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BACKGROUND: Acute kidney injury (AKI) has been associated with cardiovascular disease, but this is sparsely studied in non-selected populations and with little attention to the effect in age and renal function. Using nationwide administrative data, we investigated the hypothesis of increased one-year risk of cardiovascular event or death associated with AKI.METHODS: In a cohort study, we identified all admissions in Denmark between 2008 and 2018. AKI was defined as ≥1.5 times increase from baseline to peak creatinine during admission, or dialysis. We excluded patients with age RESULTS: Among 565,056 hospital admissions, 39,569 (7.0%) cases of AKI were present. In total, 18,642 patients sustained a cardiovascular outcome. AKI was significantly associated with cardiovascular outcome with an adjusted OR [CI] of 1.33 [1.16-1.53], 1.43 [1.33-1.54], 1.23 [1.14-1.34], 1.38 [1.18-1.62] for eGFR ≥90, 60-89, 30-59 and 15-29ml/min/1.73m 2, respectively. When omitting the outcome heart failure, these results were 1.24 [1.06-1.45], 1.22 [1.11-1.33], 1.05 [0.95-1.16], 1.25 [1.02-1.54]. Results did not change substantially in strata of age groups, in AKI stages and in the subcohort adjusted for proteinuria. CONCLUSION: Non-selected patients aged 50 years or above with AKI during admission had significantly higher one-year risk of cardiovascular event or death, especially, but not only due to heart failure, independent of age and eGFR.

Background Various prediction models have been developed to predict the risk of kidney failure in patients with CKD. However, guideline-recommended models have yet to be compared head to head, their validation in patients with advanced CKD is lacking, and most do not account for competing risks. Methods To externally validate 11 existing models of kidney failure, taking the competing risk of death into account, we included patients with advanced CKD from two large cohorts: the European Quality Study (EQUAL), an ongoing European prospective, multicenter cohort study of older patients with advanced CKD, and the Swedish Renal Registry (SRR), an ongoing registry of nephrology-referred patients with CKD in Sweden. The outcome of the models was kidney failure (defined as RRT-treated ESKD). We assessed model performance with discrimination and calibration. Results The study included 1580 patients from EQUAL and 13,489 patients from SRR. The average c statistic over the 11 validated models was 0.74 in EQUAL and 0.80 in SRR, compared with 0.89 in previous validations. Most models with longer prediction horizons overestimated the risk of kidney failure considerably. The 5-year Kidney Failure Risk Equation (KFRE) overpredicted risk by 10%-\18%. The four- and eight-variable 2-year KFRE and the 4-year Grams model showed excellent calibration and good discrimination in both cohorts. Conclusions Some existing models can accurately predict kidney failure in patients with advanced CKD. KFRE performed well for a shorter time frame (2 years), despite not accounting for competing events. Models predicting over a longer time frame (5 years) overestimated risk because of the competing risk of death. The Grams model, which accounts for the latter, is suitable for longer-term predictions (4 years).

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

Objective: A transient rise in the occurrence of hyperthyroidism ensued the introduction of iodine fortification (IF) of salt in Denmark. Older adults are at risk of complications to hyperthyroidism that could prove fatal to vulnerable individuals. We evaluated the association between thyroid function and mortality in older adults before and after nationwide implementation of IF. Design: Retrospective cohort study. Patients: All 68-year-olds from the general population in the city of Randers were invited to participate in a clinical study in 1988 and followed until death, emigration or end of study (31 December 2017) using Danish registries. Measurements: Baseline measures comprised of a questionnaire, physical examination and blood and urine samples. Kaplan–Meier survival curves and Cox regression were used to determine the association between thyroid function and death before and after IF. Time-stratification of results before and after IF was employed due to violation of proportional hazards assumptions in Cox regression. Results: Median urinary iodine concentration was 42 µg/L at baseline consistent with moderate iodine deficiency. Hyperthyroidism (thyrotropin < 0.4 mIU/L) occurred in 37 (9.1%) participants. Kaplan–Meier survival curves showed an increase in mortality among participants with hyperthyroidism after IF. There was no significant association between hyperthyroidism and mortality before IF compared to euthyroid participants, but after IF hyperthyroid subjects had an increased mortality (adjusted hazard ratio: 2.22, 95% confidence interval: 1.44–3.44). Conclusions: IF was associated with raised mortality among older adults with a history of hyperthyroidism and moderate iodine deficiency. Our results highlight the need for cautious iodine supplementation and for monitoring of IF.

Objectives: This study sought to investigate the mortality associated with atrial fibrillation (AF) in men and women with heart failure (HF) according to the sequence of presentation and rhythm versus rate control. Background: The sex-specific epidemiology of AF in HF is sparse. Methods: Using the Danish nationwide registries, all first-time cases of HF were identified and followed for all-cause mortality from 1998 to 2018. Results: Among 252,988 patients with HF (mean age: 74 ± 13 years, 45% women), AF presented before HF in 54,064 (21%) and on the same day in 27,651 (11%) individuals, similar in women and men. Among patients without AF, the cumulative 10-year incidence of AF was 18.7% (95% confidence interval [CI]: 18.2% to 19.1%) in women and 21.3% (95% CI: 21.0% to 21.6%) in men. On follow-up (mean: 6.2 ± 5.8 years), adjusted mortality rate ratios were 3.33 (95% CI: 3.25 to 3.41) in women and 2.84 (95% CI: 2.78 to 2.90) in men if AF antedated HF, 3.45 (95% CI: 3.37 to 3.56) in women versus 2.76 (95% CI: 2.69 to 2.83) in men when AF and HF were diagnosed concomitantly, and 4.85 (95% CI: 4.73 to 4.97) in women versus 3.89 (95% CI: 3.80 to 3.98) in men when AF developed after HF. Compared with rate control for AF, a rhythm-controlling strategy was associated with lowered mortality in inverse probability–weighted models across all strata and in both sexes (hazard ratio: 0.75 to 0.83), except for women who developed AF after HF onset (hazard ratio: 1.03). Conclusions: More than half of all men and women with HF will develop AF during their clinical course, with prognosis associated with AF being worse in women than men. Further studies are needed to understand the underlying mechanisms.

Aim To investigate temporal trends in inpatient vs. outpatient diagnosis of new-onset heart failure (HF) and the subsequent risk of death and hospitalization. Methods and results Using nationwide registers, 192 581 patients with a first diagnosis of HF (1997–2017) were included. We computed incidences of HF, age-standardized mortality rates, and absolute risks (ARs) of death and hospitalization (accounting for competing risk of death) to understand the importance of the diagnosis setting in relation to subsequent mortality and hospitalization. The overall incidence of HF was approximately the same (170/100 000 persons) every year during 1997–2017. However, in 1997, 77% of all first diagnoses of HF were made during a hospitalization, whereas the proportion was 39% in 2017. As inpatient diagnoses decreased, outpatient diagnoses increased from 23% to 61%. Outpatients had lower mortality and hospitalization rates than inpatients throughout the study period, although the 1-year age-standardized mortality rate decreased for each inpatient (24 to 14/100-person) and outpatient (11 to 7/100-person). One-year and five-year AR of death decreased by 11.1% and 17.0%, respectively, for all HF patients, while the risk of hospitalization for HF did not decrease significantly (1.13% and 0.96%, respectively). Conclusion Between 1997 and 2017, HF changed from being primarily diagnosed during hospitalization to being mostly diagnosed in the outpatient setting. Outpatients had much lower mortality rates than inpatients throughout the study period. Despite a significant decrease in mortality risk for all HF patients, neither inpatients nor outpatients experienced a reduction in the risk of an HF hospitalization.

