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The anterolateral thigh (ALT) flap is widely used in the reconstruction of a variety of soft tissue defects. Descriptions of patients with severe obesity in the literature are scarce. We report a case where a reverse pedicled fasciocutaneous ALT flap was successfully used for resurfacing of a knee defect measuring 12×6 cm in a patient with a body mass index (BMI) of 47.3. The flap was supercharged to the greater saphenous vein to optimise flap survival. Reconstruction of the soft tissue of the knee was achieved as planned. There were no flap or donor site complications.

Background: Tissue levels of n-3 polyunsaturated fatty acids (PUFAs) have been inversely related with risk of myocardial infarction (MI). Whether ratios of n-3 to n-6 PUFAs, reflecting both dietary intake of n-3 PUFAs and competing n-6 PUFAs, are better predictors of future MI than n-3 PUFA fractions is unclear. We aimed at investigating whether such ratios in adipose tissue better predict MI than n-3 PUFA fractions.Methods: Subcutaneous adipose tissue biopsies were obtained in a random sample (n=3,500) of the Diet, Cancer and Health cohort (n=57,053). Adipose tissue content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), arachidonic acid (AA) and linoleic acid (LA) was determined using gas chromatography. Fractions of selected n-3 PUFAs and n-3/n-6 PUFA ratios were correlated to the 15-year occurrence of MI in a case-cohort design.Results: A total of 2,406 participants experienced an MI during follow-up. Adipose tissue total marine n-3 PUFAs, EPA+DHA, EPA, EPA/AA, DHA/AA and (EPA+DPA+DHA)/AA were all inversely associated with risk of incident MI. Evaluating the predictive power (Harrel's C-index) of the selected metrics, fractions of marine n-3 PUFAs and ratios of EPA/AA, DHA/AA, (EPA+DHA)/AA and (EPA+DPA+DHA)/AA all refined risk prediction over age and sex alone. At multivariable analyses, however, the above ratios were the only metrics providing additional risk prediction. Differences in ratios were related to differences in food intake.Conclusions: Both adipose tissue n-3 PUFAs fractions and ratios of n-3 PUFAs/AA were associated with a lower occurrence of MI, but ratios provided superior risk prediction. Dietary strategies affecting n-3/n-6 PUFA ratios should be further investigated for prediction of MI with dietary interventions at the population level and in intervention studies. Background: Tissue levels of n-3 polyunsaturated fatty acids (PUFAs) have been inversely related with risk of myocardial infarction (MI). Whether ratios of n-3 to n-6 PUFAs, reflecting both dietary intake of n-3 PUFAs and competing n-6 PUFAs, are better predictors of future MI than n-3 PUFA fractions is unclear. We aimed at investigating whether such ratios in adipose tissue better predict MI than n-3 PUFA fractions. Methods: Subcutaneous adipose tissue biopsies were obtained in a random sample (n = 3,500) of the Diet, Cancer and Health cohort (n = 57,053). Adipose tissue content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), arachidonic acid (AA) and linoleic acid was determined using gas chromatography. Fractions of selected n-3 PUFAs and n-3/n-6 PUFA ratios were correlated to the 15-year occurrence of MI in a case-cohort design. Results: A total of 2,406 participants experienced an MI during follow-up. Adipose tissue total marine n-3 PUFAs, EPA+DHA, EPA, EPA/AA, DHA/AA and (EPA + DPA + DHA)/AA were all inversely associated with risk of incident MI. Evaluating the predictive power (Harrel's C-index) of the selected metrics, fractions of marine n-3 PUFAs and ratios of EPA/AA, DHA/AA, (EPA + DHA)/AA and (EPA + DPA + DHA)/AA all refined risk prediction over age and sex alone. At multivariable analyses, however, the above ratios were the only metrics providing additional risk prediction. Differences in ratios were related to differences in food intake. Conclusions: Both adipose tissue n-3 PUFAs fractions and ratios of n-3 PUFAs/AA were associated with a lower occurrence of MI, but ratios provided superior risk prediction. Dietary strategies affecting n-3/n-6 PUFA ratios should be further investigated for prediction of MI with dietary interventions at the population level and in intervention studies.

A man in his mid-30s was admitted with a thunderclap headache. He was conscious and hypertensive. A decade earlier, severe hypertension had been diagnosed and extensively investigated without revealing an underlying cause. Brain imaging showed subarachnoid haemorrhage caused by a ruptured pericallosal aneurysm. Endovascular occlusion was attempted, but as the sheath could not pass the aortic arch, it was converted to surgical aneurismal clipping. Intraoperative blood pressure measurement revealed a peak-to-peak gradient of 100 mm Hg across the aortic arch and an ankle/brachial index of 0.46 (normal range 0.9–1.2). Aortic coarctation was suspected, and angiographic imaging and echocardiography confirmed the diagnosis. Subacute direct stenting was performed, which normalised the peak-to-peak gradient and ankle/brachial index. To minimise the risk of severe complications, early diagnosis of aortic coarctation is important and can be facilitated by ankle/brachial index and echocardiography in the suprasternal view.

Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health - Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications. Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio-and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.

