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Introduction How e-cigarette use relates to changes in smoking status and respiratory symptoms in the population remains controversial. The aim was to study the association between e-cigarette use and, changes in smoking status and changes in respiratory symptoms. Methods A prospective, population-based study of random samples of the population (age 16–69 years) was performed within The Obstructive Lung Disease in Northern Sweden (OLIN) study and West Sweden Asthma Study (WSAS). A validated postal questionnaire containing identical questions was used in OLIN and WSAS at baseline in 2006–2008 and at follow-up in 2016. In total, 17325 participated on both occasions. Questions about respiratory symptoms and tobacco smoking were included in both surveys, while e-cigarette use was added in 2016. Results In 2016, 1.6% used e-cigarettes, and it was significantly more common in persistent tobacco smokers (10.6%), than in those who quit smoking (2.1%), started smoking (7.8%), or had relapsed into tobacco smoking at follow-up (6.4%) (p

Abstract Background Evidence on the role of exogenous female sex steroid hormones in asthma development in women remains conflicting. We sought to quantify the potential causal role of hormonal contraceptives and menopausal hormone therapy (MHT) in the development of asthma in women. Methods We conducted a matched case–control study based on the West Sweden Asthma Study, nested in a representative cohort of 15,003 women aged 16–75 years, with 8-year follow-up (2008–2016). Data were analyzed using Frequentist and Bayesian conditional logistic regression models. Results We included 114 cases and 717 controls. In Frequentist analysis, the odds ratio (OR) for new-onset asthma with ever use of hormonal contraceptives was 2.13 (95% confidence interval [CI] 1.03–4.38). Subgroup analyses showed that the OR increased consistently with older baseline age. The OR for new-onset asthma with ever MHT use among menopausal women was 1.17 (95% CI 0.49–2.82). In Bayesian analysis, the ORs for ever use of hormonal contraceptives and MHT were, respectively, 1.11 (95% posterior interval [PI] 0.79–1.55) and 1.18 (95% PI 0.92–1.52). The respective probability of each OR being larger than 1 was 72.3% and 90.6%. Conclusions Although use of hormonal contraceptives was associated with an increased risk of asthma, this may be explained by selection of women by baseline asthma status, given the upward trend in the effect estimate with older age. This indicates that use of hormonal contraceptives may in fact decrease asthma risk in women. Use of MHT may increase asthma risk in menopausal women.

In Sweden and the other Scandinavian countries children are offered a curricular based combination of care and teaching before and after compulsory school hours. These leisure time centers, so-called "fritidshem," are offered to children aged between 6 and 12 whose parents' study or work, as well as to children that require special development support. The aim of this systematic literature review was to investigate how similar activities are described in international research. The focus was on children aged 6-12 who have been assessed to need special support. The initial step in this literature survey was the reading of 108 abstracts from academic articles. The second step included 21 articles that were read in their entirety. Fourteen of them met the sampling criteria and were included in the result section. The Nordic model combines care and curricular activities before and after compulsory school hours. In other countries activities taking place after school hours are separated into activities meeting children's need of care and activities supplementing school. Another result that became clear in this research is the need of further studies to map pre- and after-school activities where children are simultaneously offered development support and care, with special focus on children in need of extra support.

Summary: SAMHD1 is a dNTP triphosphohydrolase governing nucleotide pool homeostasis and can detoxify chemotherapy metabolites controlling their clinical responses. To understand SAMHD1 biology and investigate the potential of targeting SAMHD1 as neoadjuvant to current chemotherapies, we set out to discover selective small-molecule inhibitors. Here, we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for rigorous characterization of the screen output. The identified small molecules, TH6342 and analogs, accompanied by inactive control TH7126, demonstrated specific, low μM potency against both physiological and oncology-drug-derived substrates. By coupling kinetic studies with thermal shift assays, we reveal the inhibitory mechanism of TH6342 and analogs, which engage pre-tetrameric SAMHD1 and deter oligomerization and allosteric activation without occupying nucleotide-binding pockets. Altogether, our study diversifies inhibitory modes against SAMHD1, and the discovery pipeline reported herein represents a thorough framework for future SAMHD1 inhibitor development.