Introduction Prednisolone has important potential side-effects, one of which is steroid-induced diabetes mellitus (DM). Due to the exposure to a high cumulative dosage of steroids during first-line treatment, patients with non-Hodgkin lymphoma (NHL) could face increased risk of new onset steroid-induced DM or dysregulation of a pre-existing DM. This nationwide observational cohort study evaluated the risk of new onset DM in lymphoma patients and the impact on pre-existing DM in lymphoma survivors following treatment with steroid-containing regimens. Methods Adult NHL patients (≥18 years) treated with ≥3 cycles of steroid-containing immunochemotherapy, such as R-CHOP(-like) and R-CVP, between 2002 and 2015 were identified in the Danish Lymphoma Register and matched to five random individuals from the general population on birth year, sex, Charlson Comorbidity Index score, baseline DM status (DM or not), and DM duration. NHL patients and matched comparators were followed from start of treatment for the patients until the event of interest (DM, insulin prescription), death, relapse, NHL diagnosis (for matched comparators), or censoring (emigration, missing, or end of study on 31 December 2018), whichever came first. DM was captured by either a diagnosis of any DM (ICD-10 codes: E10-E14) in the Danish National Patient Register or any redeemed anti-diabetic prescription registered in the National Prescription Register (insulin or oral anti-diabetic medicine; ATC A10A or A10B). In the analysis of insulin prescriptions following lymphoma treatment initiation, patients with any redeemed prescription of insulin prior to start of lymphoma treatment were excluded. Time-varying incidence rates (IRs) per 1,000 person years and incidence rate ratios (IRRs) with 95% confidence intervals were estimated using a spline-based Poisson regression approach with two-month time splits and five knots. The Aalen-Johansen estimator was used to compute the cumulative risk of an event treating death, relapse, and NHL diagnosis (in comparators) as competing events. Risk differences at specific time points were calculated using pseudo-observations. Crude and adjusted cause-specific hazard ratios (HR) were obtained using Cox regression. Results A total of 4,703 NHL patients were included in the present study. Median age was 66 years and median follow-up was 8.5 years. Among the NHL patients, 4,325 patients did not have pre-existing DM and were matched to 21,625 comparators without DM. The time-varying IR of DM among comparators was 8-10 cases/1000 person years. The IRR of DM for patients vs comparators was higher for patients in the first year following treatment initiation (maximum IRR: 2.40), lower from 1 to 5 years (minimum IRR: 0.52), and higher from 5 to 10 years (maximum IRR: 1.18) (Fig. 1). The cumulative incidence of DM was higher for NHL patients at six months (0.58 percentage units (%U), p Among the NHL patients, 378 had pre-existing non-insulin dependent DM and were matched to 1,890 comparators. The cumulative incidence difference of any insulin use was higher for patients at 6 months (14.29%U, p Conclusion In conclusion, patients treated with steroid-containing immunochemotherapy did not experience a higher risk of diabetes mellitus compared to matched comparators beyond the first year. Matched comparators had a higher cumulative incidence of diabetes mellitus after 2 years, which was partly explained by the high competing risk of death in the patient group. NHL patients with pre-existing non-insulin dependent diabetes mellitus had an increased cumulative incidence of any insulin prescriptions; however, the difference was diminished when assessing the risk of at least five insulin prescriptions, suggesting that the impact of steroids on diabetes regulation is limited in time when taking competing risks into account. Figure 1 Figure 1. Disclosures Øvlisen: Abbvie: Other: Travel expenses. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Vestergaard: Novo Nordisk Foundation: Other: Head of Research at Steno Diabetes Center North Jutland funded by the Novo Nordisk Foundation, Research Funding. Jørgensen: Gilead: Consultancy; Novartis: Consultancy; Roche: Consultancy; Celgene: Consultancy. Clausen: Gilead: Consultancy, Other: Travel expences 15th ICML ; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Ekstroem Smedby: Janssen Cilag: Research Funding; Takeda: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee.

OBJECTIVE To assess the risk of major adverse cardiovascular events (MACE), all-cause mortality, and initiation of medical treatment in subjects with prediabetes according to first-time measured HbA1c. RESEARCH DESIGN AND METHODS Through registry databases, we identified 326,305 Danish patients with a first HbA1c between 40 and 51 mmol/mol (5.8–6.8%) from 2011 to 2017. After exclusion of patients with prior disease, 84,678 patients were followed 12 months after first HbA1c measurement. Cox regression models were used to estimate hazard ratios (HRs) of MACE and standardized absolute risks. Cumulative incidences were used to analyze initiation of glucose-lowering, antihypertensive, cholesterol-lowering, and antithrombotic medication. RESULTS The 12-month risk of MACE and all-cause mortality increased gradually with increasing HbA1c until 47 mmol/mol (6.5%). In comparisons of subjects with HbA1c 40–41 mmol/mol (5.8–5.9%), subjects with HbA1c 46–47 mmol/mol (6.4–6.5%) had a 0.79% (95% CI 0.33–1.24) higher standardized absolute risk and an HR of 2.21 (95% CI 1.67–2.92) of MACE. Patients with HbA1c 48–49 mmol/mol (6.5–6.6%) had a 0.09% (95% CI −0.35 to 0.52) lower absolute risk and an HR of 1.33 (95% CI 0.87–2.05) of MACE. Initiation of medication was significantly lower among patients with HbA1c of 46–47 mmol/mol (6.4–6.5%) than among patients with HbA1c of 48–49 mmol/mol (6.5–6.6%). CONCLUSIONS In the Danish population screened for diabetes with HbA1c, the highest risk of MACE and all-cause mortality was found in subjects with HbA1c just below the diagnostic threshold for diabetes. Our results highlight the need for increased focus on the treatment of cardiovascular risk factors for subjects with prediabetes.

AIMS: This study aimed to examine whether socioeconomic differences exist in long-term outcomes after out-of-hospital cardiac arrest (OHCA).METHODS: We included 2309 30-day OHCA survivors ≥ 30 years of age from the Danish Cardiac Arrest Registry, 2001-2014, divided in tertiles of household income (low, medium, high). Absolute probabilities were estimated using logistic regression for 1-year outcomes and cause-specific Cox regression for 5-year outcomes. Differences between income-groups were standardized with respect to age, sex, education and comorbidities.RESULTS: High-income compared to low-income patients had highest 1-year (96.4% vs. 84.2%) and 5-year (87.6% vs. 64.1%) survival, and lowest 1-year (11.3% vs. 7.4%) and 5-year (13.7% vs. 8.6%) risk of anoxic brain damage/nursing home admission. The corresponding standardized probability differences were 8.2% (95%CI 4.7-11.6%) and 13.9% (95%CI 8.2-19.7%) for 1- and 5-year survival, respectively; and -4.5% (95%CI -8.2 to -1.2%) and -5.1% (95%CI -9.3 to -0.9%) for 1- and 5-year risk of anoxic brain damage/nursing home admission, respectively. Among 831 patients < 66 years working prior to OHCA, 72.1% returned to work within 1 year and 80.8% within 5 years. High-income compared to low-income patients had the highest chance of 1-year (76.4% vs. 58.8%) and 5-year (85.3% vs. 70.6%) return to work with the corresponding absolute probability difference of 18.0% (95%CI 3.8-32.7%) for 1-year and 9.4% (95%CI -3.4 to 22.3%) for 5-year.CONCLUSION: Patients of high socioeconomic status had higher probability of long-term survival and return to work, and lower risk of anoxic brain damage/nursing home admission after OHCA compared to patients of low socioeconomic status.

Cognitive behavioral therapy (CBT) is the first choice of treatment of obsessive–compulsive disorder (OCD) in children and adolescents. However, there is often a lack of access to appropriate treatment close to the home of the patients. An internet-based CBT via videoconferencing could facilitate access to state-of-the-art treatment even in remote areas. The aim of this study was to investigate feasibility and acceptability of this telemedical approach. A total of nine children received 14 sessions of CBT. The first session took place face-to-face, the remaining 13 sessions via videoconference. OCD symptoms were recorded with a smartphone app and therapy materials were made accessible in a data cloud. We assessed diagnostic data before and after treatment and obtained measures to feasibility, treatment satisfaction and acceptability. Outcomes showed high acceptance and satisfaction on the part of patients with online treatment (89%) and that face-to-face therapy was not preferred over an internet-based approach (67%). The majority of patients and their parents classified the quality of treatment as high. They emphasized the usefulness of exposures with response prevention (E/RP) in triggering situations at home. The app itself was rated as easy to operate and useful. In addition to feasibility, a significant decrease in obsessive–compulsive symptoms was also achieved. Internet-based CBT for pediatric OCD is feasible and well received by the patients and their parents. Furthermore, obsessive–compulsive symptomatology decreased in all patients. The results of this study are encouraging and suggest the significance of further research regarding this technology-supported approach, with a specific focus on efficacy.Trial registration number: Clinical trials AZ53-5400.1-004/44.

