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A magnetic vector hysteresis model is presented using play hysterons as building blocks. The main difference compared to earlier play based magnetic hysteresis models is that instead of forming a superposition of plays with different coercivities, this work uses a set of identical plays which are connected in a chain so that the output of one play acts as input to the next. Like models using a superposition, this yields far more complex minor loop behavior than a single play is capable of. Comparisons are made with measurements on a nonoriented electric steel for BH curves and alternating and rotational losses, showing satisfactory agreement. The approach is found to have both advantages and disadvantages compared to models using superpositions of plays. The problem of determining model parameters becomes simpler and the model can be reversed so either magnetic field or magnetization may be used as known variable. On the other hand, there is no apparent connection to underlying physical processes.

Purpose: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival. Methods: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March–September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure. Results: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5–34.4) and 4.2 (1.1–15.7), respectively. Conclusion: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.

the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival.All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure.A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively.In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.

BACKGROUND BK virus (BKV) infection after kidney transplantation leads to BKV-associated nephropathy (BKVAN) in up to 10% of recipients, and is associated with an increased risk of allograft dysfunction or loss. The objective of this study was to estimate the incidence of BKVAN and to analyze whether enhanced induction is associated with an increased risk of BKVAN, possibly justifying more intensive surveillance. MATERIAL AND METHODS This was a single-center retrospective cohort study. All patients who underwent kidney transplantation or simultaneous pancreas and kidney transplantation at the Uppsala University Hospital in Sweden between 2005 and 2014 were included, a period when BKV screening was not yet implemented. The effect of enhanced induction, defined as treatment with thymoglobulin, rituximab, and/or eculizumab, often in combination with IVIg and glycosorb, immunoadsorption and/or plasmapheresis/apheresis, was analyzed in a multivariable Cox proportional hazards model together with sex, age, cytomegalovirus mismatch (donor+/recipient-) and rejection treatment as co-predictors. Further, the effects of BKVAN on graft survival was analyzed in a univariable Cox proportional hazards model. RESULTS In total 44 of 928 (4.7%) patients developed a biopsy-verified BKVAN 4.8 (1.5-34.2) months after transplantation. Male sex was identified as a risk factor (HR 2.02, P=0.04) but not enhanced induction. Patients with BKVAN experienced a significantly higher risk of graft loss (HR 4.37, P

One major result of implementing the Water Frame Directive (WFD) for the water industry is the likelihood of more stringent requirements for the efficiency of removal of the pollutants included in the list of WFD priority substances. During the last decade, an ongoing debate on the technical aspects of water treatment and on the fate and effects of its constituents after discharge are taking place. Due to the recent development of analytical techniques, the knowledge about the chemistry and toxicology of the waste water has increased considerable. Characterization of the oil treatment efficiency by total petroleum hydrocarbon concentration (TPH) is not sufficient any more. Waste water before and after treatment should be characterized by toxicity and amounts of the individual compounds and mixtures which trigger the toxicity. In the situations where more efficient oil removal from waste water is required to meet the requirements, there are a number of treatment options available, including some tertiary ("polishing") treatment systems. New generation tertiary wastewater treatment system for removal or reducing of the oil compounds, including dissolved polycyclic aromatic hydrocarbons, bearing along most toxic potential, was developed under a Eureka funded project. The new waste water treatment system involves novel monitoring device to verify that the dissolved and bioavailable fraction of the contaminants are degraded, and that the final effluent is cleaner also from a toxicity point of view. Previous studies showed that more toxic compounds might be produced during the treatment process due to the transformation of the original chemicals. The monitoring device consists of a membrane-based diffusive, time integrative (2-30 days) sampler. The newly developed fast analytical method for the analysis of membrane extracts enable to give us information on the dissolved concentrations for more than 80 oil related compounds in the effluents as well as the toxicity results, by using standard bio-assay tests. Moreover the monitoring system is capable to accurately sample most of the WFD priority substances in waste water treatment effluent waters. lt was found that some of the compounds were effectively removed in waste water treatment plant (WWTP), but other compounds remained in the dissolved phase at the same concentrations. Furthermore, volatilization of low molecular weight PAHs during the treatment process was studied by means of the new monitoring system, resulting in the identification of significant release of WFD pollutants to the air. The changes in time-integrative toxicity during the treatment process were evaluated by standard ecotoxicity analysis using the same membrane extracts. The three bio-assays used were Daphnia magna, Microtox and Algal but also other organism- or cell test systems will be tested further. Our developed monitoring device is the state-of-art method for screening for environmental toxicity by integrating biologically and chemically based techniques for early warning and ecosystem health assessment purposes. It can provide invaluable information in highly polluted environments where bioindicator organisms would not survive or behave normally.

Coronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days., The study was supported through grants from the dedSciLifeLab/KAW national COVID-19 research program project grant (MH), by Scilifelab, the Knut and Alice Wallenberg Foundation and in part by the Swedish Research Council (RF, grant no 2014-02569 and 2014-07606), and the Netherlands Thrombosis Foundation (GN).

Due to the current, rapidly increasing Coronavirus disease 2019 (COVID-19) pandemic, efficient and highly specific diagnostic methods are needed. The receptor-binding part of the spike (S) protein, S1, has been suggested to be highly virus-specific; it does not cross-react with antibodies against other coronaviruses. Three recombinant partial S proteins of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) expressed in mammalian or baculovirus-insect cells were evaluated as antigens in a Luminex-based suspension immunoassay (SIA). The best performing antigen (S1; amino acids 16-685) was selected and further evaluated by serum samples from 76 Swedish patients or convalescents with COVID-19 (previously PCR and/or serologically confirmed), 200 pre-COVID-19 individuals (180 blood donors and 20 infants), and 10 patients with acute Epstein-Barr virus infection. All 76 positive samples showed detectable antibodies to S1, while none of the 210 negative controls gave a false positive antibody reaction. We further compared the COVID-19 SIA with a commercially available enzyme immunoassay and a previously evaluated COVID-19 rapid antibody test. The results revealed an overall assay sensitivity of 100%, a specificity of 100% for both IgM and IgG, a quantitative ability at concentrations up to 25 BAU/mL, and a better performance as compared to the commercial assays, suggesting the COVID-19 SIA as a most valuable tool for efficient laboratory-based serology.

Contrasting the antigen-presenting dendritic cells (DCs) in the conducting airways, the alveolar DC populations in human lungs have remained poorly investigated. Consequently, little is known about how alveolar DCs are altered in diseases such as chronic obstructive pulmonary disease (COPD). This study maps multiple tissue DC categories in the distal lung across COPD severities. Specifically, single-multiplex immunohistochemistry was applied to quantify langerin/CD207+, CD1a+, BDCA2+, and CD11c+ subsets in distal lung compartments from patients with COPD (GOLD stage I–IV) and never-smoking and smoking controls. In the alveolar parenchyma, increased numbers of CD1a+langerin− (p < 0.05) and BDCA-2+ DCs (p < 0.001) were observed in advanced COPD compared with controls. Alveolar CD11c+ DCs also increased in advanced COPD (p < 0.01). In small airways, langerin+ and BDCA-2+ DCs were also significantly increased. Contrasting the small airway DCs, most alveolar DC subsets frequently extended luminal protrusions. Importantly, alveolar and small airway langerin+ DCs in COPD lungs displayed site-specific marker profiles. Further, multiplex immunohistochemistry with single-cell quantification was used to specifically profile langerin DCs and reveal site-specific expression patterns of the maturation and activation markers S100, fascin, MHC2, and B7. Taken together, our results show that clinically advanced COPD is associated with increased levels of multiple alveolar DC populations exhibiting features of both adaptive and innate immunity phenotypes. This expansion is likely to contribute to the distal lung immunopathology in COPD patients.

According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases., Highlights • 339 approved, investigational and experimental safe-in-human antivirals were identified. • 59 compounds, which target ≥3 viral diseases, were selected. • 55 of the 59 compounds were tested against 8 RNA and DNA viruses. • 7 compounds were found to possess novel antiviral activities.