Abstract Background Diabetes and prediabetes are known risk factors for cardiovascular disease and associated with increased mortality risk. Whether patients with a random elevated blood glucose level but no history of diabetes are at a higher mortality and cardiovascular risk is not entirely known. Methods A retrospective cohort study where patients (18–80 years) with no history of diabetes between 2006 and 2016 attending the emergency department (ED) in Sweden were included. Based on the first (index) blood glucose level patients were categorized into four groups: hypoglycemia ( 11.1 mmol/L). Data was collected from four nationwide registers (National Patient Register, National Cause of Death Register, Prescribed Drug Register and Statistics Sweden). Cox regression was used to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI) for all-cause mortality and cardiovascular outcomes using NGT as reference. Results 618,694 patients were included during a mean follow-up time of 3.9 years. According to the index blood glucose level: 1871 (0.3%) had hypoglycemia, 525,636 (85%) had NGT, 77,442 (13%) had dysglycemia, and 13,745 (2%) patients had hyperglycemia, respectively. During follow-up 44,532 (7.2%) deaths occurred. After multiple adjustments, mortality risk was highest in patients with hypoglycemia HR 2.58 (2.26–2.96) followed by patients with hyperglycemia HR 1.69 (1.63–1.76) and dysglycemia HR 1.16 (1.13–1.19). Risk for cardiovascular events: i.e., myocardial infarction, stroke and heart failure, were highest among patients with hyperglycemia HR 2.28 (2.13–2.44), HR 1.62 (1.51–1.74) and HR 1.60 (1.46–1.75), respectively. Conclusion Patients with disturbed blood glucose level at ED admission have a higher mortality risk than patients with NGT. Patients with hyperglycemia have almost a two folded increased long-term mortality risk and more than a doubled risk for cardiovascular events compared to patients with NGT.

Abstract Background Over the last decade, computational sciences have contributed immensely to characterization of phenotypes of airway diseases, but it is difficult to compare derived phenotypes across studies, perhaps as a result of the different decisions that fed into these phenotyping exercises. We aim to perform a systematic review of studies using computational approaches to phenotype obstructive airway diseases in children and adults. Methods and analysis We will search PubMed, Embase, Scopus, Web of Science, and Google Scholar for papers published between 2010 and 2020. Conferences proceedings, reference list of included papers, and experts will form additional sources of literature. We will include observational epidemiological studies that used a computational approach to derive phenotypes of chronic airway diseases, whether in a general population or in a clinical setting. Two reviewers will independently screen the retrieved studies for eligibility, extract relevant data, and perform quality appraisal of included studies. A third reviewer will arbitrate any disagreements in these processes. Quality appraisal of the studies will be undertaken using the Effective Public Health Practice Project quality assessment tool. We will use summary tables to describe the included studies. We will narratively synthesize the generated evidence, providing critical assessment of the populations, variables, and computational approaches used in deriving the phenotypes across studies Conclusion As progress continues to be made in the area of computational phenotyping of chronic obstructive airway diseases, this systematic review, the first on this topic, will provide the state of the art on the field and highlight important perspectives for future works. Ethics and dissemination No ethical approval is needed for this work is based only on the published literature and does not involve collection of any primary or human data. Registration and reporting Systematic review registration PROSPERO CRD42020164898

Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 48 imidazo [1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an IC50 value of 1.0 µM. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound’s metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding.

The extraction of timber is expensive, energy intensive, and potentially damaging to the forest soil. Machine development aims to mitigate risks for environmental impact and decrease energy consumption while maintaining or increasing cost efficiency. The development of rubber-tracked forwarders has gained renewed interest, not least due to climate change leading to unreliable weather in combination with low tolerance for soil damage. The increased cost of rubber tracks compared to wheels is believed to be compensated by higher driving speed enabled by semi-active suspension. Thus, the aim of this study was to theoretically investigate how the productivity and cost efficiency of rubber-tracked forwarders are affected by variations in driving speed and machine costs. The calculations were made with fixed stand parameters, to evaluate performance in well-defined working conditions, and with parameters from 2500 final felling stands in central Sweden, to evaluate performance in varied working conditions. Scenarios were compared to a baseline corresponding to mid-sized wheeled forwarders. The results show higher productivity with the increased driving speed enabled by rubber tracks and suspension at all extraction distances, with larger differences at long extraction distances. Assuming a 15% higher machine price for the rubber-tracked forwarder and a variable cost increase proportional to speed increase, extraction costs break even with the baseline at 400 m and 700 m extraction distance for moderate and fast driving speed, respectively. Furthermore, a rubber-tracked forwarder is likely to enable access to a larger part of the harvest area during longer seasons. For the studied set of stands, the year-round accessible volumes are estimated to increase from 9% to 92% with a rubber-tracked forwarder. With rubber tracks instead of wheels, good accessibility has the potential to be combined with low soil impact and cost efficiency in a favourable way for both industry and ecosystem.

