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Kasper Bruun Kristensen,1 Lars Christian Lund,1 Peter Bjødstrup Jensen,1 Anne Broe,1 Emelie Rotbain,2 Per Damkier,1,3,4 Anton Pottegård,1 Jacob Harbo Andersen,1 Mikkel Højlund,1,5 Morten Olesen,1 Lotte Rasmussen,1 Morten Rix Hansen,1,3,4 Martin Thomsen Ernst,1 Rikke Wesselhoeft,1,6 Daniel Pilsgaard Henriksen,3 Mette Reilev,1 Mette Bliddal,1,7 Jesper Hallas1 1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark; 6Child and Adolescent Psychiatry Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark; 7Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Jesper Hallas, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, Odense, 5000, Denmark, Tel +4565503010, Email jhallas@health.sdu.dkPurpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices.Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥ 40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables.Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883– 0.890) exceeded that of the CCI (0.871, 95% CI 0.868– 0.874) and ECI (0.866, 95% CI 0.863– 0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779– 0.784) to 0.838 (95% CI 0.834– 0.842).Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.Keywords: multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score

Background: Osteogenesis imperfecta (OI) is a rare hereditary disease mainly resulting in reduced or altered collagen type I. Collagen type I is a major constituent of the respiratory system, and normal collagen type I is vital for pulmonary tissue function., Research Question: Do patients with OI have increased admission rates resulting from pulmonary diseases compared with the general population?, Study Design and Methods: This was a register-based, nationwide cohort study, including all patients with OI in Denmark and a reference population. From January 1, 1995, through December 31, 2018, we evaluated the rates of admissions resulting from asthma, COPD, and pneumonia as well as the use of bronchodilator drugs and antibiotics comparing individuals with OI with the reference population., Results: We included 862 individuals with OI and 4,283 people from the reference population covering 15,952 and 79,471 person-years of observation, respectively, in the two cohorts. The admissions rate (incidence rate [IR]) was highest in women with OI 65 years of age or older, with 56.3 admissions per 1,000 person-years and 29.4 admissions per 1,000 person-years in the reference population (amounting to an admissions incident rate ratio [IRR] of 1.91 [95% CI, 1.38-2.70]). The highest admission rate in men with OI was found among participants 0 to 18 years of age, with an IR of 30.4 per 1,000 person-years compared with an IR of 7.7 per 1,000 person-years in the reference population (IRR, 4.92 [95% CI, 3.79-6.38]). We found a higher proportion of long-acting and short-acting bronchodilator drug users in the OI cohort, but no increased use of antibiotics., Interpretation: Overall, the admission rates for respiratory diseases were low in the OI cohort, but a higher relative risk of hospitalizations resulting from respiratory disease compared with the general population. Timely diagnosis and treatment of respiratory complications in individuals with OI is warranted., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of diabetes and coexisting multimorbidity rises worldwide. Treatment of this patient group can be complex. Providing an evidence-based, coherent, and patient-centred treatment of patients with multimorbidity poses a challenge in healthcare systems, which are typically designed to deliver disease-specific care. We propose an intervention comprising multidisciplinary team conferences (MDTs) to address this issue. The MDT consists of medical specialists in five different specialities meeting to discuss multimorbid diabetes patients. This protocol describes a feasibility test of MDTs designed to coordinate care and improve quality of life for people with diabetes and multimorbidity., Methods: A mixed-methods one-arm feasibility test of the MDT. Feasibility will be assessed through prospectively collected data. We will explore patient perspectives through patient-reported outcomes (PROs) and assess the feasibility of electronic questionnaires. Feasibility outcomes are recruitment, PRO completion, technical difficulties, impact of MDT, and doctor preparation time. During 17 months, up to 112 participants will be recruited. We will report results narratively and by the use of descriptive statistics. The collected data will form the basis for a future large-scale randomised trial., Discussion: A multidisciplinary approach focusing on better management of diabetic patients suffering from multimorbidity may improve functional status, quality of life, and health outcomes. Multimorbidity and diabetes are highly prevalent in our healthcare system, but we lack a solid evidence-based approach to patient-centred care for these patients. This study represents the initial steps towards building such evidence. The concept can be efficiency tested in a randomised setting, if found feasible to intervention providers and receivers. If not, we will have gained experience on how to manage diabetes and multimorbidity as well as organisational aspects, which together may generate hypotheses for research on how to handle multimorbidity in the future., Administrative Information: Protocol version: 01 TRIAL REGISTRATION: NCT05913726 - registration date: 21 June 2023., (© 2024. The Author(s).)

Purpose: Older people have the highest use of antibiotics for acute and chronic urinary tract infection (UTI), despite diagnostic uncertainty and the growing problem of antibiotic resistance. We aim to describe use-patterns of UTI antibiotics two years prior to and following care home admission in Denmark., Methods: This was a register-based nationwide drug-utilization study. In a cohort comprising all Danish residents admitted into a care home from 2015 to 2021, we described the use of UTI antibiotics, and examined differences between regions and individual care homes in rates of UTI antibiotic use. Further, we described trends in UTI-related contacts with hospitals in the two years prior to and following care home admission., Results: The cohort comprised 101,297 residents (61% female; median age 84 years). UTI antibiotic use doubled from 7 to 14 treatments/100 residents/month two months prior to care home admission and remained at 10 treatments/100 residents/month the following two years. Prescription of pivmecillinam (55%) was most common. Primary care practitioners prescribed the majority (92%) of UTI antibiotics. UTI-related hospital contacts peaked at two months prior to care home admission, with 6 admissions/100 residents/month, subsequently dropping to 2 admission/100 residents/month. We found considerable variation in UTI antibiotic use, with 10% of care homes responsible for 20% of treatments in 2021., Conclusion: Use of UTI antibiotics increased prior to and remained at a stable high level following care home admission in Denmark. Despite variation in use across regions and individual care homes, an overall decrease was seen throughout the years 2016-2021., (© 2024. The Author(s).)