Most people tend to overstate positive aspects of their experiences, that is, a positive valence bias. However, some people tend to have attenuated attention for negative aspects of perceived information, that is, negative valence bias. This dispositional tendency in either valence is especially significant for emotion regulation as it influences the intensity of later stages of emotional experiences. Heart rate variability (HRV) is used as an index of emotion regulation and for the effect dispositional valence bias has on social cognition. The aim of the current study was to investigate whether a positivity or negativity bias in processing ambiguous facial expressions would predict high or lower HRV, respectively, in a healthy sample. The Reading the Mind in the Eyes Test was presented to a sample of 128 healthy participants (N = 86 women participants), and resting HRV was acquired. In multiple linear regression analyses, the mean accuracy scores for items with positive, negative, and neutral valences were included as predictors of HRV. As a follow-up analysis, we tested whether a general tendency to interpret negative stimulus as positive, that is, a positivity bias, predicted HRV. Higher accuracy on items with negative emotional valence predicted lower HRV. There was no association between accuracy scores on items of positive or neutral valence and HRV. Higher positivity bias predicted higher HRV. The present findings suggest that a dispositional valence bias relates to levels of HRV and, as such, is influenced by the functioning of the vagal system. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Mercury (Hg) is a pollutant of global concern. Due to anthropogenic emissions, the atmospheric and surface ocean Hg burden has increased substantially since preindustrial times. Hg emitted into the atmosphere gets transported on a global scale and ultimately reaches the oceans. There it is transformed into highly toxic methylmercury (MeHg) that effectively accumulates in the food web. The international community has recognized this serious threat to human health and in 2017 regulated Hg use and emissions under the UN Minamata Convention on Mercury. Currently, the first effectiveness evaluation of the Minamata Convention is being prepared, and, in addition to observations, models play a major role in understanding environmental Hg pathways and in predicting the impact of policy decisions and external drivers (e.g., climate, emission, and land-use change) on Hg pollution. Yet, the available model capabilities are mainly limited to atmospheric models covering the Hg cycle from emission to deposition. With the presented model MERCY v2.0 we want to contribute to the currently ongoing effort to improve our understanding of Hg and MeHg transport, transformation, and bioaccumulation in the marine environment with the ultimate goal of linking anthropogenic Hg releases to MeHg in seafood. Here, we present the equations and parameters implemented in the MERCY model and evaluate the model performance for two European shelf seas, the North and Baltic seas. With the model evaluation, we want to establish a set of general quality criteria that can be used for evaluation of marine Hg models. The evaluation is based on statistical criteria developed for the performance evaluation of atmospheric chemistry transport models. We show that the MERCY model can reproduce observed average concentrations of individual Hg species in water (normalized mean bias: HgT 17 %, Hg0 2 %, MeHg −28 %) in the two regions mentioned above. Moreover, it is able to reproduce the observed seasonality and spatial patterns. We find that the model error for HgT(aq) is mainly driven by the limitations of the physical model setup in the coastal zone and the availability of data on Hg loads in major rivers. In addition, the model error in calculating vertical mixing and stratification contributes to the total HgT model error. For the vertical transport we find that the widely used particle partitioning coefficient for organic matter of log(kd)=5.4 is too low for the coastal systems. For Hg0 the model performance is at a level where further model improvements will be difficult to achieve. For MeHg, our understanding of the processes controlling methylation and demethylation is still quite limited. While the model can reproduce average MeHg concentrations, this lack of understanding hampers our ability to reproduce the observed value range. Finally, we evaluate Hg and MeHg concentrations in biota and show that modeled values are within the range of observed levels of accumulation in phytoplankton, zooplankton, and fish. The model performance demonstrates the feasibility of developing marine Hg models with similar predictive capability to established atmospheric chemistry transport models. Our findings also highlight important knowledge gaps in the dynamics controlling methylation and bioaccumulation that, if closed, could lead to important improvements of the model performance.

Background: Alzheimer’s disease (AD) carries a significant economic burden, with costs peaking around the time of diagnosis. However, the cost of diagnosis, including the time leading up to it, has not been studied thoroughly. Furthermore, regionalized healthcare structure could result in differences in the pre-diagnostic costs for people with suspected AD. Objective: This study set out to estimate the excess healthcare costs before and after AD diagnosis compared to a matched non-AD population and to investigate regional variation in AD healthcare costs in Denmark. Methods: We used a register-based cohort of 25,523 matched pairs of new cases of AD and non-AD controls. The healthcare costs included costs on medication, and inpatient-, outpatient-, and primary care visits. Generalized estimating equations were employed to estimate the excess healthcare cost attributable to diagnosing AD, and the variation in costs across regions. Results: Mean excess costs attributable to AD were € 3,284 and € 6,173 in the year before and after diagnosis, respectively. Regional differences in healthcare costs were identified in both the AD and control groups and were more pronounced in patients with AD (PwAD). Conclusion: PwAD incur higher healthcare costs across all cost categories in the year before and after diagnosis. Regional differences in healthcare utilization by PwAD may reveal potential variation in access to healthcare. These findings suggest that a more standardized and targeted diagnostic process may help reduce costs and variation in access to healthcare.

The rise in offshore oil and gas operations, maritime shipping, and tourism in northern latitudes enhances the risk of oil spills to sub-Arctic and Arctic coastal environments. Therefore, there is a need to understand the potential adverse effects of petroleum on key species in these areas. Here, we investigated the effects of oil exposure on the early life stages of capelin (Mallotus villosus), an ecologically and commercially important Barents Sea forage fish species that spawns along the coast of Northern Norway. Capelin embryos were exposed to five different concentrations (corresponding to 0.5–19 µg/L total PAHs) of water-soluble fraction (WSF) of crude oil from 6 days post fertilization (dpf) until hatch (25 dpf), and development of larvae in clean seawater was monitored until 52 dpf. None of the investigated endpoints (embryo development, larval length, heart rate, arrhythmia, and larval mortality) showed any effects. Our results suggest that the early life stages of capelin may be more robust to crude oil exposure than similar life stages of other fish species.