Abstract Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for the hydrolysis of triacylglycerols stored in adipocytes. To increase our understanding of the genetic regulation of body fat distribution and total body fat, we set out to determine if genetic variants associated with body mass index (BMI) or waist-hip-ratio adjusted for BMI (WHRadjBMI) in genome-wide association studies (GWAS) mediate their effect by influencing adipocyte lipolysis. We utilized data from the recent GWAS of spontaneous and isoprenaline-stimulated lipolysis in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort. GENiAL consists of 939 participants who have undergone abdominal subcutaneous adipose biopsy for the determination of spontaneous and isoprenaline-stimulated lipolysis in adipocytes. We report 11 BMI and 15 WHRadjBMI loci with SNPs displaying nominal association with lipolysis and allele-dependent gene expression in adipose tissue according to in silico analysis. Functional evaluation of candidate genes in these loci by small interfering RNAs (siRNA)-mediated knock-down in adipose-derived stem cells identified ZNF436 and NUP85 as intrinsic regulators of lipolysis consistent with the associations observed in the clinical cohorts. Furthermore, candidate genes in another BMI-locus (STX17) and two more WHRadjBMI loci (NID2, GGA3, GRB2) control lipolysis alone, or in conjunction with lipid storage, and may hereby be involved in genetic control of body fat. The findings expand our understanding of how genetic variants mediate their impact on the complex traits of fat storage and distribution.

The grain texture of the as-printed material evolves during the laser-based powder bed fusion (PBF-LB) process. The resulting mechanical properties are dependent on the obtained grain texture and the properties vary depending on the chosen process parameters such as scan velocity and laser power. A coupled 2D Cellular Automata and Finite Element model (2D CA-FE) is developed to predict the evolution of the grain texture during solidification of the nickel-based superalloy 625 produced by PBF-LB. The FE model predicts the temperature history of the build, and the CA model makes predictions of nucleation and grain growth based on the temperature history. The 2D CA-FE model captures the solidification behavior observed in PBF-LB such as competitive grain growth plus equiaxed and columnar grain growth. Three different nucleation densities for heterogeneous nucleation were studied, 1 × 1011, 3 × 1011, and 5 × 1011. It was found that the nucleation density 3 × 1011 gave the best result compared to existing EBSD data in the literature. With the selected nucleation density, the aspect ratio and grain size distribution of the simulated grain texture also agrees well with the observed textures from EBSD in the literature.

Additive manufacturing by laser-based powder bed fusion is a promising technique for bulk metallic glass production. But, reheating by deposition of subsequent layers may cause local crystallisation of the alloy. To investigate the crystalline phase evolution during laser scanning of a Zr-based metallic glass-forming alloy, a simulation strategy based on the finite element method and the classical nucleation theory has been developed and compared with experimental results from multiple laser remelting of a single-track. Multiple laser remelting of a single-track demonstrates the crystallisation behaviour by the influence of thermal history in the reheated material. Scanning electron microscopy and transmission electron microscopy reveals the crystalline phase evolution in the heat affected zone after each laser scan. A trend can be observed where repeated remelting results in an increased crystalline volume fraction with larger crystals in the heat affected zone, both in simulation and experiment. A gradient of cluster number density and mean radius can also be predicted by the model, with good correlation to the experiments. Prediction of crystallisation, as presented in this work, can be a useful tool to aid the development of process parameters during additive manufacturing for bulk metallic glass formation.

This paper examines the interior as a condition that is continuously in production through the arrangement of objects and furniture. This is done along two lines of inquiry. First by examining a few different historical and contemporary conceptions of the domestic interior through the lens of architectural representation. Second by using the technique of laser scanning to document a number of inhabited interiors in two apartment buildings. Through a series of representations, or cloud drawings, produced from the scans, the paper presents three ways of reading the interior: as environments, as assemblies, and as materialities. Departing from Robin Evans’ writing on drawing techniques for representing the interior and their correlation to ways of inhabitation, the paper poses questions around how the understanding of the interior may shift when using emerging techniques for architectural representation. Through readings of Walter Benjamin as well as Sylvia Lavin, the paper discusses such shifts in relation to changes in the conception of the interior and the objects that it contains.