Introduction: Out-of-hours primary care services cannot provide the same continuity and coordination of care as general practice. Thus, patients with high risk of complex care trajectories should, when possible, be treated by the general practitioner during daytime opening hours. This study aims to analyse the variation among general practices in the frequencies of daytime services for persons aged ≥75 years and how it relates to the patients' use of out-of-hours services., Methods and Analysis: Register-based cohort study of all Danish citizens aged ≥75 years, of whom >98% are listed with a general practice. Using Poisson regression, we will estimate each practice's excess variation in delivered daytime services compared with the expected based on the characteristics of its listed patients. Delivered daytime services will be analysed overall and separately for face-to-face, phone, email, home visit and preventive services. The association with the use of out-of-hours services will be analysed by Poisson regression., Ethics and Dissemination: Complying with European data protection rules, the legal services at University of Southern Denmark (Research & Innovation Organisation) approved the data processing activities regarding this project (journal number 11.593). According to section 14.2 of the Act on Research Ethics Review of Health Research Projects, because the study is based solely on register data, approval from the ethics committee and informed consent are not required. Results from the study will be disseminated as publications in peer-reviewed scientific journals and at international conferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gabapentin and pregabalin have been associated with an increased risk of fragility fractures. Due to differences in pharmacokinetics, we aimed to assess the fracture-risk difference between the two medicines. We performed a Danish nationwide new user, high-dimensional propensity score-matched cohort study to assess the 90-day risk of fragility fractures among adults, from January 1996 to December 2018. We applied a high-dimensional propensity score to match new users of gabapentin with new users of pregabalin in a 1:1 intention-to-treat approach. Hazard ratios (HRs), incidence rates (IRs) and incidence rate difference (IRD) were obtained. We identified 388 236 eligible patients of which 294 223 and 98 869 initiated gabapentin and pregabalin, respectively. We included 48 272 matched pairs for further analysis. The mean age was 56 (IQR 44-69) years, and the average follow-up was approximately 11 500 person-years (PY). The IRs of fragility fractures were 23.7 (95%CI 21.0-26.7) and 23.2 (95%CI 20.5-26.2) per 1000 PY for gabapentin and pregabalin-exposed patients, respectively. This yielded an HR of 1.02 (95%CI 0.86-1.21) when using gabapentin as the intervention drug and pregabalin as the reference drug. The IRD was estimated to 0.5 PY (95%CI -3.5-4.5). In conclusion, short-term risk of fragility fractures among gabapentin initiators was not different compared to those initiating pregabalin., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objectives: The study aimed to investigate how the 'natural experiment' of reconfiguring the emergency healthcare system in Denmark affected in-hospital and 30-day mortality on a national level. The reconfiguration included the centralisation of hospitals and the establishment of emergency departments with specialists present around the clock., Design: Hospital-based cohort study., Setting: All public hospitals in Denmark., Participants: Patients with an unplanned contact from 1 January 2007 until 31 December 2016., Interventions: Stepped-wedge reconfiguration of the Danish emergency healthcare system., Main Outcome Measures: We determined the adjusted ORs for in-hospital mortality and HRs for 30-day mortality using logistic and Cox regression analysis adjusted for sex, age, Charlson Comorbidity Index, income, education, mandatory referral and the changes in the out of hours system in the Capital Region. The main outcomes were stratified by the time of arrival. We performed subgroup analyses on selected diagnoses: myocardial infarction, stroke, pneumonia, aortic aneurysm, bowel perforation, hip fracture and major trauma., Results: We included 11 367 655 unplanned hospital contacts. The adjusted OR for overall in-hospital mortality after reconfiguration of the emergency healthcare system was 0.998 (95% CI 0.968 to 1.010; p=0.285), and the adjusted OR for 30-day mortality was 1.004 (95% CI 1.000 to 1.008; p=0.045)). Subgroup analyses showed some possible benefits of the reconfiguration such as a reduction in-hospital and 30-day mortality for myocardial infarction, stroke, aortic aneurysm and major trauma., Conclusions: The Danish emergency care reconfiguration programme was not associated with an improvement in overall in-hospital mortality trends and was associated with a slight slowing of prior improvements in 30-day mortality trends., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Multidisciplinary Team Conferences (MDTs) are complex interventions in the modern healthcare system and they promote a model of coordinated patient care and management. However, MDTs within chronic diseases are poorly defined. Therefore, the aim of this scoping review was to summarise the current literature on physician-led in-hospital MDTs in chronic non-malignant diseases., Method: Following the PRISMA-ScR guideline for scoping reviews, a search on MDT interventions in adult patients, with three or more medical specialties represented, was performed., Results: We identified 2790 studies, from which 8 studies were included. The majority of studies were non-randomised and focused on a single disease entity such as infective endocarditis, atrial fibrillation, IgG4-related disease, or arterial and venous thrombosis. The main reason for referral was confirmation or establishment of a diagnosis, and the MDT members were primarily from medical specialties gathered especially for the MDT. Outcomes of the included studies were grouped into process indicators and outcome indicators. Process indicators included changes in diagnostic confirmation as well as therapeutic strategy and management. All studies reporting process indicators demonstrated significant changes before and after the MDT., Conclusion: MDTs within chronic diseases appeared highly heterogeneous with respect to structure, reasons for referral, and choice of outcomes. While process indicators, such as change in diagnosis, and treatment management/plan seem improved, such have not been demonstrated through outcome indicators., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Aims: To assess the gabapentinoid-oedema-loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark., Methods: This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs., Results: Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06-1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75-0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23-2.04). Pooled estimated incidence of the gabapentinoid-loop diuretic prescribing cascade was 8.14 (95% CI, 1.92-34.49) events per 1000 patient-years., Conclusion: We identified evidence of the gabapentinoid-oedema-loop diuretic prescribing cascade in 2 countries., (© 2022 British Pharmacological Society.)

In November 2013, the Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease was published, recommending statins for all individuals 50 years or older with an estimated glomerular filtration rate below 60 ml/min/1.73 m 2 to lower the risk of major cardiovascular events. We quantified the prevalence of statin use among the target population before and after the guideline publication in a large Danish cohort of individuals with an estimated glomerular filtration rate below 60 ml/min/1.73 m 2 , to investigate the effect of the guideline, but found no difference in the prevalence of statin use prior to and after the guideline publication., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Long-term oral corticosteroid (OCS) treatment for severe asthma is known to cause significant adverse effects, but knowledge on effects of lower exposures in general asthma populations is limited. We aimed to explore this in a nationwide Danish asthma population., Methods: Users of asthma medication aged 18-45   years were identified in the Danish nationwide registers during 1999-2018 and followed prospectively in an open-cohort design. Incident OCS users were matched 1:4 to nonusers by propensity scores with replacement. Associations between OCS use and incident comorbidities were examined by Cox regression. Mortality rates, causes of death and rates of unscheduled hospital visits were assessed., Results: OCS users (n=30 352) had, compared with nonusers (n=121 408), an increased risk of all outcomes with evident dose-response relationships starting at cumulative doses of ≤500 mg (prednisolone-equivalent). Hazard ratios ranged from 1.24 (95% CI 1.18-1.30) for fractures to 8.53 (95% CI 3.97-18.33) for adrenal insufficiency. Depression/anxiety had the highest incidence rate difference at 4.3 (95% CI 3.6-5.0) per 1000 person-years. Asthma-specific mortality rates were generally low at 0.15 (95% CI 0.11-0.20) and 0.04 (95% CI 0.02-0.06) per 1000 person-years for OCS users and nonusers, respectively. Mortality rates and unscheduled hospital visits increased with increasing OCS exposure., Conclusion: The study findings should be interpreted with their observational nature in mind. However, we found that even at low cumulative exposure, OCS use in asthma management was associated with increased risk of comorbidities, mortality and unscheduled hospital visits. Effective strategies for optimising asthma control and reducing OCS use are pivotal in asthma management., Competing Interests: Conflict of interest: I.R. Skov reports grants paid to her institution from AstraZeneca, Teva, Novartis, the Odd Fellow Lodge of Haderslev Denmark, the Region of Southern Denmark and the University of Southern Denmark; and personal fees for lectures from Roche, outside the submitted work. A. Pottegård reports participation in research projects funded by Alcon, Almirall, Astellas, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Servier and LEO Pharma, all regulator-mandated phase IV studies, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the submitted work. J.R. Davidsen reports grants and personal fees for advisory board participation and lectures from Roche and Boehringer Ingelheim, and personal fees for lectures from Chiesi, outside the submitted work. H. Madsen, D.P. Henriksen and J.H. Andersen have nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

The association between lithium use and chronic kidney disease (CKD) needs further evaluation. We aimed to investigate this association using Danish nationwide healthcare registers and routinely collected plasma creatinine measurements from the Funen Laboratory Cohort. We conducted a case-control study nested within the population of Funen, 2001-2015. Incident cases of CKD (estimated glomerular filtration rate <60 ml/min/1.73m 2 ; n = 21 432) were matched with four CKD-free controls on age, sex and calendar time (n = 85 532). We estimated odds ratios (OR) for the association between lithium exposure and CKD using conditional logistic regression models, adjusted for known risk factors for CKD. Ever-use of lithium was associated with an increased risk of CKD (adjusted OR [aOR]: 1.57; 95% confidence interval [CI]: 1.33-1.85). A stronger association was seen with current use of lithium (aOR: 1.92; 95%CI: 1.58-2.33) and long-term use of lithium (>10 years: aOR: 3.02; 95%CI: 2.00-4.56). Furthermore, we found evidence of a dose-response relationship between cumulative dose of lithium and the risk of CKD. In conclusion, the use of lithium, especially long-term, is associated with an increased risk of CKD, although the extent to which detection bias and confounding by indication contribute to the association is unclear. Monitoring of kidney function in lithium users remains mandatory to identify individuals in which switching to alternative medications should be considered., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: Arterial punctures (APs) for arterial blood gas (ABG) analyses are much-used medical procedures. To date, no large studies have been conducted on the major complication rate of APs. We aimed to describe the risk of major complications within 7 days after puncture and investigate whether using antithrombotic medication affected this., Methods: We included all APs performed for ABG analysis at three Danish hospitals from January 1, 1993 to February 25, 2013. We excluded APs ordered by the anaesthesiology department, intensive care unit (ICU) or in patients <18 years old. Data on the patient level were extracted from the Danish National Patient Registry, Danish Civil Registration System and Odense Pharmaco-Epidemiologic Database (OPED), the latter providing us with information on antithrombotic medication. Initially, two clinicians compiled a list with all procedures and diagnoses that could possibly be a consequence of APs. The selected procedures and diagnoses were further categorised independently by three surgeons and used to indicate the complication rate., Results: We analysed 473 327 APs and found 669 (0.14%, 95% CI 0.13-0.15) APs led to major complications: embolisms or thrombosis (49.0%), aneurysms (15.4%), nerve damage (1.5%), arteriovenous fistulas (0.6%) or of another kind (33.5%). The identified major complication rates in patients on antithrombotic medication were increased (OR 1.31, 95% CI 1.07-1.61)., Conclusion: APs for ABG analyses are safe procedures. The major complication rate within 7 days was 0.14% (95% CI 0.13-0.15). Patients on antithrombotic medication carry an increased risk of developing major complications., Competing Interests: Conflicts of interest: The authors declare that they have no conflict of interest., (Copyright ©The authors 2022.)