Background Coronavirus disease 19 (COVID-19) is known to present with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels of extracellular histone H3 (H3), neutrophil elastase (NE) and cfDNA in relation to other plasma parameters, including the immune modulators GAS6 and AXL, ICU scoring systems and mortality in patients with severe COVID-19. Methods We measured plasma H3, NE, cfDNA, GAS6 and AXL concentration in plasma of 83 COVID-19-positive and 11 COVID-19-negative patients at admission to the Intensive Care Unit (ICU) at the Uppsala University hospital, a tertiary hospital in Sweden and a total of 333 samples obtained from these patients during the ICU-stay. We determined their correlation with disease severity, organ failure, mortality and other blood parameters. Results H3, NE, cfDNA, GAS6 and AXL were increased in plasma of COVID-19 patients compared to controls. cfDNA and GAS6 decreased in time in in patients surviving to 30 days post ICU admission. Plasma H3 was a common feature of COVID-19 patients, detected in 40% of the patients at ICU admission. Although these measures were not predictive of the final outcome of the disease, they correlated well with parameters of tissue damage (H3 and cfDNA) and neutrophil counts (NE). A subset of samples displayed H3 processing, possibly due to proteolysis. Conclusions Elevated H3 and cfDNA levels in COVID-19 patients illustrate the severity of the cellular damage observed in critically ill COVID-19 patients. The increase in NE indicates the important role of neutrophil response and the process of NETosis in the disease. GAS6 appears as part of an early activated mechanism of response in Covid-19., The study was supported through grants from the dedSciLifeLab/KAW national COVID-19 research program project grant (MH), by Scilifelab, the Knut and Alice Wallenberg Foundation and in part by the Swedish Research Council (RF, grant no 2014-02569 and 2014-07606), and the Netherlands Thrombosis Foundation (GN).

Modeling of electrical machines is constantly refined, and it is now possible to couple numerical thermal models and electromagnetic models, thereby allowing to examine the thermal effects on motor materials. In this article, it is shown how a 3-D model of an interior permanent magnet motor, including power loss in the end windings and the effect of air and liquid cooling can be made where simulation results are compared with measurements. Further, it is shown how the coolant inlet temperature and volumetric flow rate affects the heat transfer coefficient of the cooling duct for some load points within the torque-speed range of the motor.

Viruses are one of the major causes of various acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signalling pathways. A collective view of these multiple studies could advance our understanding of viral evasion mechanisms and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape.

IL-33 represents a potential link between the airway epithelium and induction of a Th2-type inflammatory response in asthma. However, the association with markers of eosinophilic airway inflammation has not previously been reported in patients with steroid-free asthma.To describe the relationship between airway IL-33 and markers of eosinophilic airway inflammation, as well potential triggers of IL-33, in mild, steroid-free asthma.IL-33 mRNA expression and IL-33 immunoreactivity were measured in bronchial biopsies from patients with asthma untreated with inhaled steroids and healthy individuals. Furthermore, fractional exhaled nitric oxide (FeNO) and eosinophils in sputum and BAL were measured, as well as airway hyperresponsiveness to mannitol and methacholine. Epithelial integrity was assessed by computerized image analysis on haematoxylin-stained sections, and TLR mRNA expression by PCR.A total of 23 patients with asthma and 10 healthy individuals were examined (age: 24 years (20-40); females: 53%). The level of IL-33 mRNA expression was significantly higher in patients with asthma compared to healthy individuals (Median (IQR) 1.12 (0.78) vs. 0.86, P = 0.04). There was a positive correlation between IL-33 mRNA expression and the level of FeNO (r = 0.56, P = 0.01), whereas there was no association with airway or blood eosinophils. IL-33 expression was unrelated to loss of epithelial integrity, but correlated with an increased expression of TLR2 and TLR4 (TLR2: r = 0.47, P = 0.04; TLR4: 0.68, P 0.001), as well allergy to house dust mites (HDMs).In mild untreated asthma, the expression of IL-33 mRNA in bronchial mucosa is related to innate immune activation and allergic sensitization to HDM, rather than epithelial damage, and correlates with FeNO. These findings suggest that in mild allergic asthma, IL-33 may represent a link between innate immune activation and FeNO production.

With the increasing pace of global warming, it is important to understand the role of meteorological factors in influenza virus (IV) epidemics. In this study, we investigated the impact of temperature, UV index, humidity, wind speed, atmospheric pressure, and precipitation on IV activity in Norway, Sweden, Finland, Estonia, Latvia and Lithuania during 2010&ndash, 2018. Both correlation and machine learning analyses revealed that low temperature and UV indexes were the most predictive meteorological factors for IV epidemics in Northern Europe. Our in vitro experiments confirmed that low temperature and UV radiation preserved IV infectivity. Associations between these meteorological factors and IV activity could improve surveillance and promote development of accurate predictive models for future influenza outbreaks in the region.