Objectives This study aimed to investigate the potential of a novel 3-dimensional (3D) mechanical wave velocity mapping technique, based on the natural mechanical waves produced by the heart itself, to approach a noninvasive 3D stiffness mapping of the left ventricle. Background Myocardial fibrosis is recognized as a pathophysiological substrate of major cardiovascular disorders such as cardiomyopathies and valvular heart disease. As fibrosis leads to increased myocardial stiffness, ultrasound elastography measurements could provide important clinical information. Methods A 3D high frame rate imaging sequence was implemented on a high-end clinical ultrasound scanner to achieve 820 volumes/s when gating over 4 consecutive cardiac cycles. Five healthy volunteers and 10 patients with various degrees of aortic stenosis were included to evaluate feasibility and reproducibility. Mechanical waves were detected using the novel Clutter Filter Wave Imaging approach, shown to be highly sensitive to the weak tissue displacements caused by natural mechanical waves. Results 3D spatiotemporal maps of mechanical wave velocities were produced for all subjects. Only the specific mechanical wave at atrial contraction provided a full 3D coverage of the left ventricle (LV). The average atrial kick propagation velocity was 1.6 ± 0.2 m/s in healthy volunteers and 2.8 ± 0.8 m/s in patients (p = 0.0016). A high correlation was found between mechanical wave velocity and age (R2 = 0.88, healthy group), septal wall thickness (R2 = 0.73, entire group), and peak jet velocity across the aortic valve (R2 = 0.70). For 3 of the patients, the higher mechanical wave velocity coexisted with the presence of late gadolinium enhancement on cardiac magnetic resonance. Conclusions In this study, 3D LV mechanical wave velocities were visualized and measured in healthy volunteers and patients with aortic stenosis. The proposed imaging sequence and measurement technique allowed, for the first time, the measurement of full spatiotemporal 3D elasticity maps of the LV using ultrasound. (Ultrasonic markers for myocardial fibrosis and prognosis in aortic stenosis; NCT03422770 )

Immersive virtual reality (IVR) is an adjunctive form of anesthesia intended to distract patients from their intraoperative environment and reduce other side effects of sedating or narcotic agents. While this technology has been applied sparingly in various orthopedic procedural environments, its clinical utility has not been widely evaluated in major, nonelective surgical settings. The use of IVR in the geriatric hip fracture population represents a novel indication with potential benefit to reduced cognitive dysfunction and delirium. We report a case of a 100-year-old patient who received IVR adjunctive to neuraxial anesthesia during conversion total hip arthroplasty via posterolateral approach for treatment of failed peritrochanteric hip fracture fixation.

Peter Ascanius Jacobsen,1,2 Kristian Hay Kragholm,2,3 Christian Torp-Pedersen,4 Daisy JA Janssen,5,6 Martijn A Spruit,5,7,8 Ulla Møller Weinreich1,2 1Department of Respiratory Diseases, Aalborg University Hospital, Aalborg, Denmark; 2The Clinical Institute, Aalborg University, Aalborg, Denmark; 3Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; 4Department of Clinical Research, Hillerød Hospital, Hillerød, Denmark; 5Department of Research and Development, Ciro, Horn, the Netherland; 6Department of Health Services Research, Care and Public Health Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands; 7Nutrim School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands; 8Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, the NetherlandsCorrespondence: Peter Ascanius JacobsenDepartment of Respiratory Diseases, Aalborg University Hospital, Aalborg, DenmarkTel +45 97 66 48 00Email peter.jacobsen@rn.dkIntroduction: The understanding of whether and to what extent employment status affects readmission and mortality is limited in patients with COPD.Aim: To explore how employment status affects readmission and mortality after first admission to the hospital with acute exacerbation of COPD (AECOPD).Methods: This study used Danish national registry-based data. All patients admitted for the first time to the hospital between 1999 and 2014 with a diagnosis of AECOPD, age 35– 59, without a previous asthma diagnosis were included in the study. Employment status effect on 30-, 90-, and 365-day readmission and mortality was examined using logistic regression, adjusting for relevant confounders.Results: A total of 11,850 COPD patients were included in the study of which 3563 (30%) were working, 1368 (12%) unemployed, 840 (7%) on sick leave, and 6079 (51%) receiving early retirement. Patients receiving early retirement had, compared to patients working, an adjusted increased likelihood of readmission at 30, 90, and 365 days (odds ratio (OR) 1.26 (CI95% (1.06– 1.49)), 1.33 (CI95% (1.16– 1.53)), and 1.48 (CI95% (1.33– 1.66)), respectively). An increased likelihood was also seen in unemployed at 365 days follow-up (OR 1.44 (CI95% (1.22– 1.68))). Early retirement was associated with an increased mortality at 30, 90, and 365 days (OR 1.39 (CI95% (1.07– 1.80)) 1.37 (CI95% (1.09– 1.79)) and 1.48 (CI95% (1.25– 1.75)), respectively). An increased likelihood was also seen in patients receiving sick leave (OR 1.57 (CI95% (1.21– 2.04))).Conclusion: Patients with COPD who are not working at the time of first admission have a higher likelihood of readmission and mortality.Keywords: chronic obstructive pulmonary disease, employment, mortality, readmission

AIMS: Despite adequate treatment, recent studies have hypothesized that malaria may affect long-term cardiovascular function. We aimed to investigate the long-term risk of cardiovascular events and death in individuals with a history of imported malaria in Denmark.METHODS: Using nationwide Danish registries, we followed individuals with a history of malaria for the risk of incident heart failure (HF), myocardial infarction (MI), cardiovascular death and all-cause death (1 January 1994 to 1 January 2017). The population was age- and sex-matched with individuals without a history of malaria from the Danish population (ratio 1:9). We excluded patients with known HF and ischaemic heart disease at inclusion.RESULTS: We identified 3912 cases with a history of malaria (mean age 33 ± 17 years, 57% male, 41% Plasmodium falciparum infections). The median follow-up was 9.8 years (interquartile range 3.9-16.4 years). Event rates per 1000 person-years for individuals with a history vs. no history of malaria were HF: 1.84 vs. 1.32; MI: 1.28 vs. 1.30; cardiovascular death: 1.40 vs. 1.77; and all-cause death: 5.04 vs. 5.28. In Cox proportional hazards models adjusted for cardiovascular risk factors, concomitant pharmacotherapy, region of origin, household income and educational level, malaria was associated with HF (HR: 1.59 [1.21-2.09], P = 0.001), but not MI (HR: 1.00 [0.72-1.39], P = 1.00), cardiovascular death (HR: 1.00 [0.74-1.35], P = 0.98) or all-cause death (HR 1.11 [0.94-1.30], P = 0.21). Specifically, P. falciparum infection was associated with increased risk of HF (HR: 1.64 [1.14-2.36], P = 0.008).CONCLUSION: Individuals with a history of imported malaria, specifically P. falciparum, may have an increased risk of incident HF.

The aim of the European Heart Journal (EHJ) is to attract innovative, methodologically sound, and clinically relevant research manuscripts able to change clinical practice and/or substantially advance knowledge on cardiovascular diseases. As the reference journal in cardiovascular medicine, the EHJ is committed to publishing only the best cardiovascular science adhering to the highest ethical principles. EHJ uses highly rigorous peer-review, critical statistical review and the highest quality editorial process, to ensure the novelty, accuracy, quality, and relevance of all accepted manuscripts with the aim of inspiring the clinical practice of EHJ readers and reducing the global burden of cardiovascular diseases. This review article summarizes the quality standards pursued by the EHJ to fulfill its mission.

PURPOSE: In pharmacoepidemiology, correctly defining the exposure period of pharmacological treatment is a challenging step when information on the time in treatment is missing or incomplete.METHODS: In this review, we describe several methods for defining exposure to pharmacological treatments using secondary data sources that lack such information.RESULTS AND CONCLUSION: Several methods for assessing the duration of redeemed prescriptions and combining them into temporal sequences are available. We present a set of considerations to make researchers aware of the potentials and pitfalls of these methods that may aid in minimizing biases in research using these methods. Additionally, we highlight that, to date, there is no one-size-fits-all solution. Thus, the choice of method should be based on their area of applicability combined with a careful mapping to the research scenario under investigation.

Aims We examined cardiovascular outcomes associated with initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) vs. sodium–glucose co-transporter-2 inhibitor (SGLT-2i) treatment in a real-world setting among patients with type 2 diabetes. Methods and results This Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first-ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015 with follow-up until end of 2018. All analyses were standardized with respect to age, sex, diabetes duration, comorbidity, and comedication. The main outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Furthermore, the components of the composite outcome and hospitalization for heart failure were evaluated. Standardized average 3-year risks of outcomes and differences thereof were estimated using doubly robust estimation combining cause-specific Cox regression with propensity score regression. We identified 8913 new users of GLP-1RA and 5275 new users of SGLT-2i. The standardized 3-year risk associated with initiating GLP-1RA and SGLT-2i, respectively, was as follows: composite cardiovascular outcome, 5.6% [95% confidence interval (CI): 5.2–6.1] vs. 5.6% (95% CI: 4.8–6.3); cardiovascular mortality, 1.6% (95% CI: 1.3–1.9) vs. 1.5% (95% CI: 1.1–1.8); hospitalization for heart failure, 1.7% (95% CI: 1.5–2.0) vs. 1.8% (95% CI: 1.2–2.5); myocardial infarction, 2.1% (95% CI: 1.8–2.4) vs. 2.1% (95% CI: 1.5–2.6); and stroke, 2.5% (95% CI: 2.2–2.9) vs. 2.6% (95% CI: 2.2–3.1). Conclusion In this nationwide study of patients with type 2 diabetes, initiating GLP-1RA vs. SGLT-2i was not found to be associated with significant differences in cardiovascular risk.