Oral corticosteroids (OCS) are used in asthma management but can cause serious adverse effects. We aimed to investigate the usage trends in a nationwide asthma cohort in Denmark from 1999 to 2018. Using national registers, we identified young adults (18-45 years) with two or more asthma drug collections within 12 months since the age of 15 years as indicative of active asthma. OCS exposure level was stratified as high use (≥5 mg prednisolone/day/year) and low use (<5 mg/day/year). Lorenz curves were computed to illustrate potential skewness of consumption among the OCS users. We identified 318 950 individuals with a median age of 29 years (IQR 20-38 years) whereof 57% were women. The 1-year prevalence of OCS users was stable at 4.8% (median, IQR 4.7%-4.8%), but with nearly 40% decrease in high-users from 0.54% in 1999 to 0.33% in 2018. The median annual exposure decreased from 500 mg/year (1999) to 250 mg/year (2018). We found a substantial skewness in the distribution of OCS usage with 10% of users accounting for almost 50% of all OCS use. The prevalence of OCS users among young adults with active asthma has been relatively stable from 1999 to 2018, but with a decreasing prevalence of high-users and annual consumption., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background: The lifetime prevalence of chronic urticaria (CU) is 0.5%-1%. In some patients with CU, symptomatic control is not achieved with non-sedating second-generation H1 antihistamines (nsAH1) alone, even with quadrupled standard doses as recommended in international guidelines. In these cases, biological treatment with omalizumab can be added. Since omalizumab is expensive compared to antihistamines, lack of adherence to guidelines for high dose nsAH1 (up to four-fold standard dose per day) may be associated with substantial unnecessary costs. The aim was to measure the use nsAH1 before and during omalizumab use for the first time in an omalizumab treated CU population., Methods: We identified all Danish patients with CU who initiated omalizumab from March 2014 to December 2018 and evaluated new and ongoing nsAH1 treatments using the Danish nationwide registries., Results: A total of 955 CU patients initiated treatment with omalizumab within the study period (median age 40 years [IQR 28-50], 74.5% females). During the 12 months prior to omalizumab initiation, 95.6% of the patients filled at least one prescription with nsAH1 at some point, while 84.7% filled at least one prescription during the three months before omalizumab. From 3 months before omalizumab initiation till 3 months after, the proportions of users of high-dose nsAH1 was maximum 31.1%., Conclusions: Omalizumab was usually administered before sufficient nsAH1 treatment was tried. In despite of the labelling that omalizumab should be co-administered with high dose nsAH1, this does not happen This may lead to substantial unnecessary costs., Competing Interests: None., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Organ failure is both a frequent and dangerous condition among adult patients on arrival to an emergency department (ED). The risk of an unfavourable outcome could depend on the underlying aetiology. Knowledge of the relation between aetiology and prognosis could improve the risk stratification at arrival., Objectives: To describe the relation between organ failure, aetiology and prognosis through 7-day all-cause mortality., Methods: An observational three-year cohort study at the ED at Odense University Hospital, Denmark, including all acute adult patients.First-measured vital signs and laboratory values were included to evaluate the presence of the following organ failures: respiratory, coagulation, hepatic, circulatory, cerebral or renal.The primary outcome was 7-day all-cause mortality. Aetiological disease categories were based on primary discharge diagnoses. We described the association between 7-day mortality, aetiology category, site of organ failures and number of patients at risk., Results: Of 40 423 patients with a first-time visit at the ED, 5883(14.6%) had an organ failure on arrival. The median age was 69 (IQR 54-80), and 50% were men. The most frequent aetiology was infection (1495, 25.4%). Seven-day all-cause mortality ranged between aetiologies from 0.0% (95% confidence interval [CI], 0.0-14.2) allergy) to 45.6% (95% CI, 41.3-50.0) (cardiac). Combining aetiology and site of organ failure, 7-day all-cause mortality was the highest in the cardiac category, from 14.8% (95% CI, 4.2-3.7) with hepatic failure to 79.2% (95% CI, 73.6-84.1) with cerebral failure. The combination of infection and respiratory failure characterised most patients (n = 949)., Conclusion: Infection was the most prevalent aetiology, and 7-day all-cause mortality was highly associated with the site of organ failure and aetiology., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The impact of a pandemic on unplanned hospital attendance has not been extensively examined. The aim of this study is to report the nationwide consequences of the COVID-19 pandemic on unplanned hospital attendances in Denmark for 7 weeks after a 'shelter at home' order was issued., Methods: We merged data from national registries (Civil Registration System and Patient Registry) to conduct a study of unplanned (excluding outpatient visits and elective surgery) hospital-based healthcare and mortality of all Danes. Using data for 7 weeks after the 'shelter at home' order, the incidence rate of unplanned hospital attendances per week in 2020 was compared with corresponding weeks in 2017-2019. The main outcome was hospital attendances per week as incidence rate ratios. Secondary outcomes were general population mortality and risk of death in-hospital, reported as weekly mortality rate ratios (MRRs)., Results: From 2 438 286 attendances in the study period, overall unplanned attendances decreased by up to 21%; attendances excluding COVID-19 were reduced by 31%; non-psychiatric by 31% and psychiatric by 30%. Out of the five most common diagnoses expected to remain stable, only schizophrenia and myocardial infarction remained stable, while chronic obstructive pulmonary disease exacerbation, hip fracture and urinary tract infection fell significantly. The nationwide general population MRR rose in six of the recorded weeks, while MRR excluding patients who were COVID-19 positive only increased in two., Conclusion: The COVID-19 pandemic and a governmental national 'shelter at home' order was associated with a marked reduction in unplanned hospital attendances with an increase in MRR for the general population in two of 7 weeks, despite exclusion of patients with COVID-19. The findings should be taken into consideration when planning for public information campaigns., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Sodium-glucose cotransporter-2 inhibitors (SGLT2-I) are frequently used in type 2 diabetes and have recently been associated with lower rates of gout compared to glucagon-like peptide-1 receptor agonists (GLP1-RA). Our objective was to assess the association between SGLT2-I initiation and gout using a cohort study design and a symmetry analysis., Methods: Using the Danish nationwide health registries, we conducted an active comparator, new user cohort study comparing the 3-year risk of gout among SGLT2-I users with propensity score matched GLP1-RA users. Individuals were followed according to the intention-to-treat, and incidence rate differences (IRD) and hazard ratios (HR) were obtained. To address unmeasured confounding that is stable over time, a corresponding symmetry analysis was performed., Results: 11 047 pairs of SGLT2-I and GLP1-RA users were identified, contributing 42 201 person-years of follow-up. The incidence rate of gout was 4.1 and 7.0 events per 1000 person years among SGLT2-I and GLP1-RA users, yielding an IRD of -3.0 (95% confidence interval: -4.4 to -1.5) and HR of 0.58 (0.44 to 0.75). In the symmetry analysis, 80 individuals initiated SGLT2-Is prior to gout; 118 patients initiated treatment after gout. The trend adjusted SR was 0.63 (0.47 to 0.84) and the active comparator adjusted estimate was 0.67 (0.44 to 0.86)., Conclusions: Initiation of SGLT2-Is was associated with a markedly decreased risk of gout compared to initiation of GLP1-RAs. The findings are comparable to prior studies addressing this association., (© 2021 John Wiley & Sons Ltd.)