Abstract Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.

Heidi Andersén,1 Pinja Ilmarinen,1 Jasmin Honkamäki,1 Leena E Tuomisto,2 Hanna Hisinger-Mölkänen,3 Helena Backman,4 Bo Lundbäck,5 Eva Rönmark,4 Lauri Lehtimäki,1 Anssi Sovijärvi,3 Päivi Piirilä,3 Hannu Kankaanranta1 1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 2Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Etelä-Pohjanmaa, Finland; 3Faculty of Medicine, University of Helsinki, Helsinki, Uusimaa, Finland; 4Department of Public Health and Clinical Medicine, Umeå University, Umeå, Norrbotten, Sweden; 5Department of Internal Medicine, Krefting Research Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Västra Götaland, SwedenCorrespondence: Heidi AndersénFaculty of Medicine and Health Technology, Tampere University, Kalevantie 4, Tampere, 33100, FinlandEmail heidi.andersen@tuni.fiPurpose: Asthma is a heterogeneous disease, and factors associated with different asthma phenotypes are poorly understood. Given the higher prevalence of farming exposure and late diagnosis of asthma in more rural Western Finland as compared with the capital of Helsinki, we investigated the relationship between childhood farming environment and age at asthma diagnosis.Methods: A cross-sectional population-based study was carried out with subjects aged 20– 69 years in Western Finland. The response rate was 52.5%. We included 3864 participants, 416 of whom had physician-diagnosed asthma at a known age and with data on the childhood environment. The main finding was confirmed in a similar sample from Helsinki. Participants were classified as follows with respect to asthma diagnosis: early diagnosis (0– 11 years), intermediate diagnosis (12– 39 years), and late diagnosis (40– 69 years).Results: The prevalence of asthma was similar both without and with childhood exposure to a farming environment (11.7% vs 11.3%). Allergic rhinitis, family history of asthma, ex-smoker, occupational exposure, and BMI ≥ 30 kg/m2 were associated with a higher likelihood of asthma. Childhood exposure to a farming environment did not increase the odds of having asthma (aOR, 1.10; 95% CI, 0.87– 1.40). It did increase the odds of late diagnosis (aOR, 2.30; 95% CI, 1.12– 4.69), but the odds were lower for early (aOR, 0.49; 95% CI, 0.30– 0.80) and intermediate diagnosis of asthma (aOR, 0.75; 95% CI, 0.47– 1.18).Conclusion: Odds were lower for early diagnosis of asthma and higher for late diagnosis of asthma in a childhood farming environment. This suggests a new hypothesis concerning the etiology of asthma when it is diagnosed late.Keywords: agriculture, early-diagnosed asthma, intermediate-diagnosed asthma, late-diagnosed asthma, risk factors, phenotypes

Lina Rönnebjerg,1 Malin Axelsson,2 Hannu Kankaanranta,1,3,4 Helena Backman,5 Madeleine Rådinger,1 Bo Lundbäck,1 Linda Ekerljung1 1Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 2Department of Care Science, Faculty of Health and Society, Malmö University, Malmö, Sweden; 3Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland; 4Tampere University Respiratory Research Group, Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland; 5Department of Public Health and Clinical Medicine, Umeå University, Umeå, SwedenCorrespondence: Lina RönnebjergKrefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Box 424, 405 30, Gothenburg, SwedenTel +46 31 786 67 09Email lina.ronnebjerg@gu.sePurpose: Current guidelines primarily use medication levels to distinguish severe asthma from other types of asthma. In addition, severe asthma must also be uncontrolled at high-intensity treatment or become uncontrolled if treatment level is decreased. To date, only a few studies have used this definition to investigate the prevalence and clinical characteristics of severe asthma in population-based samples. Therefore, the aim of this study was to evaluate the prevalence and clinical characteristics of individuals with severe asthma in the population-representative West Sweden Asthma Study.Materials and Methods: In this cross-sectional population-based study, a randomly selected sample (n=1172) and a separate asthma sample (n=744) underwent clinical examinations, completed a structured interview and responded to questionnaires. Severe asthma was defined as at least one feature of uncontrolled asthma despite treatment in line with the Global Initiative for Asthma (GINA) steps 4/5. This treatment level required a minimum medium dose of inhaled corticosteroids (ICS) plus a second controller or oral corticosteroids.Results: The prevalence of severe asthma was 1.1% in the adult random sample and 9.5% within the asthma sample. Individuals with severe asthma were older and had more symptoms, activity limitations, heart disease and blood neutrophils compared to those with other asthma. They also had lower lung function and despite these impairments, 32% did not have annual contact with a healthcare provider.Conclusion: The prevalence of severe asthma was higher compared to previous studies, and many individuals with severe asthma did not have regular contact with healthcare providers. Due to the high burden of symptoms and impairments for individuals with severe asthma, it is important that the healthcare system implement strategies to improve follow-up and evaluate these patients according to existing guidelines.Keywords: asthma epidemiology, asthma control, asthma-medication, asthma severity symptoms, lung function