Background Angiogenesis is prominent in metastatic renal cell carcinoma (mRCC). We compared two angiogenesis assessment methods: dynamic contrast-enhanced computed tomography (DCE-CT)-derived blood volume (BV) and blood flow (BF) and core biopsy microvessel density (MVD). Methods As planned in DaRenCa Study-1 study, DCE-CT and core biopsy were performed from the same tumour/metastasis at baseline. MVD was assessed by CD34 immunostaining in tumour (CD34-indexT) or tumour including necrosis (CD34-indexTN). BV and BF were assessed using the DCE-CT software. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier analysis. Spearman coefficient (rho) tested the correlation between MVD and BV, BF, or CT density (HU). Results At baseline, 25 patients had analysable scans and tissue. BVdeconv, BVPatlak, and BFdeconv > median were associated with favourable OS (43.2 versus 14.6 months, p = 0.002; 31.6 versus 20.2 months, p = 0.015; and 31.6 versus 24.5 months, p = 0.019). CD34-indexT and CD34-indexTN did not correlate with age (p = 0.543), sex (p = 0.225), treatment (p = 0.848), International mRCC Database Consortium category (p = 0.152), synchronous versus metachronous metastatic disease (p = 0.378), or tumour volume (p = 0.848). CD34-indexT or CD34-indexTN > median was not associated with PFS (p = 0.441 and p = 0.854, respectively) or OS (p = 0.987 and p =0.528, respectively). CD34-indexT or CD34-indexTN was not correlated with BV, BF, or HU (rho 0.20–0.26). Conclusions Differently from MVD, DCE-CT-derived BV and BF had prognostic impact and may better reflect angiogenesis in mRCC. Trial registration NCT01274273

Background: Mounting evidence suggests that dermatomyositis/polymyositis (DM/PM) are associated with increased risk of atherosclerotic events and venous thromboembolism. However, data on the association between DM/PM and other cardiac outcomes, especially heart failure (HF), are scarce. Objectives: To examine the long-term risk and prognosis associated with adverse cardiac outcomes in patients with DM/PM. Methods: Using Danish administrative registries, we included all patients ≥18 years with newly diagnosed DM/PM (1996–2018). Risks of incident outcomes were compared with non-DM/PM controls from the background population (matched 1:4 by age, sex, and comorbidity). In a secondary analysis, we compared mortality following HF diagnosis between DM/PM patients with HF and non-DM/PM patients with HF (matched 1:4 by age and sex). Results: The study population included 936 DM/PM patients (median age 58.5 years, 59.0% women) and 3744 matched non-DM/PM controls. The median follow-up was 6.9 years. Absolute 10-year risks of incident outcomes for DM/PM patients vs matched controls were as follows: HF, 6.98% (CI, 5.16–9.16%) vs 4.58% (3.79–5.47%) (P = 0.002); atrial fibrillation, 10.17% (7.94–12.71%) vs 7.07% (6.09–8.15%) (P = 0.005); the composite of ICD implantation/ventricular arrhythmias/cardiac arrest, 1.99% (1.12–3.27%) vs 0.64% (0.40–0.98%) (P = 0.02); and all-cause mortality, 35.42% (31.64–39.21%) vs 16.57% (15.10–18.10%) (P

Purpose: TP53 aberration (TP53 mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each TP53 aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) TP53 aberrations remains unclear, particularly in the context of targeted agents. Patients and Methods: We performed deep sequencing of TP53 using baseline samples collected from 51 TP53 aberrant patients treated with ibrutinib in a phase II study (NCT01500733). Results: We identified TP53 mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit TP53, respectively. The multi-hit TP53 subgroup was enriched with younger patients who had prior treatments and unmutated immunoglobulin heavy-chain variable region gene status. We observed significantly shorter overall survival, progression-free survival (PFS), and time-to-progression (TTP) in patients with multi-hit TP53 compared with those with single-hit TP53. Clinical outcomes were similar in patient subgroups stratified by 2 or >2 TP53 aberrations. In multivariable analyses, multi-hit TP53 CLL was independently associated with inferior PFS and TTP. In sensitivity analyses, excluding mutations below 1% VAF demonstrated similar outcome. Results were validated in an independent population-based cohort of 112 patients with CLL treated with ibrutinib. Conclusions: In this study, single-hit TP53 defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit TP53 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit TP53 CLL. See related commentary by Bomben et al., p. 4462

The present study aimed to investigate the long-term quality of life (QoL) in a large sample of pediatric obsessive–compulsive disorder (OCD) patients. The study included 220 pediatric OCD patients from the Nordic Long-term OCD Treatment Study (NordLOTS) who were evaluated at seven time points before, during, and after stepped-care treatment over a 3-year follow-up period. Data from three symptom severity trajectory classes formed the basis of the QoL evaluation: acute (n = 127, N = 147), slow (n = 46, N = 63), and limited responders (n = 47, N = 59). Patients’ QoL was assessed using parent and child ratings of the revised Questionnaire for Measuring Health-related Quality of Life in Children and Adolescents (KINDL-R). QoL was analyzed by trajectory class using a random mixed effects model. The association between pre-treatment factors and long-term QoL was investigated across classes in a multivariate model. Three years after treatment, the acute responder class had reached QoL levels from a general population, whereas the limited responder class had not. The slow responder class reached norm levels for the child-rated QoL only. Higher levels of co-occurring externalizing symptoms before treatment were associated with lower parent-rated QoL during follow-up, while adolescence and higher levels of co-occurring internalizing symptoms were associated with lower child-rated QoL during follow-up. For some patients, residual OCD symptoms in the years after treatment, even at levels below assumed clinical significance, are associated with compromised QoL. Co-occurring symptoms could be part of the explanation. Assessing QoL after OCD treatment, beyond the clinician-rated symptom severity, could detect patients in need of further treatment and/or assessment. Trial registry: Nordic Long-term Obsessive–Compulsive Disorder (OCD) Treatment Study; www.controlled-trials.com ; ISRCTN66385119.

Background Data on long-term cardiovascular outcomes in systemic lupus erythematosus (SLE) are sparse. Objectives This study sought to examine the long-term risk and prognosis associated with cardiovascular outcomes, including heart failure (HF), in patients with SLE. Methods Using Danish administrative registries, risks of outcomes were compared between SLE patients (diagnosed 1996 to 2018, no history of cardiovascular disease) and age-, sex-, and comorbidity-matched control subjects from the background population (matched 1:4). Furthermore, mortality following HF diagnosis was compared between SLE patients developing HF and age- and sex-matched non-SLE control subjects with HF (matched 1:4). Results A total of 3,411 SLE patients (median age: 44.6 years [25th to 75th percentile: 31.9 to 57.0 years]; 14.1% men) were matched with 13,644 control subjects. The median follow-up was 8.5 years (25th to 75th percentile: 4.0 to 14.4 years). Absolute 10-year risks of outcomes were: HF, 3.71% (95% confidence interval [CI]: 3.02% to 4.51%) for SLE patients, 1.94% (95% CI: 1.68% to 2.24%) for control subjects; atrial fibrillation, 4.35% (95% CI: 3.61% to 5.18%) for SLE patients, 2.82% (95% CI: 2.50% to 3.16%) for control subjects; ischemic stroke, 3.75% (95% CI: 3.06% to 4.54%) for SLE patients, 1.92% (95% CI: 1.66% to 2.20%) for control subjects; myocardial infarction, 2.17% (95% CI: 1.66% to 2.80%) for SLE patients, 1.49% (95% CI: 1.26% to 1.75%) for control subjects; venous thromboembolism, 6.03% (95% CI: 5.17% to 6.98%) for SLE patients, 1.68% (95% CI: 1.44% to 1.95%) for control subjects; and the composite of implantable cardioverter-defibrillator implantation/ventricular arrhythmias/cardiac arrest, 0.89% (95% CI: 0.58% to 1.31%) for SLE patients, 0.30% (95% CI: 0.20% to 0.43%) for control subjects. SLE with subsequent HF was associated with higher mortality compared with HF without SLE (adjusted hazard ratio: 1.50; 95% CI: 1.08 to 2.08). Conclusions SLE patients had a higher associated risk of HF and other cardiovascular outcomes compared with matched control subjects. Among patients developing HF, a history of SLE was associated with higher mortality.