Modelling of electrical machines is constantly refined and it is now possible to couple CFD thermal models with FEM electromagnetic models, thereby considering the thermal effects on motor materials. Usually, the models are reduced as much as possible (i.e. 2-D instead of 3-D or using symmetry conditions) in order to reduce calculation time and computer resources. However, in this paper it is shown how to model an interior permanent magnet transverse flux (TF -IPM) motor in 3-D so to be able to include magnet, core and copper loss and the effect of air and liquid cooling. The simulation results are compared with results of a comparably sized liquid-cooled radial flux IPM (RF-IPM) motor. It is shown that the TF-motor cooling is very efficient due to the lack of end-windings.

BACKGROUND: Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol.METHODS: AHR to inhaled mannitol was measured in 23 non-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell associated genes was measured by real-time PCR.RESULTS: The proportion of submucosal MCTC was higher in asthmatic individuals with AHR to mannitol compared with asthmatic individuals without AHR (median: 40.3% vs. 18.7%, p=0.03). Increased submucosal MCTC numbers were associated with increased levels of mRNA for TSLP and CPA3 in asthmatics. Reactivity to mannitol correlated significantly with eosinophils in submucosa (r(s): 0.56, p=0.01).CONCLUSION: AHR to inhaled mannitol is associated with an altered submucosal mast cell profile in asthmatic individuals. This mast cell profile is associated with increased levels of TSLP and CPA3. The degree of AHR to mannitol is correlated with the degree of eosinophilic inflammation in the airway submucosa.CAPSULE SUMMARY: Airway hyperresponsiveness to mannitol and methacholine is associated with an increased proportion of chymase-positive mast cells in airway submucosa, which in turn correlated to the expression level of TSLP and CPA3. Finally, airway hyperresponsiveness to mannitol, but not methacholine, is related to submucosal eosinophilic inflammation. This article is protected by copyright. All rights reserved.

Allergic asthma is characterized by eosinophilic inflammation and airway obstruction. There is also an increased risk of pulmonary infection caused by Streptococcus pneumoniae, in particular during severe asthma where high levels of the glycoprotein, osteopontin (OPN), are present in the airways. Eosinophils can be recruited by chemokines activating the receptor CCR3 including eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26, RANTES/CCL5, and MEC/CCL28. In addition to inducing chemotaxis, several of these molecules have defensin-like antibacterial properties. This study set out to elucidate the functional consequences of OPN binding to eosinophil-recruiting chemokines.Antibacterial activities of the chemokines were investigated using viable count assays and electron microscopy. Binding studies were performed by means of surface plasmon resonance. The potential interference of OPN with antibacterial, receptor-activating, and lipopolysaccharide-neutralizing abilities of these chemokines was investigated.We found that OPN bound all eosinophil-recruiting chemokines with high affinity except for CCL5. The eosinophil-recruiting chemokines all displayed bactericidal activity against S. pneumoniae, but only CCL26 and CCL28 retained high antibacterial activity in the presence of sodium chloride at physiologic concentrations. Preincubation of the chemokines with OPN strongly inhibited their antibacterial activity against S. pneumoniae but did not affect their ability to activate CCR3. All chemokines investigated showed LPS-neutralizing activity that was impaired by OPN only in the case of CCL24.The data suggest that OPN may impair host defense activities of the chemokines without affecting their eosinophil-recruiting properties. This could be one mechanism explaining the increased vulnerability to acquire pneumococcal infection in parallel with sustained allergic inflammation in asthma.

Modelling of electrical machines is constantly refined and it is now possible to couple CFD thermal models with FEM electromagnetic models, thereby considering the thermal effects on motor materials. Usually, the models are made as small as possible in order to reduce calculation time and computer resources. However, in this paper it is shown how to model an interior permanent magnet (IPM) motor in 3-D so to be able to include magnet, core and copper loss (including losses in the end windings) and the effect of air and liquid cooling. It is shown that the simulation results agree fairly well with referenced measurements. Further, it is shown how the liquid cooling input temperature affects the efficiency for a set of load points within the torque-speed range of the motor.