Abstract Background High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is passively released during cell death and secreted by activated cells of many lineages. HMGB1 contains three conserved redox-sensitive cysteine residues: cysteines in position 23 and 45 (C23 and C45) can form an intramolecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking. Methods Primary human macrophages or murine macrophage-like RAW 264.7 cells were activated in cell cultures by redox-modified or point-mutated (C45A) recombinant HMGB1 preparations or by lipopolysaccharide (E. coli.0111: B4). Cellular phosphorylated NF-κB p65 subunit and subsequent TNF-α release were quantified by commercial enzyme-linked immunosorbent assays. Results Cell cultures with primary human macrophages and RAW 264.7 cells demonstrated that fully reduced HMGB1 with all three cysteines expressing thiol side chains failed to generate phosphorylated NF-КB p65 subunit or TNF-α. Mild oxidation forming a C23-C45 disulfide bond, while leaving C106 with a thiol group, was required for HMGB1 to induce phosphorylated NF-КB p65 subunit and TNF-α production. The importance of a C23–C45 disulfide bond was confirmed by mutation of C45 to C45A HMGB1, which abolished the ability for cytokine induction. Further oxidation of the disulfide isoform also inactivated HMGB1. Conclusions These results reveal critical post-translational redox mechanisms that control the proinflammatory activity of HMGB1 and its inactivation during inflammation.

Abstract Background Alarmins are considered proximal mediators of the immune response after tissue injury. Understanding their biology could pave the way for development of new therapeutic targets and biomarkers in human disease, including multiple trauma. In this study we explored high-resolution concentration kinetics of the alarmin interleukin-33 (IL-33) early after human trauma. Methods Plasma samples were serially collected from 136 trauma patients immediately after hospital admission, 2, 4, 6, and 8 h thereafter, and every morning in the ICU. Levels of IL-33 and its decoy receptor sST2 were measured by immunoassays. Results We observed a rapid and transient surge of IL-33 in a subset of critically injured patients. These patients had more widespread tissue injuries and a greater degree of early coagulopathy. IL-33 half-life (t1/2) was 1.4 h (95% CI 1.2–1.6). sST2 displayed a distinctly different pattern with low initial levels but massive increase at later time points. Conclusions We describe for the first time early high-resolution IL-33 concentration kinetics in individual patients after trauma and correlate systemic IL-33 release to clinical data. These findings provide insight into a potentially important axis of danger signaling in humans.

As the Swedish governing documents state that the School-age educare should supplement the education in the compulsory school, the support for pupils with special needs could be expected to continue after school at the School-age educare. The purpose of this study is to elucidate how special education teachers in school and teachers at the School-age educare collaborate in the work with pupils in need of special support. A total of 30 teachers participated. The results were analyzed using Bronfenbrenner's ecological model and show that collaboration exists to a limited extent when teaching children with special needs. It is evident in the results that a clearer focus on inclusion is desirable and that a collaboration between professions will enable the school-age educare to be a complement to school.

Residual stresses in metal additive manufactured components are a well-known problem. It causes distortion of the samples when removing them from the build plate, as well as acting detrimental with regard to fatigue. The understanding of how residual stresses in a printed sample are affected by process parameters is crucial to allow manufacturers to tune their process parameters, or the design of their component, to limit the negative influence of residual stresses. In this paper, residual stresses in additive manufactured samples are simulated using a thermo-mechanical finite element model. The elasto-plastic behavior of the material is described by a mechanism-based material model that accounts for microstructural and relaxation effects. The heat source in the finite element model is calibrated by fitting the model to experimental data. The residual stress field from the finite element model is compared with experimental results attained from synchrotron X-ray diffraction measurements. The results from the model and measurement give the same trend in the residual stress field. In addition, it is shown that there is no significant difference in trend and magnitude of the resulting residual stresses for an alternation in laser power and scanning speed.