BACKGROUND AND AIM: Venous thromboembolism (VTE) is associated with excess mortality and morbidity in cancer, and is influenced by patient-, tumor-, and treatment-related factors. We aimed to investigate the impact of such factors in a national cohort of patients with epithelial ovarian cancer (EOC).METHODS: Patients in the Danish Gynecologic Cancer Database (DGCD) with EOC from 2005 to 2014 were followed from time of diagnosis to VTE, or censoring. Surgery, chemotherapy, and vascular epithelial growth factor (VEGF)-inhibitors were included as time-varying exposures in Cox proportional hazard regression models.RESULTS: A total of 551 VTE events were registered in 4991 EOC patients. Median follow-up time was 2.9 years. The 2-year cumulative incidence of VTE was 7.2%. Patients were at highest risk during the first year after EOC diagnosis. Previous VTE was associated with a hazard ratio (HR) of 3.26 (95% confidence interval [CI] 2.42-4.39). Exposure to major pelvic surgery was associated with a HR of 3.21 (95% CI 2.29-4.50). Exposure to chemotherapy or (VEGF)-inhibitors were associated with HRs of 1.91 (95% CI 1.56-2.33) and 1.05 (95% CI 0.57-1.93), respectively. Hazard ratios for patients with clear cell histopathology was 1.46 (95% CI 0.97-2.20) and 2.42 for International Federation of Gynaecology and Obstetrics stage III--IV (95% CI 1.93-3.03).CONCLUSIONS: EOC is associated with a high risk of VTE, particularly within the first year after diagnosis. Major pelvic surgery and chemotherapy were strongly associated with VTE. Person-related risk factors were increasing age and previous VTE. Advanced stage was an independent tumor-related risk factor. These findings support the indication for thrombosis prophylaxis during chemotherapy.

Bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory properties; however, the effects on diabetic wound healing remain poorly understood. The wound healing potential of LFcinB was investigated with in vitro, ex vivo, and in vivo models. Cell migration and proliferation were tested on keratinocytes and on porcine ears. A type 1 diabetic mouse model was also used to evaluate wound healing kinetics, bacterial diversity patterns, and the effect of LFcinB on oxidative stress, macrophage phenotype, angiogenesis, and collagen deposition. LFcinB increased keratinocyte migration in vitro (p < 0.05) and ex vivo (p < 0.001) and improved wound healing in diabetic mice (p < 0.05), though not in normoglycemic control mice. In diabetic mouse wounds, LFcinB treatment led to the eradication of Bacillus pumilus, a decrease in Staphylococcus aureus, and an increase in the Staphylococcus xylosus prevalence. LFcinB increased angiogenesis in diabetic mice (p < 0.01), but this was decreased in control mice (p < 0.05). LFcinB improved collagen deposition in both diabetic and control mice (p < 0.05). Both oxidative stress and the M1-to-M2 macrophage ratios were decreased in LFcinB-treated wounds of diabetic animals (p < 0.001 and p < 0.05, respectively) compared with saline, suggesting a downregulation of inflammation in diabetic wounds. In conclusion, LFcinB treatment demonstrated noticeable positive effects on diabetic wound healing., Graphical Abstract, Topical delivery of bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory actions and improves wound closure and changes the bacterial diversity of diabetic wounds. Hallmarks of diabetic wound healing impairments like inflammation, oxidative stress, disrupted angiogenesis, and collagen deposition improved by LFcinB indicate its therapeutic potential.

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

Aims Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out-of-hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA-risk of opioids in the community. Methods We conducted 2 population-based case–control studies separately in the Netherlands (2009–2018) and Denmark (2001–2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non-OHCA-controls according to age, sex and OHCA-date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results We included 5473 OHCA-cases matched with 21 866 non-OHCA-controls in the Netherlands, and 35 017 OHCA-cases matched with 175 085 non-OHCA-controls in Denmark. We found that use of opioids (the Netherlands: cases: 5.4%, controls: 1.8%; Denmark: cases: 11.9%, controls: 4.4%) was associated with increased OHCA-risk in both regions (the Netherlands: OR 2.1 [95% CI 1.8–2.5]; Denmark: OR 1.8 [95% CI 1.5–2.1]). The association was observed in both sexes, and in individuals with cardiovascular disease (the Netherlands: OR 1.8 [95% CI 1.5–2.1]; Denmark: OR 1.6 [95% CI 1.5–1.7]) or without (the Netherlands: OR 3.4 [95% CI: 2.4–4.8],PinteractionPinteraction Conclusion Use of opioids is associated with increased OHCA-risk in both sexes, independently of concomitant cardiovascular disease. These findings should be considered when evaluating the harms and benefits of treatment with opioids.

BACKGROUND: Bleeding safety in relation to use of systemic fluconazole and topical azoles among patients with atrial fibrillation treated with apixaban, rivaroxaban, or dabigatran is insufficiently explored, despite clinical relevance and several reports suggesting associations.METHODS: Using nationwide Danish registers, we identified patients with atrial fibrillation initiated on apixaban, rivaroxaban, or dabigatran from 2012-2018. We investigated associations between bleeding incidents and systemic fluconazole or topical azole treatment using a case-crossover design with 30-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI).RESULTS: We included 32,340 (36%), 32,409 (36%), and 24,940 (28%) patients initiated on apixaban, rivaroxaban, and dabigatran, respectively. Patients on apixaban were older (median age: 77 years; interquartile range [IQR] 70-84) compared with rivaroxaban users (median age: 75 years; IQR 68-82) and patients on dabigatran (median age: 73 years; IQR 66-80). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found among rivaroxaban and dabigatran users: ORs of 0.9 (95% CI, 0.2-3.0) and 1.7 (95% CI, 0.5-5.6), respectively. As to bleeding risk pertaining to topical azole exposure among apixaban, rivaroxaban, and dabigatran users, no association was found, with corresponding ORs of 0.8 (95% CI, 0.5-1.3); 1.3 (95% CI, 0.9-2.1); and 1.2 (95% CI 0.8-1.8), respectively.CONCLUSION: In patients with atrial fibrillation on either apixaban, rivaroxaban, or dabigatran, an association between an elevated bleeding risk and use of systemic fluconazole was found among patients on apixaban. We found no increased risk of bleeding following co-exposure to topical azoles.

Objectives: Antibodies to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are a key factor in protecting against coronavirus disease 2019 (COVID-19). We examined longitudinal changes in seroprevalence in healthcare workers (HCWs) in Copenhagen and the protective effect of antibodies against SARS-CoV-2. Methods: In this prospective study, screening for antibodies against SARS-CoV-2 (ELISA) was offered to HCWs three times over 6 months. HCW characteristics were obtained by questionnaires. The study was registered at ClinicalTrials.gov, NCT04346186. Results: From April to October 2020 we screened 44 698 HCWs, of whom 2811 were seropositive at least once. The seroprevalence increased from 4.0% (1501/37 452) to 7.4% (2022/27 457) during the period (p < 0.001) and was significantly higher than in non-HCWs. Frontline HCWs had a significantly increased risk of seropositivity compared to non-frontline HCWs, with risk ratios (RRs) at the three rounds of 1.49 (95%CI 1.34–1.65, p < 0.001), 1.52 (1.39–1.68, p < 0.001) and 1.50 (1.38–1.64, p < 0.001). The seroprevalence was 1.42- to 2.25-fold higher (p < 0.001) in HCWs from dedicated COVID-19 wards than in other frontline HCWs. Seropositive HCWs had an RR of 0.35 (0.15–0.85, p 0.012) of reinfection during the following 6 months, and 2115 out of 2248 (95%) of those who were seropositive during rounds one or two remained seropositive after 4–6 months. The 133 of 2248 participants (5.0%) who seroreverted were slightly older and reported fewer symptoms than other seropositive participants. Conclusions: HCWs remained at increased risk of infection with SARS-CoV-2 during the 6-month period. Seropositivity against SARS-CoV-2 persisted for at least 6 months in the vast majority of HCWs and was associated with a significantly lower risk of reinfection.

Aims We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in stable, optimally treated myocardial infarction (MI) patients without heart failure (HF). Methods and results Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive, free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differences (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26% sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age 61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD (95% confidence intervals)] correspondingly; 0.1% (−0.3% to 0.5%), 0.2% (−0.7% to 1.2%), and 1.2% (−0.2% to 2.7%). Conclusions In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.