The use of a phase-retrieval technique for propagation-based phase-contrast neutron imaging with a polychromatic beam is demonstrated. This enables imaging of samples with low absorption contrast and/or improving the signal-to-noise ratio to facilitate e.g. time-resolved measurements. A metal sample, designed to be close to a phase pure object, and a bone sample with canals partially filled with D2O were used for demonstrating the technique. These samples were imaged with a polychromatic neutron beam followed by phase retrieval. For both samples the signal-to-noise ratios were significantly improved and, in the case of the bone sample, the phase retrieval allowed for separation of bone and D2O, which is important for example for in situ flow experiments. The use of deuteration contrast avoids the use of chemical contrast enhancement and makes neutron imaging an interesting complementary method to X-ray imaging of bone.

Background: Influenza vaccines have been demonstrated to effectively reduce the incidence of influenza infection and potentially associated risks of cardiovascular events in patients with cardiovascular disease (CVD). Despite strong guideline and public health endorsements, global influenza vaccination rates in patients with CVD are highly variable. This prespecified analysis of NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) examined the effect of digital behavioral nudges on influenza vaccine uptake based on the presence of CVD. Methods: NUDGE-FLU was a randomized, pragmatic, nationwide, register-based trial that included Danish citizens 65 years of age or older during the 2022 to 2023 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 electronic letters with designs based on behavioral concepts. Danish nationwide registers were used to collect baseline and outcome data. The primary end point was receipt of an influenza vaccine on or before January 1, 2023. The effects of the intervention letters were examined according to the presence of CVD and across cardiovascular subgroups that included heart failure, ischemic heart disease, and atrial fibrillation. Results: Of 964 870 NUDGE-FLU participants from 691 820 households, 264 392 (27.4%) had CVD. During follow-up, 83.1% of participants with CVD versus 79.2% of participants without CVD received an influenza vaccination ( P P for interaction=0.41). A repeated letter strategy with a reminder follow-up letter 14 days later was also effective in increasing influenza vaccination, irrespective of CVD (CVD: absolute difference, +0.80 percentage points [99.55% CI, –0.27 to 1.86]; no CVD: +0.67 percentage points [99.55% CI, –0.06 to 1.40]; P for interaction=0.77). Effectiveness of both nudging strategies was consistent across all major CVD subgroups. None of the other 7 nudging strategies were effective, regardless of CVD status. Conclusions: Electronic letter interventions emphasizing the potential cardiovascular benefits of influenza vaccination and using a reminder letter strategy were similarly beneficial in increasing influenza vaccination rates among older adults with and without CVD and across cardiovascular subgroups. Electronic nudges may improve influenza vaccine uptake in individuals with CVD. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05542004.

Introduction: It is unknown whether the cardiovascular risks associated with non-steroidal anti-inflammatory drug (NSAID) use differ according to lifestyle and socioeconomic position. Objective: We examined the association between NSAID use and major adverse cardiovascular events (MACE) within subgroups defined by lifestyle and socioeconomic position. Methods: We conducted a case-crossover study of all adult first-time respondents to the Danish National Health Surveys of 2010, 2013, or 2017, without previous cardiovascular disease, who experienced a MACE from survey completion through 2020. We used a Mantel-Haenszel method to obtain odds ratios (ORs) of the association between NSAID use (ibuprofen, naproxen, or diclofenac) and MACE (myocardial infarction, ischemic stroke, heart failure, or all-cause death). We identified NSAID use and MACE via nationwide Danish health registries. We stratified the analyses by body mass index, smoking status, alcohol consumption, physical activity level, marital status, education, income, and employment. Results: Compared with non-use, the OR of MACE was 1.34 (95% confidence interval: 1.23–1.46) for ibuprofen, 1.48 (1.04–2.43) for naproxen, and 2.18 (1.72–2.78) for diclofenac. When comparing NSAID use with non-use or the individual NSAIDs with each other, we observed no notable heterogeneity in the ORs within subgroups of lifestyle and socioeconomic position for any NSAID. Compared with ibuprofen, diclofenac was associated with increased risk of MACE in several subgroups with high cardiovascular risk, e.g., individuals with overweight (OR 1.52, 1.01–2.39) and smokers (OR 1.54, 0.96–2.46). Conclusions: The relative increase in cardiovascular risk associated with NSAID use was not modified by lifestyle or socioeconomic position.

Søren Hauge Okholm,1 Dávid Nagy,1 Dóra Körmendiné Farkas,1 Cecilia Hvitfeldt Fuglsang,1 Frederikke Schønfeldt Troelsen,1 Victor W Henderson,1,2 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 2Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USACorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43-45, Aarhus N, 8200, Denmark, Tel +45 87 16 82 15, Email hts@clin.au.dkIntroduction: Cancer may increase the risk of bleeding. However, whether subdural hematoma is a marker of occult cancer remains unknown. We examined the association between non-traumatic subdural hematoma and cancer risk in a cohort study.Materials and Methods: Using Danish nationwide health registries, we identified 2713 patients with non-traumatic subdural hematoma and no previous cancer diagnosis, who were hospitalized between April 1, 1996 and December 31, 2019. We computed age-, sex-, and calendar year-standardized incidence ratios (SIRs) as the ratio of the observed to expected number of patients with cancer by using national incidence rates as reference as a measure of relative risk.Results: We identified 77 cancer cases within the first year of follow-up and 272 cancer cases thereafter. The one-year risk of cancer was 2.8% (95% confidence interval: 2.2– 3.5), and the one-year SIR was 1.7 (95% confidence interval: 1.3– 2.1). During the subsequent years, the SIR was 1.0 (95% confidence interval: 0.9– 1.1). The relative risk was elevated for some hematological and liver cancers.Conclusion: The risk of a new cancer diagnosis was clearly increased in patients with non-traumatic subdural hematoma compared with the general population during the first year of follow-up. However, the absolute risk was low, thus limiting the clinical relevance of pursuing early cancer detection in these patients.Keywords: cancer, cohort study, epidemiology, non-traumatic subdural hematoma, population-based