Irreversible thermal demagnetization effects can sometimes play a significant role in, for instance, rotating Preisach model (PM) machines. Modeling such phenomena requires field simulation methods such as finite element (FE) analysis in combination with a temperature-dependent vector hysteresis model. This paper explores the feasibility of applying a formalism for temperature-dependent structural hysteresis to magnetics. The net magnetization is expressed as a superposition of contributions from plays. By allowing the anhysteretic curve and the coercivity to depend on temperature, irreversible thermal effects resembling experiments emerge automatically without additional assumptions or adjustable parameters. Incorporating this temperature dependence has negligible impact on the computational efficiency or complexity of the model.

Rationale The alveolar pathology in chronic obstructive pulmonary disease (COPD) involves antigen-driven immune events. However, the induction sites of alveolar adaptive immune responses have remained poorly investigated. Objectives To explore the hypothesis that interfaces between the alveolar lumen and lymphoid aggregates (LAs) provide a structural basis for increased alveolar antigen uptake in COPD lungs. Methods Lung samples from patients with mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), moderate–severe (GOLD II–III), and very severe (GOLD IV) COPD were subjected to detailed histological assessments of adaptive immune system components. Never smokers and smokers without COPD served as controls. Results Quantitative histology, involving computerised three-dimensional reconstructions, confirmed a rich occurrence of alveolar-restricted LAs and revealed, for the first time, that the vast majority of vascular or bronchiolar associated LAs had alveolar interfaces but also an intricate network of lymphatic vessels. Uniquely to COPD lungs, the interface epithelium had transformed into a columnar phenotype. Accumulation of langerin (CD207) + dendritic cells occurred in the interface epithelium in patients with COPD but not controls. The antigen-capturing capacity of langerin + dendritic cells was confirmed by increased alveolar protrusions and physical T cell contact. Several of these immune remodelling parameters correlated with lung function parameters. Conclusions Severe stages of COPD are associated with an emergence of remodelled and dendritic cell-rich alveolar–lymphoid interfaces. This novel type of immune remodelling, which predicts an increased capacity to respond to alveolar antigens, is suggested to contribute to aggravated inflammation in COPD.

Background The effectiveness of bronchial thermoplasty (BT) has been reported in patients with severe asthma, yet its effect on different bronchial structures remains unknown. Objective We sought to examine the effect of BT on bronchial structures and to explore the association with clinical outcome in patients with severe refractory asthma. Methods Bronchial biopsy specimens (n = 300) were collected from 15 patients with severe uncontrolled asthma before and 3 months after BT. Immunostained sections were assessed for airway smooth muscle (ASM) area, subepithelial basement membrane thickness, nerve fibers, and epithelial neuroendocrine cells. Histopathologic findings were correlated with clinical parameters. Results BT significantly improved asthma control and quality of life at both 3 and 12 months and decreased the numbers of severe exacerbations and the dose of oral corticosteroids. At 3 months, this clinical benefit was accompanied by a reduction in ASM area (median values before and after BT, respectively: 19.7% [25th-75th interquartile range (IQR), 15.9% to 22.4%] and 5.3% [25th-75th IQR], 3.5% to 10.1%, P P = 0.02), submucosal nerves (1.0 ‰ [25th-75th IQR, 0.7-1.3 ‰] immunoreactivity and 0.3 ‰ [25th-75th IQR, 0.1-0.5 ‰] immunoreactivity, P 2 and 62.7 [25th-75th IQR, 0.0-230.3] immunoreactive pixels per mm 2 , P = .02), and epithelial neuroendocrine cells (4.9/mm 2 [25th-75th IQR, 0-16.4/mm 2 ] and 0.0/mm 2 [25th-75th IQR, 0-0/mm 2 ], P = .02). Histopathologic parameters were associated based on Asthma Control Test scores, numbers of exacerbations, and visits to the emergency department (all P ≤ .02) 3 and 12 months after BT. Conclusion BT is a treatment option in patients with severe therapy-refractory asthma that downregulates selectively structural abnormalities involved in airway narrowing and bronchial reactivity, particularly ASM, neuroendocrine epithelial cells, and bronchial nerve endings.