As a result of globalization, high investment volume in infrastructure projects, and more use of standardization, foreign construction companies are establishing in Norway. The purpose of this paper is to explore the risks of involving foreign contractors and developing suggestions for future projects. In addition to a literature review, two Norwegian bridge projects built by Chines International Contractors studied through a document study and semi-structured interviews with key personnel. The key personnel is from a public project owner, two Chinese construction companies, and subcontractors involved in the two case projects. Some of the risks identified are language barriers, weather conditions, difficulty in managing subcontractors, and different perceptions of safety levels. In the future, project owners should consider preparing the contract documents, handbooks, and standards in both Norwegian and English. If the language risk is managed properly, it influences the other risks as well. Cross projects experience sharing will also help in identifying risks early and taking mitigation measures.

Objectives To estimate the incidence of COVID-19 hospitalization in patients with inflammatory rheumatic disease (IRD); in patients with RA treated with specific DMARDs; and the incidence of severe COVID-19 infection among hospitalized patients with RA. Methods A nationwide cohort study from Denmark between 1 March and 12 August 2020. The adjusted incidence of COVID-19 hospitalization was estimated for patients with RA; spondyloarthritis including psoriatic arthritis; connective tissue disease; vasculitides; and non-IRD individuals. Further, the incidence of COVID-19 hospitalization was estimated for patients with RA treated and non-treated with TNF-inhibitors, HCQ or glucocorticoids, respectively. Lastly, the incidence of severe COVID-19 infection (intensive care, acute respiratory distress syndrome or death) among hospital-admitted patients was estimated for RA and non-IRD sp - individudals. Results Patients with IRD (n = 58 052) had an increased partially adjusted incidence of hospitalization with COVID-19 compared with the 4.5 million people in the general population [hazard ratio (HR) 1.46, 95% CI: 1.15, 1.86] with strongest associations for patients with RA (n = 29 440, HR 1.72, 95% CI: 1.29, 2.30) and vasculitides (n = 4072, HR 1.82, 95% CI: 0.91, 3.64). There was no increased incidence of COVID-19 hospitalization associated with TNF-inhibitor, HCQ nor glucocorticoid use. COVID-19 admitted patients with RA had a HR of 1.43 (95% CI: 0.80, 2.53) for a severe outcome. Conclusion Patients with IRD were more likely to be admitted with COVID-19 than the general population, and COVID-19 admitted patients with RA could be at higher risk of a severe outcome. Treatment with specific DMARDs did not affect the risk of hospitalization.

The opioid crisis in the USA makes it very likely that a large number of patients who are opioid-dependent will require surgical procedures. Perioperative pain control in those patients poses a formidable challenge to the surgical and anesthesia care team. Previously, patients received only additional opioids to cover the postoperative pain and would then be referred back to their primary care physician with often escalation of opioid dosing. Various strategies and recommendations to help with postoperative pain control in these challenging situations are available and can be applied successfully in various ambulatory and hospital settings. Opioid-dependent patients presenting for surgery will challenge a health care system to provide optimal patient care, requiring close communication among the surgical team, anesthesiologists, referring physicians, and pain specialists. Regional anesthesia and multimodal analgesia are best suited to reduce or possibly avoid opioids altogether. Surgery location and monitoring may need to be adapted from standard care according to the chronic pain therapy and the presence of opioid use disorder (OUD). The preoperative visit is the most important time with the patient to set goals and expectations as well as developing a strategy for perioperative pain control.

Background Glioblastomas (GBMs) are known for having a vastly heterogenous histopathology. Several studies have shown that GBMs can be histologically undergraded due to sampling errors of small tissue samples. We sought to explore to what extent histological features in GBMs are dependent on the amount of viable tissue on routine slides from both biopsied and resected tumors. Methods In 106 newly diagnosed GBM patients, we investigated associations between the presence or degree of 24 histopathological and two immunohistochemical features and the tissue amount on hematoxylin-eosin (HE) slides. The amount of viable tissue was semiquantitatively categorized as “sparse,” “medium,” or “substantial” for each case. Tissue amount was also assessed for associations with MRI volumetrics and the type of surgical procedure. Results About half (46%) of the assessed histological and immunohistochemical features were significantly associated with tissue amount. The significant features were less present or of a lesser degree when the tissue amount was smaller. Among the significant features were most of the features relevant for diffuse astrocytic tumor grading, i.e., small necroses, palisades, microvascular proliferation, atypia, mitotic count, and Ki-67/MIB-1 proliferative index (PI). Conclusion A substantial proportion of the assessed histological features were at risk of being underrepresented when the amount of viable tissue on HE slides was limited. Most of the grading features were dependent on tissue amount, which underlines the importance of considering sampling errors in diffuse astrocytic tumor grading. Our findings also highlight the importance of adequate tissue collection to increase the quality of diagnostics and histological research.

Background During awake craniotomy, securing the patient's airway might be necessary electively or emergently. The objective of this study was to compare the feasibility of airway management using a laryngeal mask airway (LMA) and 4 alternative airway management techniques in an awake craniotomy simulation. Methods After completing a questionnaire, 9 anesthesia providers attempted airway management in a cadaver positioned to simulate awake craniotomy conditions. Following the simulation, participants rated and ranked the devices in their order of preference. Results Only 3 approaches resulted in the successful securement of an airway device for 100% of participants: LMA (median; interquartile range time to secure the airway 6 s, 5 to 10 s), fiberoptic bronchoscopy through an LMA (41 s; 23 to 51 s), and video laryngoscopy (49 s; 43 to 127 s). In contrast, the oral and nasal fiberoptic approaches demonstrated only 44.4% (154.5 s; 134.25 to 182 s) and 55.6% (75 s; 50 to 117 s) success rates, respectively. The LMA was the fastest and most reliable primary method to secure the airway (P=0.001). After the simulation, 100% of participants reported that an LMA would be their first choice for emergency airway management, followed by fiberoptic intubation through the LMA (7 of 9 participants) if the LMA failed to properly seat. Conclusions We demonstrated that an LMA was the fastest and most reliable primary method to secure an airway in a laterally positioned cadaver with 3-pin skull fixation. Fiberoptic and video laryngoscope airway equipment should be readily available during awake craniotomy procedures, and an attempt to visualize the vocal cords through the LMA should be attempted before removing it for alternative techniques.

Background: Pneumonia and influenza are major health concerns and constitute a high economic burden. However, few data are available on the associated risk of pneumonia and influenza and work exposure on a large population scale. Aim: This study aimed to examine the associated risk of pneumonia and influenza by type of work exposure. Methods: By cross-linking administrative Danish registries, we classified people in 10 different profession types. The main outcome was hospitalisation with pneumonia or influenza. A multivariable Poisson regression analysis was used to assess the associated incidence rate ratio (IRR) of being hospitalised with pneumonia or influenza by type of profession. Results: A total of 1,327,606 people added risk time to the analyses. In a multivariable model, work in day care, public transportation, sewers and nursing home care was associated with an increased risk of hospitalisation with pneumonia compared to work within public administration: IRR=1.20 (95% confidence interval (CI) 1.12–1.28), IRR=1.21 (95% CI 1.09–1.34), IRR=1.61 (95% CI 1.19–2.19) and IRR=1.10 (95% CI 1.03–1.18), respectively. In a multivariable analysis, people working within public transportation were associated with an increased risk of hospitalisation with influenza compared to people working within public administration: IRR=2.54 (95% CI 1.79–3.58). Conclusions: Working in day care, public transportation, sewers and nursing home care increased the associated risk of hospitalisation with pneumonia, and working within public transportation increased the associated risk of being hospitalised with influenza compared to working within public administration.

Despite the long-term renoprotective effects of Metformin, a recent study on data from the U.S. Food and Drug Administration reported a possible nephrotoxic effect, contributing to the development of acute kidney injury (AKI). We investigated the association between metformin and AKI in patients admitted with the AKI-prone condition of acute infection and compared results with corresponding results of other antidiabetics. In a nationwide register-based case–control study, we identified Danish patients with type 2 diabetes hospitalized with acute infection between 2008 and 2018. Cases of AKI had an increase in plasma creatinine ≥ × 1.5 during admission, controls did not. Antidiabetics were identified up to 6 months before admission. Odds ratio (OR) of each antidiabetic was computed in separate multiple logistic regression models adjusted for relevant medication and comorbidities and results compared. We included 46,811 patients, hereof 9454 AKIs (20%) and 2186 (4.7%) severe AKIs. Overall, 56% were males, median age (IQR) was 73 (65–81). Sixty percent received metformin, 13% sulfonylurea, 31% insulin and 8% dipeptidyl peptidase-4 inhibitors (DPP-4i), with equal distribution between cases and controls. Metformin was associated with increased OR (CI) for AKI, 1.07 (1.02–1.12), equally to sulfonylurea, 1.10 (1.03–1.18) and DPP-4i, 1.11 (1.02–1.20), but not insulin, 0.99 (0.93–1.05). In severe AKI, results for metformin were 1.27 (1.25–1.40) but increased equivalently to other antidiabetics. In patients with type 2 diabetes hospitalized with acute infection, metformin was not independently associated with AKI, since other antidiabetics were also significantly associated, indicating confounding by indication.