This indirect comparison of dupilumab, mepolizumab and omalizumab for patients with severe type 2 asthma fulfilling start-up criteria for more than one drug shows no significant efficacy differences https://bit.ly/3pK9Nf9., Competing Interests: Conflict of interest: K. Prætorius has nothing to disclose. Conflict of interest: D.P. Henriksen has nothing to disclose. Conflict of interest: J.M. Schmid has nothing to disclose. Conflict of interest: P. Printzlau has nothing to disclose. Conflict of interest: L. Pedersen has nothing to disclose. Conflict of interest: H. Madsen has nothing to disclose. Conflict of interest: E.A. Galijatovic has nothing to disclose. Conflict of interest: L.K. Madsen has nothing to disclose. Conflict of interest: B.L. Chawes has nothing to disclose., (Copyright ©The authors 2021.)

Aims/hypothesis: Sodium-glucose cotransporter 2 inhibitors (SGLT2Is) may reduce nephrolithiasis risk by increasing urine flow. We aimed to investigate whether initiation of SGLT2I was associated with reduced nephrolithiasis risk., Methods: We conducted an active-comparator new-user cohort study using the Danish health registries in the period 11 November 2012 to 31 December 2018. Individuals aged ≥40 years initiating SGLT2Is or glucagon-like peptide-1 receptor agonists (GLP1 RAs) were followed from treatment initiation until an inpatient or outpatient diagnosis of nephrolithiasis, death, emigration or end of study. New users of SGLT2Is were matched 1:1 on propensity scores to new users of GLP1 RAs. In supplementary analyses, risk of recurrent nephrolithiasis was assessed in individuals with a history of nephrolithiasis before treatment initiation., Results: We identified 24,290 and 19,576 eligible users of SGLT2Is and GLP1 RAs, respectively. After matching, 12,325 patient pairs remained. The median age was 61 years and median follow-up was 2.0 years. The nephrolithiasis rate was 2.0 per 1000 person-years in SGLT2I initiators compared with 4.0 per 1000 person-years in GLP1 RA initiators, with a rate difference of -1.9 per 1000 person-years (95% CI -2.8, -1.0) and an HR of 0.51 (95% CI 0.37, 0.71). For recurrent nephrolithiasis (n = 731 patient pairs), the rate difference was -17 per 1000 person-years (95% CI -33, -1.5) and the HR was 0.68 (95% CI 0.48, 0.97)., Conclusions/interpretation: Initiation of treatment with SGLT2Is was associated with a clinically significant reduced risk of incident and recurrent nephrolithiasis.

Background: Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) are two distinct phenotypes of chronic lung allograft dysfunction (CLAD) in lung transplant (LTx) recipients. Contrary to BOS, RAS can radiologically present with a pleuroparenchymal fibroelastosis (PPFE) pattern. This study investigates lung ultrasound (LUS) to identify potential surrogate markers of PPFE in order to distinguish CLAD phenotype RAS from BOS., Methods: A prospective cohort study performed at a National Lung Transplantation Center during June 2016 to December 2017. Patients were examined with LUS and high-resolution computed tomography of the thorax (HRCT)., Results: Twenty-five CLAD patients (72% males, median age of 54 years) were included, corresponding to 19/6 BOS/RAS patients. LUS-identified pleural thickening was more pronounced in RAS vs. BOS patients (5.6 vs. 2.9 mm) compatible with PPFE on HRCT. LUS-identified pleural thickening as an indicator of PPFE in RAS patients' upper lobes showed a sensitivity of 100% (95% CI; 54-100%), specificity of 100% (95% CI; 82-100%), PPV of 100% (95% CI; 54-100%), and NPV of 100% (95% CI; 82-100%)., Conclusion: Apical pleural thickening detected by LUS and compatible with PPFE on HRCT separates RAS from BOS in patients with CLAD. We propose LUS as a supplementary tool for initial CLAD phenotyping.

Background: The Danish health-care system has witnessed noticeable changes in the acute hospital care organization. The reconfiguration includes closing hospitals, centralizing acute care functions and investing in new buildings and equipment., Objective: To examine the impact on the length of stay (LOS) and the proportion of overnight stays for hospitalized acute care patients., Methods: This nationwide interrupted time series examined trend changes in LOS and overnight stay. Admissions were stratified based on admission time (weekdays/weekends and time of day), age and the level of co-morbidity., Results: In 2007-2016, the global average LOS declined 2.9% per year (adjusted time ratio [CI (confidence interval) 95%] 0.971 [0.970-0.971]). The reconfiguration was overall not associated with change in trend of LOS (time ratio [CI 95%] 1.001 [1.000-1.002]). When admissions were stratified for either weekdays or weekends, the reconfiguration was associated with reduction of the underlying downward trend for weekdays (time ratio [CI 95%] 1.004 [1.003-1.005]) and increased downward trend for weekend admissions (time ratio [CI 95%] 0.996 [0.094-0.098]). Admissions at night were associated with a 0.7% trend change in LOS (time ratio [CI 95%] 0.993 [0.991-0.996]). The reconfiguration was not associated with trend changes for overnight stays., Conclusion: The nationwide reconfiguration of acute hospital care was overall not associated with change in trend for the registered LOS and no change in trend for overnight stays. However, the results varied according to hospitalization time, where admissions during weekends and nights after the reconfiguration were associated with shortened LOS., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate the efficacy and safety of bronchial thermoplasty (BT) in clinical practice in adults with severe, refractory asthma. Methods: Prospective, single-center, open, observational study comprising patients with uncontrolled asthma (asthma control questionnaire (ACQ) >1.5) and/or frequent exacerbations despite treatment with at least high dose inhaled corticosteroids plus a second controller. Efficacy outcomes was change from baseline 4, 8, 12 and 24 months in FEV 1 , FVC and FEV 1 /FVC ratio, asthma control questionnaire (ACQ) score and asthma quality of life score (mini-AQLQ). Results are presented as median with interquartile ranges (IQR). The following were recorded as adverse events: Un-scheduled health care contacts, rescue courses of oral corticosteroid (OCS) and/or antibiotics for exacerbation for exacerbations/respiratory tract infections (RTI). Results: Six-teen patients were enrolled (nine males, median age 50 years; 14 followed for 24 months). Compared to baseline, an improvement in FEV 1 , FVC, FEV 1 /FVC ratio, mini-AQLQ and ACQ was observed, i.e.FEV 1 (IQR) 1.98 L (1.65-2.45) vs. 2.45 L (2.09-2.93) ( p  = 0.006), FVC (IQR) 3.23 L (2.76-4.05) vs. 3.75 L (3.22-4.36) ( p  = 0.041), FEV 1 /FVC 0.60 (IQR: 0.55-0.70) vs. 0.66 (IQR: 0.63-0.71) ( p  = 0.016), mini-AQLQ 4.0 (IQR: 3.2-4.9) vs. 5.6 (IQR 4.5-6.5) ( p  = 0.008, and ACQ 2.9 (IQR: 2.1-3.7) versus 1.5 (IQR 1.0-2.4) ( p  = 0.004). On the other hand, an increase was observed in unscheduled visits ( p  = 0.005), as well as use of OCS and antibiotics ( p  = 0.009 and p  = 0.003, respectively). Conclusion: BT in adults with severe asthma improved ACQ, mini-AQLQ and lung function, but resulted in an increased frequency of unscheduled doctor-visits and rescue courses of OCS and antibiotics.