Item does not contain fulltext BACKGROUND: The incidence of superficial vein thrombosis (SVT) of the legs and the subsequent risk of venous thromboembolism during pregnancy and the post-partum period is unknown. To better understand the clinical course of SVT during these times, we aimed to estimate the incidence rate of SVT during pregnancy and in the post-partum period, as well as the risk of subsequent venous thromboembolism. METHODS: In this nationwide cohort study, we collected data on all pregnant women who delivered between Jan 1, 1997, and Dec 31, 2017, in Denmark were extracted from the Danish Medical Birth Register, the Danish National Patient Registry, and the Danish National Prescription Registry. Data on ethnicity were not available. Incidence rates per 1000 person-years were calculated for each trimester and the antepartum and post-partum period. Among women with a pregnancy-related SVT, risk of subsequent venous thromboembolism within the same pregnancy or post-partum period were calculated and compared with a matched cohort of pregnant women without SVT using Cox proportional hazards analysis. FINDINGS: During 1 276 046 deliveries, 710 diagnoses of lower extremity SVT occurred from conception up to 12 weeks postpartum (0·6 per 1000 person-years [95% CI 0·5-0·6]). The incidence rates of SVT per 1000 person-years were 0·1 (95% CI 0·1-0·2) during the during the first trimester, 0·2 (0·2-0·3) during the second trimester, and 0·5 (0·5-0·6) during the third trimester. The incidence rate was 1·6 per 1000 person-years (95% CI 1·4-1·7) during the post-partum period. Of the 211 women with antepartum SVT included in the analysis, 22 (10·4%) were diagnosed with venous thromboembolism, compared with 25 (0·1%) in women without SVT (hazard ratio 83·3 [95% CI 46·3-149·7]). INTERPRETATION: The incidence rate of SVT during pregnancy and the post-partum period was low. However, if SVT during pregnancy was diagnosed, the risk of developing venous thromboembolism during the same pregnancy was high. These results might help physicians and patients to make decisions about anticoagulant management of pregnancy-related SVT. FUNDING: None.

Echocardiographic findings in chronic kidney disease (CKD) vary. We sought to estimate the prevalence of abnormal cardiac structure and function in patients with CKD and their association to estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (UACR).We prospectively enrolled 825 outpatients with non-dialysis-dependent CKD, mean age 58± 13 yrs, and 175 matched healthy controls, mean age 60±12 yrs. Echocardiography included assessment of left ventricular (LV) hypertrophy, LV ejection fraction (LVEF), global longitudinal strain (GLS) and diastolic dysfunction according to ASE/EACVI guidelines.LV hypertrophy was found in 9% of patients vs. 1.7% of controls (p=0.005) was independently associated with UACR (p=0.002). Median LVEF was 59.4% (IQR 55.2, 62.8) in patients vs. 60.8% (57.7, 64.1) in controls (p=0.002). GLS was decreased in patients with eGFR60ml/min/1.73m² (-17.6%±3.1%) vs. patients with higher eGFR (19.0%±2.2%, p0.001), who were similar to controls. Diastolic dysfunction was detected in 55% of patients and in 34% of controls.Non-random sampling, cross-sectional analysis.We report lower prevalence of hypertrophy than previous studies, but similar measurements of systolic and diastolic function. Cardiac remodeling in CKD may be influenced by treatment modalities, demographics, comorbidities and renal pathology.

DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.

In 2021, the Evidence into Practice Special Interest Group was launched with online events. At the 11th European Conference for Social Work Research in Amsterdam in April 2022, the Evidence into Practice Special Interest Group had its inaugural in-person sessions. This short article in the ‘Research, policy and practice exchange’ section of this new journal, European Social Work Research (a collaborative venture involving European Social Work Research Association), has been written to bring the launch of the Evidence into Practice Special Interest Group to a wider audience and to encourage participation. The article gives something of the context for the Evidence into Practice Special Interest Group and a flavour of the presentations at the 2022 European Conference for Social Work Research.

Norway is located in an intraplate setting with low-to-moderate seismicity. The mountainous landscape leads to a high level of landside activity throughout the country. Earthquake-induced landslides (EQILs) are common in seismically active areas, but there are only a few studies of EQILs in intraplate regions. We systematically analyse all earthquakes in Norway with magnitudes ≥ 4.5 in the time period 1800–2021 CE. For each event we search for reports of EQILs in the available macroseismic data and in the Norwegian landslide database. We furthermore consider precipitation data from the Norwegian Centre for Climate Services to evaluate the role of precipitation in the triggering of the identified potential EQILs. Through this approach, we identify 22 EQILs that have been triggered by eight earthquakes in the magnitude range 4.5–5.9. The events are widely distributed in northern and southern Norway. The maximum landslide distance limits and landslide-affected areas are much larger than those found in empirical studies of global datasets and are in agreement with data from other intraplate regions. For four of the earthquakes, it seems that landslide triggering was due to a combined effect of precipitation and earthquake ground shaking. Our observations confirm that intraplate earthquakes have the potential to trigger EQILs over large distances, most likely due to the low ground motion attenuation in such regions. Slope susceptibility seems to be another important factor in the triggering. Our conclusions demonstrate the importance of considering EQIL potential in earthquake risk management in intraplate regions.

