of CAD even after initial CAD diagnosis and treatment.

Nitrosatable drug exposure during pregnancy and risk of stillbirth.

PURPOSE: Nitrosatable drugs can react with nitrite in the stomach and form N-nitroso compounds. Exposure to nitrosatable drugs has been associated with congenital malformations and preterm birth, but use during pregnancy as a cause of fetal death is not well-known. We examined if prenatally nitrosatable drug use is associated with risk of stillbirth. METHODS: A nationwide cohort was conducted using 554 844 women with singleton and first recorded pregnancies regardless of previous pregnancy history from the Danish Medical Birth Register from 1996 to 2015. Exposure was recorded by use of the Danish National Prescription Register and defined as women who had redeemed a prescribed nitrosatable drug in the first 22 weeks of pregnancy. The reference group was women with no redeemed prescribed nitrosatable drug in this time period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for stillbirth. RESULTS: Among the 84 720 exposed women, 348 had a stillbirth compared with 1690 stillbirths among the 470 124 unexposed women. Women who used any prescribed nitrosatable drug were more likely to have a stillbirth compared with unexposed women (aHRs 1.24; 95% CI, 1.03-1.49). CONCLUSION: Nitrosatable drug use during the first 22 weeks of pregnancy might increase risk of stillbirth. The findings should be interpreted cautiously because of important unmeasured factors that might influence the observed association, including maternal vitamin C intake, dietary, and other sources of nitrate/nitrite intake.

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.

Validating registry data on statins prescriptions by blood measurements.

PURPOSE: To validate prescription registry data as a measurement of adherence to statins through a direct method using assays for selected statins in serial blood samples collected from two prospective cohorts of Danish colorectal cancer patients. METHODS: We linked information on statin prescriptions from the Aarhus University Prescription Database with the cancer cohorts from Aalborg University Hospital. For statin-prescribed patients, we calculated a prescription window covering the anticipated duration of the prescription. For each statin-prescribed patient with at least one blood sample in a prescription window, we selected without replacement a never-statin-prescribed patient matched on sex, age, and calendar year of surgery. Each of the selected blood samples were analyzed using assays to detect statins. We calculated the positive and negative predictive value of the prescription registry reporting using the assay result as the gold standard. RESULTS: We identified 73 ever-statin-prescribed patients with a total of 253 blood samples and 74 blood samples among never-statin-prescribed patients. The positive predictive value for prescribed patients, with presence of statins in at least one blood sample as the gold standard, was 93% (95% CI, 86%-97%) and the negative predictive value was 93% (95% CI, 86%-97%). Stratified results did not reveal substantial differences in predictive values. Fifty-two (71%) of the statin-prescribed patients had statins in every blood sample, suggesting continuous adherence. CONCLUSION: This study showed a high adherence with treatment with statins among colorectal cancer patients.

Fecundability among Danish women with a history of miscarriage: a prospective cohort study.

OBJECTIVE: To examine the association between history of miscarriage and fecundability (the cycle-specific probability of conception). DESIGN: Nationwide prospective cohort study using web-based questionnaires. SETTING: Denmark, 2007-2012. PARTICIPANTS: 977 women attempting to conceive, not using fertility treatment, and with a reproductive history of only miscarriage or only live birth. EXPOSURE AND OUTCOME MEASURES: Information on previous pregnancy outcomes, including miscarriage, came from self-report or from relevant registries. Participants were followed for up to 12 months or until they reported a pregnancy, stopped trying to conceive or started fertility treatment, whichever came first. We used Kaplan-Meier methods to estimate cumulative probabilities of conception for women whose reproductive history included only miscarriage or only live birth. Using proportional probabilities regression modelling, we computed fecundability ratios (FR) with 95% CI comparing women with a history of only miscarriage with women with a history of only live birth. RESULTS: After adjustment for potential confounders, the cumulative probabilities of conception within 12 cycles of follow-up were 85% (95% CI 81% to 89%) for women with a history of 1 miscarriage, 85% (95% CI 73% to 92%) for women with a history of ≥2 miscarriages and 88% (95% CI 87% to 89%) for women whose reproductive history included only live birth. Adjusted FRs were 0.87 (95% CI 0.71 to 1.07) and 0.65 (95% CI 0.36 to 1.17) for women with a history of 1 and ≥2 miscarriages, respectively. CONCLUSIONS: Our results indicate that women with a history of miscarriage may have slightly reduced fecundability compared with women with a history of only live birth. The reduction in fecundability was greater for women with repeated miscarriages, although the estimates were imprecise. Despite a potential delay in conception, women with previous miscarriage may have similar probability of pregnancy by 12 cycles of attempts to women with proven fertility.

Does low risk of infections as a marker of effective immunity predict increased risk of subsequent giant cell arteritis or polymyalgia rheumatica? A Danish population-based case-control study.

OBJECTIVE: It has been suggested that a hyper-effective immune system ("hyper-immunity") is central to the pathogenesis of giant cell arteritis and polymyalgia rheumatica (GCA/PMR). We examined if a low risk of infections, as a marker of hyper-immunity, can predict increased subsequent risk of GCA/PMR. PATIENTS AND METHODS: We conducted a population-based case-control study including all patients aged ≥50 years with incident GCA/PMR diagnosed between 1997 and 2012 in Northern Denmark. For each case, we selected 10 population controls matched on gender, age, place of residence, and time spent in the region. Complete history of hospital-treated infections and community-based anti-infective prescriptions was assessed in population-based registries. We used conditional logistic regression to compute OR of GCA/PMR associated with infections while adjusting for comorbidities, immunosuppressive treatment, and other potential confounders. RESULTS: We included 7,225 GCA/PMR cases and 72,250 controls. When excluding all infections occurring within the last year before GCA/PMR diagnosis, there was no decreased risk for GCA/PMR in people with a history of hospital-treated infection (adjusted OR=1.04, 95% CI: 0.98-1.10) or community anti-infective treatment (adjusted OR=1.07, 95% CI: 0.99-1.16). Within the last year preceding the GCA/PMR index date, patients with hospital-treated infections (adjusted OR=1.59, 95% CI: 1.44-1.75) or community anti-infective treatment (adjusted OR=1.63, 95% CI: 1.48-1.79) had a greatly increased risk of a GCA/PMR diagnosis. CONCLUSION: These results do not support the hypothesis of "hyper-immunity" leading to GCA/PMR. Instead, incident GCA/PMR is preceded by a slightly increased risk of infection, which may be related to protopathic bias or support theories that infections may be directly involved in the pathogenesis of GCA/PMR.