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors, on the basis of spontaneous adverse event reports, has recently been suspected of causing splanchnic vein thrombosis. Here, we report the results of a population-based new-user active comparator cohort study addressing this hypothesis, comparing DPP-4 inhibitor initiators (n = 75 042) with initiators of glucagon-like-peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose co-transporter-2 (SGLT2) inhibitors (n = 38 718). We estimated the hazard ratio (HR) associating DPP-4 inhibitor use with risk of splanchnic vein thrombosis using Cox regression. In a crude analysis, the incidence rate of splanchnic vein thrombosis was 0.22/1000 person-years among DPP-4 inhibitor initiators, compared to 0.17 among GLP-1RA/SGLT2 inhibitor initiators, corresponding to an unadjusted absolute incidence rate difference of 0.05 (95% confidence interval [CI] -0.04 to 0.14) and an HR of 1.29 (95% CI 0.78 to 2.15). Adjusting for potential confounders using stabilized inverse probability of treatment weighing, we obtained an absolute incidence rate difference of 0.03/1000 person-years (95% CI -0.07 to 0.14) and an HR of 1.18 (95% CI 0.62 to 2.26). No evidence of increased risk of splanchnic vein thrombosis was found in supplementary analyses, including an absence of any dose-response patterns. As such, we found no association between DPP-4 inhibitor use and splanchnic vein thrombosis risk., (© 2020 John Wiley & Sons Ltd.)

Aim: To explore, which differential diagnoses to consider in individuals with elevated troponins without acute myocardial infarction (AMI), and the mortality for those individuals., Methods: Retrospective, register-based study on a representative sample of the Danish population with the following inclusion criteria: High-sensitive troponin I (hs-TnI) ⋝25 ng/L, age ⋝18 years, and exclusion of AMI., Results: 3067 individuals without AMI but increased hs-TnI were included. Most frequent discharge diagnoses: Pneumonia (12.8%), Aortic valve disorder (11.3%), Medical observation (10.9%) and Heart failure (8.9%). The 30-days and one-year mortality was 15.8% and 32.0%, respectively., Conclusions: A selected number of alternative diagnoses must be considered in individuals with increased hs-TnI. Due to high mortality it is crucial to carefully evaluate these individuals despite the absence of AMI.

Objectives: The aim of the study was to provide evidence for, at which vital and laboratory values, increased risk of 7-day mortality in acute adult patients on arrival to an emergency department (ED)., Design: A population-based cohort study., Setting: ED at Odense University Hospital, Denmark., Participants: All patients ≥18 years with a first-time contact within the study period, 1 April 2012 to 31 March 2015., Primary and Secondary Outcome Measures: Primary outcome was 7-day all-cause mortality.Variables were first recorded vital and laboratory values included in risk stratification scores; respiratory frequency, blood pressure, heart rate, Glasgow Coma Scale, temperature, saturation, creatinine, PaO 2 , platelet count and bilirubin. The association between values and mortality was described using a restricted cubic spline. A predefined 7-day mortality of 2.5% was chosen as a relevant threshold., Results: We included 40 423 patients, 52.5% women, median age 57 (IQR 38-74) years and 7-day mortality 2.8%. Seven-day mortality of 2.5% had thresholds of respiratory frequency <12 and >18/min, systolic blood pressure <112 and >192 mm Hg, heart rate <54 and >102 beats/min, temperature <36.0°C and >39.8°C, saturation <97%, Glasgow Coma Scale score <15, creatinine <41 and >98 µmol/L for PaO 2 <9.9 and >12.3 kPa, platelet count <165 and >327×10 9 /L and bilirubin >12 µmol/L., Conclusion: Vital values on arrival, outside the normal ranges for the measures, are indicative of increased risk of short-term mortality, and most of the value thresholds are included in the lowest urgency level in triage and risk stratification scoring systems., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Idiopathic pulmonary fibrosis (IPF) is a well-characterised interstitial lung disease. Typically, IPF diagnosis is delayed due to nonspecific symptoms, but can also be delayed due to treatment attempts on false indication or due to treatment targeting common comorbidities. This observational study aimed to assess the dynamics in the medication and diagnosis patterns in the period before and after an IPF diagnosis., Methods: We identified all Danish patients with IPF between 2002 and 2017. We evaluated new and ongoing drug treatments and incident diagnoses 36 months before and 12 months after an IPF diagnosis by use of Danish nationwide registries. To aid interpretation, 10 random controls were recruited for each case., Results: A total of 650 IPF patients were identified (median age 73 years (interquartile range 65-78), 70.3% males). Prior to the IPF diagnosis, the most prevalent diagnoses were dyspnoea and non-IPF interstitial lung diseases. For drug use, IPF patients had higher initiation rates for antibiotics, oral corticosteroids and mucolytics. In terms of drug volume, IPF patients used more respiratory drugs, antibiotics, immunosuppressants, corticosteroids, proton pump inhibitors, benzodiazepines and opium alkaloids within the 6 months preceding their IPF diagnosis, compared to the controls. Overall drug use decreased after an IPF diagnosis, mainly due to a reduced glucocorticoid and cardiovascular drug use., Conclusion: Among IPF patients, an increased drug use was observed for diagnoses with symptoms overlapping those of IPF, particularly this was observed during the last 6 months before an IPF diagnosis. This emphasises the need for an increased IPF awareness., Competing Interests: Conflict of interest: J.R. Davidsen reports grants and personal fees from Roche, and personal fees and nonfinancial support from Boehringer Ingelheim, outside the submitted work. Conflict of interest: L.C. Lund reports participation in research projects funded by Menarini Pharmaceutical and LEO Pharma, with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. Conflict of interest: C.B Laursen has nothing to disclose. Conflict of interest: J. Hallas has nothing to disclose. Conflict of interest: D.P. Henriksen has nothing to disclose., (Copyright ©ERS 2020.)

Objectives: To examine the association between use of second-generation antipsychotics (SGA) and the risk of chronic kidney disease (CKD)., Design: Population-based case-control study., Setting: Routinely collected laboratory, prescription and diagnostic information on all inhabitants with creatinine measurements residing on the island of Funen, Denmark (2001 to 2015)., Participants: 21 434 cases with incident CKD matched with 85 576 CKD-free population controls by risk-set sampling using age, sex and calendar year., Primary and Secondary Outcome Measures: CKD was defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m 2 in a period longer than 3 months. Information on drug exposure and comorbidities were obtained from the Danish National Prescription Register and the Danish National Patient Register. We calculated OR for the association between SGA use and CKD using conditional logistic regression., Results: Use of SGAs was associated with increased risk of CKD among ever users (OR 1.24, 95% CI: 1.12 to 1.37) and current users (OR 1.26, 95% CI: 1.12 to 1.42). We found no clear evidence of dose-response relationship. Both short duration (one to two antipsychotic prescriptions; OR 1.22, 95% CI: 1.01 to 1.48) as well as long-term use (>30 prescriptions; OR 1.45, 95% CI 1.19 to 1.76) were associated with an increased risk of CKD. Both use of SGAs with mild and high risk of metabolic disturbances was associated with increased risk of CKD (OR 1.21, 95% CI: 1.06 to 1.39 and OR 1.36, 95% CI: 1.11 to 1.68, respectively). Recent use of non-steroidal anti-inflammatory drugs, prior use of lithium, hypertension or prior acute kidney injury were not clearly associated with development of CKD connected to SGA exposure. The highest risk of CKD was found for clozapine (OR 1.81, 95% CI: 1.22 to 2.69)., Conclusion: Use of SGA is associated with a small-to-moderately increased risk of incident CKD. All investigated SGAs, except for aripiprazole, were associated with an increased risk of CKD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Omalizumab is approved for treating severe allergic asthma from age 6, but the definition of severe asthma including a systematic assessment to rule out difficult-to-treat asthma has changed since the drug was approved in 2003., Methods: We conducted a systematic review and meta-analysis of two critical (exacerbation rate, oral corticosteroid (OCS) treatment) and eight important clinical outcomes in children, adolescents and adults, and specifically searched papers for systematic assessment of severe asthma., Results: Adults: seven studies (n = 2159) ascertaining exacerbation rate showing a 37% (95% CI 21-50) reduction in favor of omalizumab, larger than the pre-specified minimal clinically important difference (MCID) of 25%. Only one open-label study (n = 82) was identified assessing the percentage of patients experiencing reduction of OCS-maintenance treatment showing a significantly greater decrease in the omalizumab group (- 45% vs. + 18.3%, p = 0.002). Children and adolescents: four studies (n = 1551) reported data on exacerbations (no meta-analysis conducted), showed overall improvements in exacerbation rate and some passed MCID. No OCS studies were identified. No included studies provided systematic assessment of severe asthma according to current guidelines., Conclusions: Omalizumab provides clinically relevant improvements in exacerbation rate among children, adolescents, and adults and in OCS-reduction among adults. New studies incorporating a guideline-approached definition of severe asthma are warranted., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Purpose: Largely based on case series, several drugs have been implicated in drug-induced restless legs syndrome (RLS) including selective serotonin reuptake inhibitors (SSRI). We aimed to assess the association between initiation of SSRIs and RLS in a self-controlled design., Methods: We conducted a symmetry analysis, including Danish adults who filled in their first prescription of an SSRI in the period of 1997-2017 and initiated an RLS drug (quinine, ropinirole, pramipexole or rotigotine) 1 year prior to or after this date. A symmetrical distribution of prescriptions before and after SSRI initiation is expected if there is no association between SSRI and RLS (a sequence ratio (SR) of 1.0). The symmetry analysis design is robust to confounders that are stable over time. Subgroup analyses were conducted, restricting the population on sex, age, selected diagnoses and concurrent medication., Results: A total of 10,875 patients filled in their first-ever prescription of both an SSRI and an RLS drug within a 1-year interval; 5341 patients filled their prescription of SSRI prior to their prescription of an RLS drug, and 5534 patients redeemed their prescriptions in the opposite order (SR 0.97, 95% CI 0.93-1.00). Restricting the outcome to dopamine agonist initiation revealed a slightly increased sequence ratio (SR 1.34, 95% CI 1.24-1.46), which was reduced when adjusting for trends in prescription (adjusted SR 1.21, 95% CI 1.12-1.32). Restricting the outcome to quinine initiation showed no association., Conclusion: We found no association between the initiation of an SSRI and the development of RLS assessed by the prescription of an RLS drug.