International audience; Ice losses from the Greenland and Antarctic ice sheets have accelerated since the 1990s, accounting for a significant increase in the global mean sea level. Here, we present a new 29-year record of ice sheet mass balance from 1992 to 2020 from the Ice Sheet Mass Balance Inter-comparison Exercise (IMBIE). We compare and combine 50 independent estimates of ice sheet mass balance derived from satellite observations of temporal changes in ice sheet flow, in ice sheet volume, and in Earth's gravity field. Between 1992 and 2020, the ice sheets contributed 21.0±1.9 mm to global mean sea level, with the rate of mass loss rising from 105 Gt yr−1 between 1992 and 1996 to 372 Gt yr−1 between 2016 and 2020. In Greenland, the rate of mass loss is 169±9 Gt yr−1 between 1992 and 2020, but there are large inter-annual variations in mass balance, with mass loss ranging from 86 Gt yr−1 in 2017 to 444 Gt yr−1 in 2019 due to large variability in surface mass balance. In Antarctica, ice losses continue to be dominated by mass loss from West Antarctica (82±9 Gt yr−1) and, to a lesser extent, from the Antarctic Peninsula (13±5 Gt yr−1). East Antarctica remains close to a state of balance, with a small gain of 3±15 Gt yr−1, but is the most uncertain component of Antarctica's mass balance. The dataset is publicly available at https://doi.org/10.5285/77B64C55-7166-4A06-9DEF-2E400398E452 (IMBIE Team, 2021).

BackgroundVenous thromboembolism has been reported in patients with coronavirus disease 2019 (COVID-19). It remains unclear if premorbid use of prophylactic oral anticoagulation, for reasons other than COVID-19, protects against death in patients with COVID-19. The aim of this study was to estimate if the risk of all-cause mortality, hospital admission or intensive care unit (ICU) admission for individuals with verified SARS-CoV-2 was lower if patients used oral anticoagulant (OAC) therapy prior to a positive COVID-19 status.MethodsData were obtained using national health registries. Cohort entry was the day of a positive SARS-CoV-2 test, and individuals were followed for 14 days or until death or hospital admission. Adjusted Cox proportional hazard regressions and competing risk analyses were used to estimate the risk of all-cause mortality, hospital admission and ICU admission in OAC users compared with patients with no use of OAC.ResultsIn this nationwide cohort study a total of 244 522 individuals were included (median age 35 years (interquartile range 21–52); 124 095 (51%) female), among whom 3710 (1.5%) were OAC users. In the adjusted Cox regression cohort, there was no difference in risk of all-cause mortality in OACversusnon-OAC users. (hazard ratio (HR) 1.13, 95% CI 0.99–1.30). Hospital admission risk (HR 1.11, 95% CI 1.02–1.20) was slightly increased in OAC users, and there was no difference between the groups regarding the risk of ICU admission (HR 0.96, 95% CI 0.74–1.24).ConclusionsIn individuals with confirmed SARS-CoV-2, pre-existing treatment with OAC was not associated with prophylactic benefits in the prevention of hospital admission, ICU admissions or death. Prescription patterns should remain unchanged.

Understanding the nucleation and growth mechanisms of nanocrystals under hydro- and solvothermal conditions is key to tailoring functional nanomaterials. High-energy and high-flux synchrotron radiation is ideal for characterization by powder X-ray diffraction and X-ray total scattering in real time. Different versions of batch-type cell reactors have been employed in this work, exploiting the robustness of polyimide-coated fused quartz tubes with an inner diameter of 0.7 mm, as they can withstand pressures up to 250 bar and temperatures up to 723 K for several hours. Reported here are recent developments of the in situ setups available for general users on the P21.1 beamline at PETRA III and the DanMAX beamline at MAX IV to study nucleation and growth phenomena in solvothermal synthesis. It is shown that data suitable for both reciprocal-space Rietveld refinement and direct-space pair distribution function refinement can be obtained on a timescale of 4 ms.

A fundamental concept in neuroscience is the transmission of information between neurons via neurotransmitters, -modulators, and -peptides. For the past decades, the gold standard for measuring neurochemicals in awake animals has been microdialysis (MD). The emergence of genetically encoded fluorescencebased biosensors, as well as in vivo optical techniques such as fiber photometry (FP), has introduced technologically distinct means of measuring neurotransmission. To directly compare MD and FP, we performed concurrent within-animal recordings of extracellular dopamine (DA) in the dorsal striatum (DS) before and after administration of amphetamine in awake, freely behaving mice expressing the dopamine sensor dLight1.3b. We show that despite temporal differences, MD- and FP-based readouts of DA correlate well within mice. Down-sampling of FP data showed temporal correlation to MD data, with less variance observed using FP. We also present evidence that DA fluctuations periodically reach low levels, and naï ve animals have rapid, predrug DA dynamics measured with FP that correlate to the subsequent pharmacodynamics of amphetamine as measured with MD and FP. A fundamental concept in neuroscience is the transmission of information between neurons via neurotransmitters, -modulators, and -peptides. For the past decades, the gold standard for measuring neurochemicals in awake animals has been microdialysis (MD). The emergence of genetically encoded fluorescence-based biosensors, as well as in vivo optical techniques such as fiber photometry (FP), has introduced technologically distinct means of measuring neurotransmission. To directly compare MD and FP, we performed concurrent within-animal recordings of extracellular dopamine (DA) in the dorsal striatum (DS) before and after administration of amphetamine in awake, freely behaving mice expressing the dopamine sensor dLight1.3b. We show that despite temporal differences, MD- and FP-based readouts of DA correlate well within mice. Down-sampling of FP data showed temporal correlation to MD data, with less variance observed using FP. We also present evidence that DA fluctuations periodically reach low levels, and naïve animals have rapid, predrug DA dynamics measured with FP that correlate to the subsequent pharmacodynamics of amphetamine as measured with MD and FP.