Hypertension, cardiovascular diseases, and cerebrovascular diseases are associated with an increased risk of depression, but it remains unclear whether treatment with antihypertensive agents decreases or increases this risk. The effects of individual drugs are also unknown. We used Danish population-based registers to systematically investigate whether the 41 most used individual antihypertensive drugs were associated with an altered risk of incident depression. Analyses of diuretics were included for comparisons. Participants were included in the study in January 2005 and followed until December 2015. Two different outcome measures were included: (1) a diagnosis of depressive disorder at a psychiatric hospital as an inpatient or outpatient and (2) a combined measure of a diagnosis of depression or use of antidepressants. Continued use of classes of angiotensin agents, calcium antagonists, and β-blockers was associated with significantly decreased rates of depression, whereas diuretic use was not. Individual drugs associated with decreased depression included 2 of 16 angiotensin agents: enalapril and ramipril; 3 of 10 calcium antagonists: amlodipine, verapamil, and verapamil combinations; and 4 of 15 β-blockers: propranolol, atenolol, bisoprolol, and carvedilol. No drug was associated with an increased risk of depression. In conclusion, real-life population-based data suggest a positive effect of continued use of 9 individual antihypertensive agents. This evidence should be used in guiding prescriptions for patients at risk of developing depression including those with prior depression or anxiety and patients with a family history of depression.

Background: Biventricular (BiV) pacing increases transmural repolarization heterogeneity due to epicardial to endocardial conduction from the left ventricular (LV) lead. However, limited evidence is available on concomitant changes in ventricular depolarization and repolarization and long-term outcomes of BiV pacing. Therefore, we investigated associations of BiV pacing-induced concomitant changes in ventricular depolarization and repolarization with mortality (i.e., LV assist device, heart transplantation, or all-cause mortality) and sustained ventricular arrhythmia endpoints. Methods: Consecutive BiV-defibrillator recipients with digital preimplantation and postimplantation electrocardiograms recorded between 2006 and 2015 at Duke University Medical Center were included. We calculated changes in QRS duration and corrected JT (JTc) interval and split them by median values. For simplicity, these variables were named QRS decreased (≤ −12 ms), QRS increased (> –12 ms), JTc decreased (≤22 ms), and JTc increased (> 22 ms) and subsequently used to construct four mutually exclusive groups. Results: We included 528 patients (median age, 68 years; male, 69%). No correlation between changes in QRS duration and JTc interval was observed (P =.295). Compared to QRS decreased/JTc increased, increased risk of the composite mortality endpoint was associated with QRS decreased/JTc decreased (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.09-2.43), QRS increased/JTc decreased (HR = 1.86; 95% CI = 1.27-2.71), and QRS increased/JTc increased (HR = 2.25; 95% CI = 1.52-3.35). No QRS/JTc group was associated with excess sustained ventricular arrhythmia risk (P =.400). Conclusion: Among BiV-defibrillator recipients, QRS decreased/JTc increased was associated with the most favorable long-term survival free of LV assist device, heart transplantation, and sustained ventricular arrhythmias. Our findings suggest that improved electrical resynchronization may be achieved by assessing concomitant changes in ventricular depolarization and repolarization.

Landscape of somatic copy number alterations, mutations, and fusions in selected genes in newly diagnosed glioblastoma patients. The most frequent aberrations occurred in PTEN, CDKN2A/B, EGFR, RB1, and NPAS3, and the most frequent mutations were in PTEN, TP53, NF1, RB1, and EGFR. One NTRK2 fusion and three FGFR3‐TACC3 fusions were identified., Glioblastoma (GBM) is an incurable brain tumor for which new treatment strategies are urgently needed. Next‐generation sequencing of GBM has most often been performed retrospectively and on archival tissue from both diagnostic and relapse surgeries with limited knowledge of clinical information, including treatment given. We sought to investigate the genomic composition prospectively in treatment‐naïve patients, searched for possible targetable aberrations, and investigated for prognostic and/or predictive factors. A total of 108 newly diagnosed GBM patients were included. Clinical information, progression‐free survival, and overall survival (OS) were noted. Tissues were analyzed by whole‐exome sequencing, single nucleotide polymorphism (SNP) and transcriptome arrays, and RNA sequencing; assessed for mutations, fusions, tumor mutational burden (TMB), and chromosomal instability (CI); and classified into GBM subgroups. Each genomic report was discussed at a multidisciplinary tumor board meeting to evaluate for matching trials. From 111 consecutive patients, 97.3% accepted inclusion in this study. Eighty‐six (77%) were treated with radiation therapy/temozolomide (TMZ) and adjuvant TMZ. One NTRK2 and three FGFR3‐TACC3 fusions were identified. Copy number alterations in GRB2 and SMYD4 were significantly correlated with worse median OS together with known clinical variables like age, performance status, steroid dose, and O6‐methyl‐guanine‐DNA‐methyl‐transferase status. Patients with CI‐median or TMB‐high had significantly worse median OS compared to CI‐low/high or TMB‐low/median. In conclusion, performing genomic profiling at diagnosis enables evaluation of genomic‐driven therapy at the first progression. Furthermore, TMB‐high or CI‐median patients had worse median OS, which can support the possibility of offering experimental treatment already at the first line for this group.

Background Cholecystitis before cholecystectomy may increase risk of cancers in the hepato-pancreato-biliary area. Methods A population-based cohort study of all patients undergoing cholecystectomy in Denmark during 1996–2015, using nationwide healthcare registries. We retrieved information on cholecystitis within two years before the date of surgery and information on pancreatic cancer, hepatocellular carcinoma (HCC), and biliary tract cancer. We examined cancer risk using a Cox model to calculate the hazard ratios (HRs). We also computed cumulative incidence functions with 95% CIs, comparing patients with and without cholecystitis before cholecystectomy. Results We included 132,794 patients, of which 73.0% were women. In the first five years of follow-up, we observed an increased risk of biliary tract cancer, but not pancreatic cancer or HCC, in patients with prior cholecystitis. After more than five years of follow-up, patients with prior cholecystitis had an increased risk of pancreatic cancer (adjusted HR: 1.26; 95% CI: 0.98–1.63) and possibly biliary tract cancer (adjusted HR: 1.33; 95% CI: 0.64–2.77). Long-term risk of HCC was decreased in patients with prior cholecystitis. For all cancers, the 20-year absolute risks were less than 1%. Conclusion In patients undergoing cholecystectomy, prior cholecystitis was associated with increased risk of pancreatic and possibly biliary tract cancer.

Background: Research regarding out-of-hospital cardiac arrest (OHCA) survival of diabetes patients is sparse and it remains unknown whether initiatives to increase OHCA survival benefit diabetes and non-diabetes patients equally. We therefore examined overall and temporal survival in diabetes and non-diabetes patients following OHCA. Methods: Adult presumed cardiac-caused OHCAs were identified from the Danish Cardiac Arrest Registry (2001–2014). Associations between diabetes and return of spontaneous circulation upon hospital arrival and 30-day survival were estimated with logistic regression adjusted for patient- and OHCA-related characteristics. Results: In total, 28,955 OHCAs were included of which 4276 (14.8%) had diabetes. Compared with non-diabetes patients, diabetes patients had more comorbidities, same prevalence of bystander-witnessed arrests (51.7% vs. 52.7%) and bystander cardiopulmonary resuscitation (43.2% vs. 42.0%), more arrests in residential locations (77.3% vs. 73.0%) and were less likely to have shockable heart rhythm (23.5% vs. 27.9%). Temporal increases in return of spontaneous circulation and 30-day survival were seen for both groups (return of spontaneous circulation: 8.8% in 2001 to 22.3% in 2014 (diabetes patients) vs. 7.8% in 2001 to 25.7% in 2014 (non-diabetes patients); and 30-day survival: 2.8% in 2001 to 9.7% in 2014 vs. 3.5% to 14.8% in 2014, respectively). In adjusted models, diabetes was associated with decreased odds of return of spontaneous circulation (odds ratio 0.74 (95% confidence interval 0.66–0.82)) and 30-day survival (odds ratio 0.56 (95% confidence interval 0.48–0.65)) (interaction with calendar year p=0.434 and p=0.243, respectively). Conclusion: No significant difference in temporal survival was found between the two groups. However, diabetes was associated with lower odds of return of spontaneous circulation and 30-day survival.