Introduction:  Lung ultrasound (LUS) has a high diagnostic accuracy for identifying frequent conditions in the post-operative phase after lung transplantation (LTx). This study aimed to investigate the feasibility and clinical ability of LUS to identify pulmonary complications such as pleural effusions and pneumonias in the early postoperative phase after LTx., Methods:  A prospective cohort study of lung transplant recipients who consecutively underwent single LTx (SLTx) or double LTx (DLTx) at the National Lung Transplantation Center in Denmark from May 1 to October 31, 2015 was conducted. LUS was performed at four time points corresponding to post-transplant day 3, and weeks 2, 6, and 12 (LUS #1-4) to detect and monitor variation in pathological LUS findings over time. Concurrent with LUS #4, a high-resolution computed tomography examination of the thorax (HRCT) was also performed., Results:  14 patients (1 SLTx/13 DLTx, 7 (50 %) women, mean age: 50.4 years) who had undergone the four prespecified LUS examinations were included. Pleural effusion was the most common condition and most pronounced at post-LTx week 2. Findings consistent with pneumonia increased during week 2 and subsequently decreased. Corresponding to LUS #1, 2, 3, and 4, pleural effusion occurred in 85.7 %, 92.9 %, 85.7 %, and 78.6 %, and pneumonia in 21.4 %, 28.6 %, 14.3 %, and 14.3 %, respectively. HRCT findings at post-LTx week 12 were predominantly presented by unspecific ground glass opacities., Conclusion:  In a post-LTx setting, LUS represents a clinical novelty as a feasible diagnostic and monitoring tool to identify pathological pulmonary complications in the early post-operative phase., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To describe changes in unplanned acute activity and to identify and characterise unplanned contacts in hospitals in Denmark from 2005 to 2016, including following healthcare reform., Design: Descriptive study., Setting: Data from Danish nationwide registers., Population: Adults (≥18 years)., Participants: All adults with an unplanned acute hospital contacts (acute inpatient admissions and emergency care visits) in Denmark from 2005 to 2016., Primary and Secondary Outcome Measures: Outcomes were annual number of contacts, length of stay, number of contacts per 1000 citizen per year, age-adjusted contacts per 1000 citizens per year, sex, age groups, country of origin, Charlson Comorbidity Index score, discharge diagnosis and time of arrival., Results: We included a total of 13 524 680 contacts. The annual number of acute hospital contacts increased from 1 067 390 in 2005 to 1 221 601 in 2016. The number also increased with adjustment for age per 1000 citizens. In addition, regional differences were observed., Conclusions: Unplanned acute activity changed from 2005 to 2016. The national number of contacts increased, primarily because of changes in one of the five regions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The aim was to describe population-based incidence and emergency department-based prevalence and 1-year all-cause mortality of patients with new organ failure present at arrival., Design: This was a population-based cohort study of all citizens in four municipalities (population of 230 000 adults)., Setting: Emergency department at Odense University Hospital, Denmark., Participants: We included all adult patients who arrived from 1 April 2012 to 31 March 2015., Primary and Secondary Outcome Measures: Organ failure was defined as a modified Sequential Organ Failure Assessment score≥2 within six possible organ systems: cerebral, circulatory, renal, respiratory, hepatic and coagulation.The primary outcome was prevalence of organ failure, and secondary outcomes were 0-7 days, 8-30 days and 31-365 days all-cause mortality., Results: We identified in total 175 278 contacts, of which 70 399 contacts were further evaluated for organ failure. Fifty-two per cent of these were women, median age 62 (IQR 42-77) years. The incidence of new organ failure was 1342/100 000 person-years, corresponding to 5.2% of all emergency department contacts.The 0-7-day, 8-30-day and 31-365-day mortality was 11.0% (95% CI: 10.2% to 11.8%), 5.6% (95% CI: 5.1% to 6.2%) and 13.2% (95% CI: 12.3% to 14.1%), respectively, if the patient had one or more new organ failures at first contact in the observation period, compared with 1.4% (95% CI: 1.3% to 1.6%), 1.2% (95% CI: 1.1% to 1.3%) and 5.2% (95% CI: 5.0% to 5.4%) for patients without. Seven-day mortality ranged from hepatic failure, 6.5% (95% CI: 4.9% to 8.6%), to cerebral failure, 33.8% (95% CI: 31.0% to 36.8%), the 8-30-day mortality ranged from cerebral failure, 3.9% (95% CI: 2.8% to 5.3%), to hepatic failure, 8.6% (95% CI: 6.6% to 10.8%) and 31-365-day mortality ranged from cerebral failure, 9.3% (95% CI: 7.6% to 11.2%), to renal failure, 18.2% (95% CI: 15.5% to 21.1%)., Conclusions: The study revealed an incidence of new organ failure at 1342/100 000 person-years and a prevalence of 5.2% of all emergency department contacts. One-year all-cause mortality was 29.8% among organ failure patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: A subset of patients with chronic obstructive pulmonary disease (COPD) experience a decrease in exacerbation frequency, leading to a diminished need for treatment with inhaled corticosteroids (ICS). We investigated prescribing and discontinuation patterns of long-acting bronchodilators and ICS in COPD patients according to exacerbation frequency., Methods: Using the nationwide Danish health registries, we conducted a drug utilization study among patients who had at least two exacerbations or one hospitalization due to an exacerbation during 2011-2012. This study population was stratified according to consistency of exacerbation occurrence after 12, 24, 36, and 48 months of follow-up and the groups were described according to use of ICS, long-acting β 2 -agonists (LABA), and long-acting anticholinergics (LAMA), and combinations thereof., Results: We identified 29,010 COPD exacerbators during 2011-2012. Upon inclusion, 70% received ICS-containing regimens, in combination with LABA (23%) or both LABA and LAMA (41%). The proportion of prevalent users of ICS-containing regimens decreased to 56% during follow-up among exacerbation-free individuals, while it increased to 86% in individuals who experienced at least one exacerbation annually. Persistence to ICS-containing regimens was 58% after 4 years in individuals without exacerbations compared to 74% among those with annual exacerbations. Similar patterns were observed for triple therapy which was the most extensively used drug combination regardless of consistency of exacerbation occurrence., Conclusions: The extensive use of ICS and the relatively high persistence to ICS-containing regimens in individuals who had a decrease in exacerbation occurrence highlight a need for the development and implementation of de-escalation strategies in clinical practice.