The gut microbiome is shaped through infancy and impacts the maturation of the immune system, thus protecting against chronic disease later in life. Phages, or viruses that infect bacteria, modulate bacterial growth by lysis and lysogeny, with the latter being especially prominent in the infant gut. Viral metagenomes (viromes) are difficult to analyse because they span uncharted viral diversity, lacking marker genes and standardized detection methods. Here we systematically resolved the viral diversity in faecal viromes from 647 1-year-olds belonging to Copenhagen Prospective Studies on Asthma in Childhood 2010, an unselected Danish cohort of healthy mother–child pairs. By assembly and curation we uncovered 10,000 viral species from 248 virus family-level clades (VFCs). Most (232 VFCs) were previously unknown, belonging to the Caudoviricetes viral class. Hosts were determined for 79% of phage using clustered regularly interspaced short palindromic repeat spacers within bacterial metagenomes from the same children. Typical Bacteroides-infecting crAssphages were outnumbered by undescribed phage families infecting Clostridiales and Bifidobacterium. Phage lifestyles were conserved at the viral family level, with 33 virulent and 118 temperate phage families. Virulent phages were more abundant, while temperate ones were more prevalent and diverse. Together, the viral families found in this study expand existing phage taxonomy and provide a resource aiding future infant gut virome research.

Background: Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC. Methods: The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the National Heart, Lung, and Blood Institute –funded Multi-Ethnic Study of Atherosclerosis. Results: During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04–1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06–1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87–1.18]). Similarly, a very high LDL-C level ( > 193 mg/dL) versus LDL-C 0 (aHR, 2.42 [95% CI, 1.59–3.67]) but not in those without CAC (aHR, 0.92 [0.48–1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis. Conclusions: LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis.

This study aimed to investigate the effect of the different dry-off strategies based on reducing feeding level (normal vs. reduced energy density), reducing milking frequency (twice vs. once daily), and administration of a dopamine agonist after last milking (i.e. saline vs. cabergoline injection) on blood metabolites, hormones, and minerals around dry-off. In this experiment, 119 Holstein dairy cows were used in a 2 × 2 × 2 factorial arrangement. In the last week before dry-off, cows were allocated to 1 of the 4 possible dry-off strategies based on feeding level and milking frequency. Within 3 h after last milking, cows were injected with either saline or a D2 dopamine agonist (cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, e.g., no preceding reduction in feeding level or milking frequency before last milking). After dry-off, all cows were fed the same dry cow diet and data collection continued for a week. Blood samples were collected from the coccygeal vein on d -9, -6, -5, -2, 1, 2, 5, and 7 relative to dry-off. Additionally, blood was sampled at 0, 3, and 6 h relative to injection of either cabergoline or saline, equivalent to d 0.125, 0.250, and 0.375 relative to last milking (dry-off). The reduced feeding level before dry-off caused reduced glucose and insulin concentrations as well as increased free fatty acid concentrations, particularly when reduced feeding level was combined with milking the cows 2× daily. The intramuscular injection of cabergoline caused the expected reduction in circulating prolactin concentrations. In addition, dopamine-agonist cabergoline induced an atypical simultaneous pattern of plasma metabolites (i.e., increased glucose and free fatty acid concentrations), hormones (i.e., reduced insulin and increased cortisol concentrations), and minerals (i.e., reduced calcium concentration), indicating that normal metabolic and mineral homeostatic regulations were hindered after the injection of ergot alkaloid cabergoline. In conclusion, reducing milking frequency seems the best management strategy to reduce milk production at dry-off among those tested in this study.

This study aimed to evaluate the development of healthcare teamwork during and after the collaboration tabletop exercises, through observation and interview methods. Integration and maturity theoretical models were employed to explain the collaborative challenges in teams that may suffer from unequally distributed power, hierarchies, and fragmentation. Using three-level collaboration tabletop exercises and the Command and control, Safety, Communication, Assessment, Treatment, Triage, Transport (CSCATTT) instrument, 100 healthcare workers were observed during each step in the implementation of the CSCATTT instrument using two simulated scenarios. The results show a lack of integration and team maturity among participants in the first scenario, leading to the delayed start of the activity, task distribution, and decision making. These shortcomings were improved in the second scenario. In-depth interviews with 20 participants in the second phase of the study revealed improved knowledge and practical skills, self-confidence, and ability in team building within trans-professional groups in the second scenario, which in concordance with the integration theory, was due to the attempts made in the first scenario. Additionally, there was an improvement in the team’s maturity, which in concordance with the maturity theory, was due to the knowledge and practical skills during scenario plays. These results indicate the importance of continuous tabletop training, and the use of CSCATTT as a collaborative instrument, to promote the development of collaboration and to test the concept of preparedness.