Background: A unique feature of alveolar mast cells is their low high-affinity IgE receptor (FceRI) expression. Recent discoveries in uncontrolled asthma suggest that the appearance of FceRI-expressing alveolar mast cells may be a novel disease-specific feature of allergic asthma. This study investigates whether increased FceRI-expressing alveolar mast cells are present in patients with mild allergic asthma or even in non-asthmatic allergic rhinitis patients (AR) who have developed bronchial hyperactivity (BHR). Methods: Bronchial and alveolar tissues were obtained from healthy controls, AR patients with or without BHR, and AR patients with concurrent asthma. Samples were processed for immunohistochemical identification of MC(T) and MC(TC) and expression of FceRI and surface-bound IgE. Results: Bronchial mast cell expression of FceRI was high in all groups. In contrast, in the alveolar tissue, the expression of FceRI on mast cells was low in healthy controls and in the AR patient groups, whereas a high expression was present in AR patients with concurrent asthma (P = 0.006 compared to controls). The asthmatics had a 29-fold increase in numbers (P = 0.006) and a 19-fold increase in proportion (P = 0.007) of alveolar mast cells that expressed surface-bound IgE. Conclusions: The present data show that alveolar mast cells in patients with mild atopic asthma, but not atopic patients with AR, have turned into a highly FceRI- and IgE-expressing phenotype. These data support the hypothesis that increased FceRI expression on alveolar mast cells is a novel disease-specific feature of allergic asthma that is important for understanding asthma phenotypes and designing new therapeutic strategies. (Less)

The efficiency of a biologically activated carbon system for treating wastewater polluted with petroleum products was examined and the effects of process parameters on its efficacy were evaluated. In each experiment 17 alkylated and 19 non-alkylated polycyclic aromatic hydrocarbons (PAHs) and total petroleum hydrocarbons (TPHs, C(10)-C(40)) were extracted using semipermeable membrane devices from wastewater before and after treatment. The acquired data during experiments were analyzed using principal component analysis (PCA). The treatment system robustly removed dissolved PAHs across the studied ranges of the process parameters, providing overall removal efficiencies of 96.9-99.7% for the sum of 36 PAHs. However, the major contributor to their removal was sorption rather than biodegradation, and despite the general efficiency of the process there was up to a 9-fold range in the sums of quantified PAHs in the effluents between experiments. Combinations of long process contact time (24 h) with high temperature (24 degrees C) and moderate oxygen concentration (6-7 mg O(2) L(-1)) resulted in good removal of bioavailable PAHs. The removal of TPHs was more dependent on biological activities during the wastewater treatment, and consequently more dependent on the process parameters. In addition, small but significant proportions of PAHs were volatilized and released during the wastewater treatment.

A chemical and ecotoxicological assessment of treatment of wastewater that had been polluted with petroleum products using only Activated Sludge (AS) and four biologically activated sorbents (BASs), consisting of activated sludge plus: coal-based activated carbon (-C1), coconut shell-based activated carbon (-C2), zeolite (-Z), and anthracite (-A) were conducted. The efficiency and robustness of the four wastewater treatment systems were evaluated by calculating the reduced total petroleum hydrocarbon (TPH) and polycyclic aromatic hydrocarbon (PAH) contents and the acute ecotoxicity of the effluents. The chemical analysis showed that the combined treatment systems were very effective for reducing the total petroleum hydrocarbon and readily bioavailable PAH contents. The most efficient systems were the BAS-C1 and -C2, which removed 60–88% and 99.5–99.6% of TPH and PAH, respectively. The activated sludge-only treatment was the least effective for purifying the wastewater. Chemical oxygen demand was reduced by >90% by all carbon-based BASs (BAS-C1, BAS-C2 and BAS-A). Shifts in the relative composition of the individual PAHs were identified in samples taken before and after treatment. Algal and bacterial bioassays showed that the toxicities of effluents following treatment by all four systems (except AS for algae) were reduced by more than 80% and 90%, respectively. However, crustacean tests indicated that the carbon-based BASs reduced the toxicity [Vtox(50)] only by 19–67%. Our results indicated that the combination of sorption and biodegradation processes have great potential in the treatment of petroleum products polluted wastewater and is less sensitive for inhibitors of the biological process than treatments in which activated sludge alone is used. The assessment of chemical and ecotoxicological endpoints provided valuable information, but contrasting results for one of the assays indicates that further analysis on the capacity of the different treatment systems is warranted.