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

Background Infective endocarditis (IE) is associated with high mortality. Surgery may improve survival and reduce complications, but the balance between benefit and harm is difficult and may be closely related to age and type of surgical intervention. We aimed to examine how age and type of left-sided surgical intervention modified mortality in patients undergoing surgery for IE. Methods By crosslinking nationwide Danish registries we identified patients with first-time IE undergoing surgical treatment 2000–2017. Patients were grouped by age Results We included 1767 patients with IE undergoing surgery, 735 patients 75 years, respectively. Mortality at 90 days were 7.5, 13.9, and 22.3% (p Conclusions In patients undergoing surgery for IE, mortality increased significantly with age and 1 in 5 died above age 75 years. Mitral valve surgery as well as multiple valve interventions augmented mortality further.

Introduction: Colonoscopy adverse events (AEs) are commonly underreported and standardised reporting is rarely used. We aimed to investigate AEs associated with colonoscopy in a real world setting, using the American Society of Gastrointestinal Endoscopy (ASGE) lexicon. Methods: This retrospective cohort study of AEs related to outpatient colonoscopies performed in the North Denmark Region from 2015 to 2018 identified AEs from readmission within eight days or death within 30 days of colonoscopy. AEs were investigated in electronic health records and categorised, attributed and graded according to the ASGE lexicon. Results: Of 49,445 colonoscopies performed, 1141 were potentially associated with AEs (23.07‰). Electronic health record review left 489 AEs attributed to colonoscopy (9.9‰); categorised as cardiovascular (0.65‰), pulmonary (0.36‰), thromboembolic (0.10‰), instrumental incl. perforations (0.99‰), bleeding (3.07‰), infection (0.87‰), drug reactions (0.04‰), pain (2.00‰), integument (damage to skin/bones) (0.34‰) and other (1.62‰) AEs. Ten (0.20‰) AEs were fatal, but only one was procedure related (perforation). All shearing force perforations occurred in the sigmoid colon. Most polypectomy perforations occurred in the caecum (60%). Conclusions: Colonoscopy carries important procedure and non-procedure related risks. Non-procedure related AEs are likely underreported. Better attention to patients with pre-existing diseases and further colonoscopist training may lower AE rates. A standardised colonoscopy AE reporting system is warranted.

O6-methylguanine DNA methyltransferase (MGMT) promoter methylation is an important favorable predictive marker in patients with glioblastoma (GBM). We hypothesized that MGMT status could be a surrogate marker of pretreatment tumor biology observed as histopathological and radiological features. Apart from some radiological studies aiming to noninvasively predict the MGMT status, few studies have investigated relationships between MGMT status and phenotypical tumor biology. We have therefore aimed to investigate such relationships in 85 isocitrate dehydrogenase (IDH) wild-type GBMs. MGMT status was determined by methylation-specific PCR and was assessed for associations with 22 histopathological features, immunohistochemical proliferative index and microvessel density measurements, conventional magnetic resonance imaging characteristics, preoperative speed of tumor growth, and overall survival. None of the investigated histological or radiological features were significantly associated with MGMT status. Methylated MGMT status was a significant independent predictor of improved overall survival. In conclusion, our results suggest that MGMT status is not related to the pretreatment phenotypical biology in IDH wild-type GBMs. Furthermore, our findings suggest the survival benefit of MGMT methylated GBMs is not due to an inherently less aggressive tumor biology, and that conventional magnetic resonance imaging features cannot be used to noninvasively predict the MGMT status. VC 2020 American Association of Neuropathologists, Inc. 855 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Background Infective endocarditis (IE) may be complicated by acute kidney injury, yet data on the use of dialysis and subsequent reversibility are sparse. Methods Using Danish nationwide registries, we identified patients with first-time IE from 2000 to 2017. Dialysis-naïve patients were grouped into: those with and those without dialysis during admission with IE. Continuation of dialysis was followed 1 year postdischarge. Multivariable adjusted Cox proportional hazard analysis was used to examine 1-year mortality for patients surviving IE according to use of dialysis. Results We included 7307 patients with IE; 416 patients (5.7%) initiated dialysis treatment during admission with IE and these were younger, had more comorbidities and more often underwent cardiac valve surgery compared with nondialysis patients (47.4% vs 20.9%). In patients with both cardiac valve surgery and dialysis treatment (n = 197), 153 (77.7%) initiated dialysis on or after the date of surgery. The in-hospital mortality was 40.4% and 19.0% for patients with and without dialysis, respectively (P Conclusion In dialysis-naïve patients with IE, approximately 1 in 20 patients initiated dialysis treatment during admission with IE. Dialysis identified a high-risk group with an in-hospital mortality of 40% and an approximate 20% risk of continued dialysis. Those with dialysis during admission with IE showed worse long-term outcomes than those without.

The promotion of creativity in team ball sports has captured the interest of many researchers and practitioners, but no studies have explored how coaches perceive and apply creativity-nurturing activities. The purpose of this study was to examine the personal and cultural conditions that enable or obstruct the design and application of creativity exercises (CE) to facilitate elite youth soccer players’ exploration of novel action potentials during soccer training. This examination was conducted in an action research (AR) process where a researcher and a soccer coach applied a selection of creativity concepts as tools to experiment with when designing new CEs. The data comprised audio recordings of design meetings and video observations of practice experiments during AR cycles. Further, the researcher used freewriting to reflect on the process and the coach participated in a semi-structured interview. Thematic analysis showed that facilitation of creativity was envisioned to foster curios, sovereign, de-robotized, playful, and process-oriented players with unique trademarks. However, many ideas were rejected due to beliefs about quality coaching, demands for transferable situations and solutions, and the coach’s conception of creativity. While some ideas were incompatible with established practice, others were rejected since they were perceived to involve unrealistic situations and match-irrelevant solutions. Moreover, the soccer-specific curriculum and match preparation in a tight tournament program left little time to diverge, and the pressure to perform intensified the demand for quality coaching when facing bad results. Avenues for future research are outlined by discussing conceptual, pedagogical, cultural, and political tensions in the results. Lay summary: This study identifies several potentials for conducting creativity exercises during which the players solve novel challenges and explore solutions they do not usually try during training. However, result orientation and traditional views of quality coaching may limit what is seen as appropriate and therefore limit the exploitations of these potentials.Implications for practice Portrays several creativity exercises and outlines principles for designing new ones. Provides resources to interrogate own and others’ beliefs about creativity and its development. Offers key arguments and considerations for coaches who wish to promote creativity.

OBJECTIVE Recent influenza infection is associated with an increased risk of atherothrombotic events, including acute myocardial infarction (AMI) and stroke. Little is known about the association between influenza vaccination and cardiovascular outcomes in patients with diabetes. RESEARCH DESIGN AND METHODS We used nationwide register data to identify patients with diabetes in Denmark during nine consecutive influenza seasons in the period 2007–2016. Diabetes was defined as use of glucose-lowering medication. Patients who were not 18–100 years old or had ischemic heart disease, heart failure, chronic obstructive lung disease, cancer, or cerebrovascular disease were excluded. Patient exposure to influenza vaccination was assessed before each influenza season. We considered the outcomes of death from all causes, death from cardiovascular causes, and death from AMI or stroke. For each season, patients were monitored from December 1 until April 1 the next year. RESULTS A total of 241,551 patients were monitored for a median of four seasons (interquartile range two to eight seasons) for a total follow-up of 425,318 person-years. The vaccine coverage during study seasons ranged from 24% to 36%. During follow-up, 8,207 patients died of all causes (3.4%), 4,127 patients died of cardiovascular causes (1.7%), and 1,439 patients died of AMI/stroke (0.6%). After adjustment for confounders, vaccination was significantly associated with reduced risks of all-cause death (hazard ratio [HR] 0.83, P < 0.001), cardiovascular death (HR 0.84, P < 0.001), and death from AMI or stroke (HR 0.85, P = 0.028) and a reduced risk of being admitted to hospital with acute complications associated with diabetes (diabetic ketoacidosis, hypoglycemia, or coma) (HR 0.89, P = 0.006). CONCLUSIONS In patients with diabetes, influenza vaccination was associated with a reduced risk of all-cause death, cardiovascular death, and death from AMI or stroke. Influenza vaccination may improve outcome in patients with diabetes.