Organoid technologies are rapidly advancing and holds great potential and hope for disease modelling and clinical translational research. Still, they raise a number of complex, ethical questions regarding their current and future use. Patient and public involvement is important in building public trust and helping to secure responsible conduct and valued innovations; nevertheless, research into patient and public perspectives on organoid technologies remains scarce. We report on a first public dialogue on organoid technologies through three cross-country deliberative workshops with a diverse group of stakeholders to identify their perceptions and concerns. Participants generally support organoid technologies on the condition that responsible governance, ethical oversight, and sound informed consent procedures are in place. Yet, a broad set of potential concerns are identified, primarily concerning commercialization, health-care access, and cerebral organoids. Participants’ insights and recommendations can help inform researchers, ethics and policy bodies toward supporting responsible and ethical organoid approaches. Organoid technologies are rapidly advancing and hold great potential and hope for disease modeling and clinical translational research.Still, they raise a number of complex, ethical questions regarding their current and future use. Patient and public involvement is importantin building public trust and helping to secure responsible conduct and valued innovations; nevertheless, research into patient andpublic perspectives on organoid technologies remains scarce.We report on a first public dialogue on organoid technologies through threecross-country deliberative workshops with a diverse group of stakeholders to identify their perceptions and concerns. Participants generallysupport organoid technologies on the condition that responsible governance, ethical oversight, and sound informed consentprocedures are in place. Yet, a broad set of potential concerns are identified, primarily concerning commercialization, healthcare access,and cerebral organoids. Participants’ insights and recommendations can help inform researchers and ethics and policy bodies towardsupporting responsible and ethical organoid approaches.

Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels 75nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75nmol/L during pregnancy may be beneficial for testes function in adult sons.

What legitimises archaeological work in an age of global climate change, socio-political crises and economic recession? On what topics should archaeology focus its research questions, and what forms of archaeological engagement are not merely justifiable but able to make a difference in light of such challenges? Today, there is a tendency, we argue, that archaeological responses to current challenges are expected to align with a specific mode of conduct, political stance and genre, where, for example, a very particular notion of activism, responsibility and ethics is dominating. There is no denial that current challenges call for immediate instrumental reactions, but we contend that valuable reactions can – or even must – vary, and that more fundamental and slow ontological and epistemological change should also be nested within these responses. In this article, we explore what it means to care – what it means to be concerned – in the Anthropocene through archaeological practice and aesthetic engagement. By highlighting the relations between ethics and aesthetics we explore ways in which we get in touch with the objects of care, placing undecidability and speculation as dispositions equally important to urgency and impact. What legitimizes archaeological work in an age of global climate change, socio-political crises and economic recession? On what topics should archaeology focus its research questions, and what forms of archaeological engagement are not merely justifiable but able to make a difference in light of such challenges? Today, there is a tendency, we argue, that archaeological responses to current challenges are expected to align with a specific mode of conduct, political stance and genre, where, for example, a very particular notion of activism, responsibility and ethics is dominating. There is no denial that current challenges call for immediate instrumental reactions, but we contend that valuable reactions can – or even must – vary, and that more fundamental and slow ontological and epistemological change should also be nested within these responses. In this article, we explore what it means to care – what it means to be concerned – in the Anthropocene through archaeological practice and aesthetic engagement. By highlighting the relations between ethics and aesthetics, we explore ways in which we get in touch with the objects of concern, placing undecidability and speculation as dispositions equally important to urgency and impact.

We construct and run an experiment to test the most basic choice effect predicted by Salience Theory. Subjects allocate wealth between a risky and a safe investment. While we vary an apparent payoff ratio to influence salience, treatments have economically equivalent consequences. Most other theories of behavior then predict zero effect. Our experimental findings are strongly consistent with the behavioral implication of a continuous version of Salience Theory. We provide a novel structural estimate on the strength of salience. In our setting, increasing the relative payoff contrast by one percent is equivalent to an increased odds ratio by about 0.4 percent.

Emulsions are implemented in the fabrication of a wide array of foods and therefore are of great importance in food science. However, the application of emulsions in food production is restricted by two main obstacles, that is, physical and oxidative stability. The former has been comprehensively reviewed somewhere else, but our literature review indicated that there is a prominent ground for reviewing the latter across all kinds of emulsions. Therefore, the present study was formulated in order to review oxidation and oxidative stability in emulsions. In doing so, different measures to render oxidative stability to emulsions are reviewed after introducing lipid oxidation reactions and methods to measure lipid oxidation. These strategies are scrutinized in four main categories, namely storage conditions, emulsifiers, optimization of production methods, and antioxidants. Afterward, oxidation in all types of emulsions, including conventional ones (oil-in-water and water-in-oil) and uncommon emulsions in food production (oil-in-oil), is reviewed. Furthermore, the oxidation and oxidative stability of multiple emulsions, nanoemulsions, and Pickering emulsions are taken into account. Finally, oxidative processes across different parent and food emulsions were explained taking a comparative approach.

Background and purpose: Joint stability after hip replacement (HR) in patients with metastatic bone disease (MBD) is of special importance. Dislocation is the second leading cause of implant revision in HR, while survival after MBD surgery is poor with an expected 1-year survival of around 40%. As few studies have investigated the dislocation risk across different articulation solutions in MBD, we conducted a retrospective study on primary HR for patients with MBD treated in our department.Patients and methods: The primary outcome is the 1-year cumulative incidence of dislocation. We included patients with MBD who received HR at our department in 2003–2019. We excluded patients with partial pelvic reconstruction, total femoral replacement, and revision surgery. We assessed the incidence of dislocation with competing risk analysis with death and implant removal as competing risks.Results: We included 471 patients. Median follow-up was 6.5 months. The patients received 248 regular total hip arthroplasties (THAs), 117 hemiarthroplasties, 70 constrained liners, and 36 dual mobility liners. Major bone resection (MBR), defined as resection below the lesser trochanter, was performed in 63%. The overall 1-year cumulative incidence of dislocation was 6.2% (95% CI 4.0–8.3). Dislocation stratified by articulating surface was 6.9% (CI 3.7–10) for regular THA, 6.8% (CI 2.3–11) for hemiarthroplasty, 2.9% (CI 0.0–6.8) for constrained liner, and 5.6% (CI 0.0–13) for dual mobility liners. There was no significant difference between patients with and without MBR (p = 0.5).Conclusion: The 1-year cumulative incidence of dislocation is 6.2% in patients with MBD. Further studies are needed to determine any real benefits of specific articulations on the risk of postoperative dislocation in patients with MBD.