Register-based administrative data comprise the backbone of pharmacoepidemiological research. However, information from these registers lacks biochemical details. The aim of our study was to describe the creation, coverage and content of the Funen Laboratory Cohort (FLaC). FLaC is a database comprising all inhabitants of Funen, Denmark, who in the study period of January 2000 to December 2015 had their creatinine levels measured. Data were linked to the Danish nationwide registers with information on vital status, redeemed prescriptions, discharge diagnoses, and socio-economic status. A total of 693 843 individuals lived on Funen during the study period, and we included 460 365 (66.4%) individuals with a creatinine measurement. In total, 7 742 124 creatinine measurements were performed during the study period. The coverage increased with increasing age, reaching 90%-100% of all 65-90 + year-olds in 2015. We found that an overall coverage of individuals recorded in FLaC with at least one creatinine measured redeeming prescriptions from public pharmacies was 83% (interquartile range [IQR] 75%-89%) compared to the entire Funen population. In total, 94.1% of all individuals with a discharge diagnosis of chronic kidney disease (CKD) were covered in FLaC, but only 16.5% (n = 3136) of all individuals with a laboratory-confirmed CKD also had a discharge diagnosis of CKD. We described the creation and content of the FLaC - a haven and a valuable resource for pharmacoepidemiological research using Danish nationwide administrative registers enriched with individual-level biochemical information in a population-based setting., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Introduction: The knowledge of the etiology and associated mortality of undifferentiated shock in the emergency department (ED) is limited. We aimed to describe the etiology-based proportions and incidence rates (IR) of shock, as well as the associated mortality in the ED., Methods: Population-based cohort study at a University Hospital ED in Denmark from January 1, 2000, to December 31, 2011. Patients aged ≥18 years living in the ED-catchment area (N = 225,000) with a first-time ED presentation with shock (n = 1,553) defined as hypotension (systolic blood pressure ≤100 mm Hg) and ≥1 organ failures were included. Discharge diagnoses defined the etiology and were grouped as follows: distributive septic shock (SS), distributive non-septic shock (NS), cardiogenic shock (CS), hypovolemic shock (HS), obstructive shock (OS), and other conditions (OC). Outcomes were etiology-based characteristics, annual IR per 100,000 person-years at risk (95% confidence intervals [CIs]), mortality at 0 to 7-, and 0 to 90 days (95% CIs) and hazard rates (HR) at 0 to 7, 8 to 90 days (95% CIs). Poisson and Cox regression models were used for analyses., Results: Among 1,553 shock patients: 423 (27.2%) had SS, 363 (23.4%) NS, 217 (14.0%) CS, 479 (30.8%) HS, 14 (0.9%) OS, and 57 (3.7%) OC. The corresponding IRs were 16.2/100,000 (95% CI: 14.8-17.9), 13.9/100,000 (95% CI: 12.6-15.4), 8.3/100,000 (95% CI: 7.3-9.5), 18.4/100,000 (95% CI: 16.8-20.1), 0.5/100,000 (95% CI: 0.3-0.9), and 2.2/100,000 (95% CI: 1.7-2.8). SS IR increased from 8.4 to 28.5/100,000 during the period 2000 to 2011. Accordingly, the 7-, and 90-day mortalities of SS, NS, CS, and HS were 30.3% (95% CI: 25.9-34.7) and 56.2% (95% CI: 50.7-61.5), 12.7% (95% CI: 9.2-16.1) and 22.6% (95% CI: 18.1-27.7), 34.6% (95% CI: 28.2-40.9) and 52.3% (95% CI: 44.6-59.8), 19.2% (95% CI: 15.7-22.7), and 36.8% (95% CI: 33.3-43.3). SS (HR = 1.46 [95% CI: 1.03-2.07]), and CS (HR = 2.15 [95% CI: 1.47-3.13]) were independent predictors of death within 0 to 7 days, whereas SS was a predictor within 8 to 90 days (HR = 1.66 [95% CI: 1.14-2.42])., Conclusion: HS and SS are frequent etiological characteristics followed by NS and CS, whereas OS is a rare condition. We confirm the increasing trend of SS, as previously reported. Seven-day mortality ranged from 12.7% to 34.6%, while 90-day mortality ranged from 22.6% to 56.2%. The underlying etiology was an independent predictor of mortality.

Purpose: Leukotriene receptor antagonists are used in asthma and rhinitis treatment. Pharmacovigilance data have suggested an association between montelukast and depression, but the association has not been established in controlled study designs. We described the association between initiation of montelukast and depression, using prescriptions of antidepressants as a surrogate marker, and assessed whether the association was related to the underlying asthma disease., Methods: We performed a symmetry analysis, with a study period from January 1, 2000 to December 31, 2016, using 3 nationwide Danish registers. We included all adults, who filled their first prescription of montelukast and antidepressants within an interval of 1 year. In the absence of an association between montelukast and antidepressant use, a symmetrical distribution of prescriptions is expected before and after montelukast initiation (ie, a sequence ratio [r c ] of 1.0). We subcategorized the subjects after the severity of underlying asthma disease., Results: In total, 4450 subjects filled their first prescriptions of both montelukast and antidepressants within a 1-year interval: 2434 redeemed their first prescription of montelukast before antidepressants, and 2016 redeemed the medications in the opposite order (r c 1.21 [95% CI 1.14-1.28]). We found r c above unity in groups with long-acting asthma treatment, but no increase in antidepressant prescription, when stratifying by the asthma severity., Conclusion: We found a weak association between the use of montelukast and the risk of being prescribed an antidepressant, unlikely to be of clinical relevance. Stratified analyses suggest that this association may relate to asthma, rather than to montelukast., (© 2018 John Wiley & Sons, Ltd.)

Background : New, complex, and expensive therapies targeting Interleukin-5 (IL-5) to treat severe eosinophilic asthma are emerging. Objective : To assess efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab for treating severe eosinophilic asthma. Design : A systematic review and meta-analysis on randomized, placebo-controlled, clinical trials elucidating two critical (exacerbation rate and oral corticosteroid (OCS) use) and six important clinical outcomes on the efficacy and safety of mepolizumab and reslizumab. Results : Five studies (N = 2197) contributed with data for exacerbation rate, showing a reduction of 53% (95% CI 46; 59) in favour of anti-IL-5, corresponding to -0.94 annual exacerbations (95% CI -1.08;-0.82), thus exceeding the predefined minimal clinical important difference (MCID) of 25% reduction of the estimated ≥2 annual exacerbations. Quality of evidence was considered moderate, with low heterogeneity in study findings (I2 = 0%). One study (N = 135) contributed with data on percentage of patients experiencing ≥50% reduction inoral corticosteroid treatment, showing an effect of 20% (95% CI 2.3;47) in favour of anti-IL-5 treatment (mepolizumab), thus exceeding the predefined MCID of 10%. Quality of evidence was considered low. Compared to placebo, anti-IL-5 showed significant improvements in lung function, asthma control, and asthma-related quality of life, but below the MCIDs. No differences were observed for serious adverse events and number of patients, who dropped out. No studies evaluating sickleave or head-to-head comparisons were identified. By indirect comparison, we found no significant difference between mepolizumab and reslizumab in any ofthe predefined clinical outcomes. OCS treatment reduction could not be compared due to lack of reslizumab studies investigating this outcome. Conclusions : Mepolizumab and reslizumab provide significant and clinically relevant improvements in exacerbation rate and OCS reduction. Indirect, inter-study comparisons revealed no differences between the anti-IL-5 drugs in efficacy or safety measures.

Introduction: Patients in an emergency department are diverse. Some are more seriously ill than others and some even arrive in multi-organ failure. Knowledge of the prevalence of organ failure and its prognosis in unselected patients is important from a diagnostic, hospital planning, and from a quality evaluation point of view, but is not reported systematically., Objectives: To analyse the prevalence and prognosis of new onset organ failure in unselected acute patients at arrival to hospital., Methods: A systematic review of studies of prevalence and prognosis of acutely ill patients with organ failure at arrival to hospital. We searched PubMed, Cochrane Library, Embase and Cinahl, and read references in included studies. Two authors decided independently on study eligibility and extracted data. Results were summarised qualitatively., Results: Four studies were included with a total of 678,960 patients. The number of different organ failures reported in the studies ranged from one to six, and the settings were emergency departments and wards. The definitions of organ failure varied between studies. The prevalence of organ failure was 7%, 14%, 14%, and 23%, and in-hospital mortality was 5%, 11% and 15% respectively. The relative risk of in-hospital mortality for patients with organ failure compared to patients without organ failure varied from 2.58 to 8.65. Numbers of organ failures per 1,000 visits varied from 71 to 256., Conclusion: The results of this review indicate that clinicians have good reasons to be alert when a patient arrives to the emergency department; as a state of organ failure seems both frequent and highly severe. However, most studies identified were performed in patients after a diagnosis was established, and only very few studies were performed in unselected patients., Systematic Review Registration Number: PROSPERO: CRD42017060871., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The aim of this study was to evaluate the incidence, risk factors, and outcome of endoleaks related to endovascular aneurysm repair (EVAR) procedure at a single center with up to 10 years' surveillance., Materials and Methods: All patients treated with EVAR for an abdominal aorta or iliac aneurysm in a 10-year period at a single cardiovascular center in Denmark were included. Data were collected from a national database and patient journals. Follow-up computed tomography angiography and plain abdominal X-ray reports were reviewed., Results: A total of 421 patients were included. There were 125 endoleaks observed in 117 (27.8%) patients after a median 95 days (interquartile range: 90-106 days). There were 16 type I, 107 type II, 1 type III, and 1 type V endoleaks. A total of 33 (7.8%) patients had at least 1 reintervention. Patients with type II endoleaks had significantly fewer active smokers and lower plasma creatinine at baseline. They also more often had one, or both, internal iliac arteries embolized as well as an identified endoleak at the procedural completion angiogram. Non-type II endoleaks were associated with internal iliac artery embolization. There was no association between the occurrence of endoleaks and increased mortality., Conclusion: Type II endoleaks are common after EVAR, yet few lead to reintervention. Absence of smoking, low plasma creatinine, embolized iliac arteries, and endoleak on completion angiogram were associated with type II endoleaks, whereas only embolized iliac arteries were associated with non-type II endoleaks. Overall, endoleaks are not associated with increased mortality.

Roflumilast, a phosphodiesterase-4-inhibitor, is marketed as add-on treatment to inhaled bronchodilators and corticosteroids in COPD patients with frequent exacerbations. Although marketed since 2010, usage pattern of roflumilast for an entire nation has not previously been explored. This study aimed to estimate the total utilization of roflumilast in Denmark during 2010 to 2016, using the Danish nationwide health registers. We identified 1573 individuals (47% males) who used roflumilast during the study period, of whom 705 (45%) redeemed only one prescription. Of all patients initiating roflumilast, 67% discontinued treatment within the first year. The rate of treatment initiation decreased 73% from 2011 (7.5/100,000 person-years) to 2016 (2.0/100,000 person-years) concurrent with a stable prevalence of 3.0-4.0/100,000 persons throughout the study period. The median duration of roflumilast use was 76 days. Patients with severe comorbidity tended to exhibit a lower degree of early discontinuation (Charlson Comorbidity Index 3+: odds ratio [OR]: 0.59; 95% confidence interval [CI] 0.33-1.04), as well as patients with a COPD-related admission within a year prior to roflumilast initiation (OR 0.62; 95% CI 0.49-0.80). The decreasing incidence and high level of early roflumilast discontinuation could be due to lack of benefit, a low awareness of romiflulast's indication among physicians, secondary to a challenging prescribing procedure or to adverse effects., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Long-acting bronchodilators and inhaled corticosteroids (ICS) are the cornerstones in treatment of chronic obstructive and inflammatory pulmonary diseases. However, non-adherence to guidelines is widespread. Detailed information on real-life treatment patterns is needed to promote rational use. We aimed to investigate nationwide time trends in individual-level treatment patterns of long-acting bronchodilators and ICS. Using nationwide Danish health registries, we identified all Danish adults with a prescription for long-acting bronchodilators and/or ICS from 2000 to 2016. We investigated the total use of long-acting bronchodilators and ICS, the proportion of current users and the rate of new users over time. Finally, we assessed treatment persistence. We included 23,061,681 prescriptions for long-acting bronchodilators and ICS issued to 805,860 individuals from 2000 to 2016. Over this period, the total annual amount of prescribed long-acting bronchodilators and ICS increased by 39%. Similarly, the proportion of adult users increased from 2.6% to 4.5%, mainly driven by the introduction of combination therapy and long-acting muscarinic antagonist (LAMA). Although the rate of new users of fixed-dose combination drugs increased substantially over time, the overall rate of new users was stable. In general, the proportion of patients on therapy after 1 year was low (25-53%), especially among young individuals and users of ICS. We document a pronounced increase in the total use of long-acting bronchodilators and ICS over time, mainly driven by the introduction of combination drugs and LAMA. Special attention should be paid to the low level of persistence, especially among young individuals and users of ICS., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Theophylline, a dimethylxanthine, has been used the last 100 years to treat airway disease. Although it is one of the most widely prescribed medicines to treat asthma and chronic obstructive pulmonary disease (COPD) throughout the years, the utilisation patterns are not well-described., Methods: Using the Danish Register of Medicinal Products Statistics, we identified adults above 18 years redeeming one or more prescriptions of theophylline between 1997 up to 2017, with a 2-year run-in period from 1995 to 1997. Using descriptive statistics, we reported the development in prevalence, incidence, and a measure of treatment duration (proportion of patients covered)., Results: In total, 55,636 individuals redeemed 1,066,475 prescriptions of theophylline, 30,619 women (55%) and 25,017 men (45%). The prevalence decreased from 401 per 100,000 individuals in 1997 to 26 per 100,000 individuals in 2016. The incidence rate decreased throughout the entire study period (105 per 100,000 person-years in 1997 to 5 per 100,000 person-years in 2016). In total, 52% were still current users three months after theophylline initiation, 33%, 27%, and 23% were current users after 6 months, one year, and two years., Conclusions: Although newer and more efficient medicines to treat asthma and COPD has been developed, theophylline is still prescribed and used in 2016, but the incidence and prevalence have decreased markedly since 1997., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Montelukast, a leukotriene receptor antagonist, was marketed in 1998 as an oral supplementary treatment to patients with mild to moderate asthma. The aim of this study was to describe the early discontinuation pattern among montelukast users in Denmark in the period of 1 March 1998 to 31 December 2016, and to identify demographic characteristics possibly associated with early discontinuation. This nationwide drug utilization study was based on data collected from three nationwide Danish registers. All montelukast users who redeemed at least one prescription in the study period were identified. Early discontinuation was defined as failing to fill a second prescription for montelukast within at least a year after the initial montelukast prescription. Among 135,271 included montelukast users, 47,480 (35%) discontinued the use of montelukast after a single redeemed prescription. The trend in early discontinuation increased throughout the years. The most predominant demographic risk factors for early discontinuation were prescription for only nasal topical anti-allergic treatment up to a year prior to montelukast initiation [adjusted odds ratio (OR) 2.25; 95% confidence interval (CI) 2.13-2.38], as well as suspected off-label use (adjusted OR 2.02; 95% CI 1.97-2.08). Several risk factors were associated with a decreased risk of early discontinuation; most pronounced was a prescription of inhaled corticosteroids within a year up to montelukast initiation [adjusted OR 0.47 (95% CI 0.46-0.49)]. Early discontinuation was more pronounced after patent expiry in 2012 [adjusted OR 1.42 (95% CI 1.38-1.45)]. In conclusion, we found that early montelukast discontinuation increased during the last 19 years. Appropriateness of the treatment indication as estimated by concomitant prescription of adequate inhalation therapy was associated with a low risk of early discontinuation. A more pronounced early discontinuation was observed after patent expiry in 2012, which could reflect a more liberal approach to montelukast prescription., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)