The aim of the study was to investigate if black soldier fly (Hermetia illucens) larvae can be grown on sludge from a salmonid fresh-water recirculating aquaculture system facility in a small pilot-scale trial. The growth and transfer of both nutrients and unwanted components from the sludge to the insect larvae was analysed. A commercial chicken feed was used as a control growth substrate and up to 100% of the chicken feed was replaced with aquaculture sludge. Replacing 40% of the chicken feed with aquaculture sludge did not influence the growth of the larvae. A gradual decrease in growth was, however seen at a sludge inclusion of higher than 40%. Proximate (crude protein and fat, dry matter) and amino acid composition of the larvae stayed stable across treatments, while ash content increased with higher sludge inclusion. An accumulation of elements such as Zn, Fe and Se was observed in the larvae with increasing amount of sludge in the growth substrate. The larvae also accumulated unwanted elements regulated by EU feed legislation such as As, Hg and Cd. Both As and Hg in the larvae exceeded the legal EU limits for feed ingredients, but only in the two highest levels of sludge inclusion (80 and 100% sludge). Fatty acid composition reflected the substrate, with the sludge-fed larvae being enriched in marine n-3 poly unsaturated fatty acids. No salmon pathogens were detected in the larvae. The trial showed that it is possible to grow black soldier fly larvae on aquaculture sludge but points at a few feed safety risk factors which need to be further elucidated before a use of sludge as growth material for insects can be considered.

Christian Kjer Heerfordt,1 Josefin Eklöf,1 Pradeesh Sivapalan,1 Truls Sylvan Ingebrigtsen,1 Tor Biering-Sørensen,2– 4 Zitta Barrella Harboe,4,5 Jesper Koefod Petersen,6,7 Christian Østergaard Andersen,8 Jonas Bredtoft Boel,9 Anne Kathrine Bock,10 Alexander G Mathioudakis,11,12 John R Hurst,13 Shailesh Kolekar,7 Sofie Lock Johansson,14 Jette Marie Bangsborg,9 Jens Otto Jarløv,9 Ram Benny Dessau,15 Christian Borbjerg Laursen,14,16 Michael Perch,4,17 Jens-Ulrik Stæhr Jensen1,4,18 1Section of Respiratory Medicine, Department of Medicine, Copenhagen University Hospital Herlev and Gentofte Hospital, Hellerup, Denmark; 2Department of Cardiology, Herlev and Gentofte Hospital, Cardiovascular Non-Invasive Imaging Research Laboratory, University of Copenhagen, Copenhagen, Denmark; 3Faculty of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark; 4Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Department of Respiratory Medicine and Infectious Diseases, Copenhagen University Hospital, North Zealand, Denmark; 6Department of Respiratory Medicine, Zealand University Hospital Naestved, Naestved, Denmark; 7Department of Pulmonary Medicine, Zealand University Hospital, Roskilde, Denmark; 8Department of Clinical Microbiology, Hvidovre University Hospital, Hvidovre, Denmark; 9Department of Clinical Microbiology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark; 10Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 11The North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK; 12Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; 13UCL Respiratory, University College London, London, UK; 14Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark; 15Department of Clinical Microbiology, Zealand University Hospital, Slagelse Hospital, Slagelse, Denmark; 16Institute for Clinical Research, University of Southern Denmark, Odense, Denmark; 17Department of Cardiology, Section for Lung Transplantation, Rigshospitalet, Copenhagen, Denmark; 18PERSIMUNE & CHIP: Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Christian Kjer Heerfordt, Section of Respiratory Medicine, Department of Medicine, Copenhagen University Hospital Herlev and Gentofte Hospital, Hellerup, Denmark, Tel +4523303431, Email christian.kjer.heerfordt@regionh.dkBackground: Inhaled corticosteroids (ICS) are associated with an increased risk of clinical pneumonia among patients with chronic obstructive pulmonary disease (COPD). It is unknown whether the risk of microbiologically verified pneumonia such as pneumococcal pneumonia is increased in ICS users.Methods: The study population consists of all COPD patients followed in outpatient clinics in eastern Denmark during 2010– 2017. ICS use was categorized into four categories based on accumulated use. A Cox proportional hazard regression model was used adjusting for age, body mass index, sex, airflow limitation, use of oral corticosteroids, smoking, and year of cohort entry. A propensity score matched analysis was performed for sensitivity analyses.Findings:  A total of 21,438 patients were included. Five hundred and eighty-two (2.6%) patients acquired a positive lower airway tract sample with S. pneumoniae during follow-up. In the multivariable analysis ICS-use was associated with a dose-dependent risk of S. pneumoniae as follows: low ICS dose: HR 1.11, 95% CI 0.84 to 1.45, p = 0.5; moderate ICS dose: HR 1.47, 95% CI 1.13 to 1.90, p = 0.004; high ICS dose: HR 1.77, 95% CI 1.38 to 2.29, p < 0.0001, compared to no ICS use. Sensitivity analyses confirmed these results.Interpretation: Use of ICS in patients with severe COPD was associated with an increased and dose-dependent risk of acquiring S. pneumoniae, but only for moderate and high dose. Caution should be taken when administering high dose of ICS to patients with COPD. Low dose of ICS seemed not to carry this risk.Keywords: COPD, inhaled corticosteroids, Streptococcus pneumoniae, clinical epidemiology