Semipermeable membrane devices (SPMDs) were exposed at ten sampling points, each representing a different stage in the treatment process, in a municipal sewage treatment plant. Differences in SPMD uptake kinetics of polycyclic aromatic hydrocarbons (PAHs) due to variations in conditions at the sampling sites were evaluated by using five performance reference compounds (PRCs) with log K(ow) values of 4.20 to 6.34. PRC release rate constants (k(e,PRC) values) were calculated for PRCs for which 50-98% of the initial amounts were lost during the sampling period. The k(e,PRC) values were high, ranging from 0.08 to 0.11 day(-1) for the studied PRCs, at sampling site W1 (raw sewage), the only sampling site where significant amounts of the PRCs with log K(ow) values5 were released from the SPMDs. At the other sampling sites, only PRCs with log K(ow) values between 4.20 and 4.50 were released in significant amounts. The release rates at these sites were lowest (0.04 day(-1)) at sampling site W9 (the secondary clarifier) and highest (0.18 day(-1)) at W8 (the active sludge aeration basin). Differences between sampling rates (R(s)) obtained using published laboratory-calibrated data and PRC-corrected R(s) values were visualized by principal component analysis (PCA). The water concentrations of 24 studied PAHs fell substantially during the course of the sewage treatment process. However, low molecular weight PAHs were more effectively removed than high molecular weight PAHs. Significant deviations between actual and estimated water concentrations may arise unless PRC-corrected R(s) values are applied.

Recent survey results for polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, dioxins) in Baltic Sea sediments from Finland, Sweden and Denmark were merged with previously published Baltic Sea data. Regional distribution of concentration levels, differences in congener patterns, and temporal changes in sediment profiles were examined. One of the main objectives was to study if any major point sources for different PCDD/F congeners could be identified on a regional scale, based on sediment records. The survey confirmed the impact of chlorophenol production derived highly chlorinated PCDF-congeners on the total toxicity in sediments in the Gulf of Finland near the Kymijoki river estuary. Signatures of other point sources or combined point sources pertinent to specific industry branches or particular production processes (such as pulp bleaching, vinyl chloride production, thermal processes) may be discerned. However, the findings did not support any of the known point sources significantly influencing those congeners that are most abundant in Baltic herring and salmon. Instead, regional distributions in the Baltic Sea indicate that atmospheric deposition may act as a major source for those congeners and especially for 2,3,4,7,8-PeCDF. There were clear indications of declines in levels in sediment in some areas, but generally the levels of highly chlorinated PCDD/Fs on the northern coast of the Gulf of Finland were still high when compared with other areas of the Baltic Sea. Major areas with data gaps cover the south-eastern and eastern coastal regions of the Baltic Proper and the southern Gulf of Finland.

Semipermeable membrane devices (SPMDs) are previous termanext term widely used passive sampling methodology for both waterborne and airborne hydrophobic organic contaminants. The exchange kinetics ...

Presence of eosinophils in the airways is a hallmark of allergic asthma but several other asthmatic phenotypes exist including severe disease with a predominance of neutrophils. In addition to wheezing and dyspnea, there is also an increased risk of pneumoccal infections, in particular during severe asthma. Eosinophils can be recruited to the airways by chemokines including eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26, RANTES/CCL5, and MEC/CCL28 that activate CCR3 on these cells. Several of these chemokines also have defensin-like antibacterial properties. Severe asthma is associated with high expression of the glycoprotein osteopontin in the airways. Osteopontin itself has neutrophil-recruiting properties and we hypothesized that this molecule can play roles in skewing the inflammatory profile during the course of asthma. OPN bound all eosinophil-recruiting chemokines with high affinity but less so to TSLP. In OVA-sensitized mice, administration of OPN had no direct effect on airway eosinophilia. The eosinophil-recruiting chemokines all displayed bactericidal activity against the common airway pathogen S. pneumoniae , but only CCL26 and CCL28 retained high antibacterial activity in the presence of sodium chloride (140 mM). Preincubation of the chemokines with osteopontin at eqimolar amounts strongly inhibited the antibacterial activity. The results suggest that osteopontin may impair host defense activities of the chemokines, increasing the vulnerability to acquire bacterial infections. In addition, osteopontin may lead to a different inflammatory subtype during the course of asthma through its ability to recruit neutrophils.

Rationale: The airway microbiota is altered in asthma, with less Bacteriodetes and more Proteobacteria than in healthy individuals. AHR to mannitol is related to eosinophilic airway inflammation and mast cell activation, but the relationship between AHR to mannitol and changes in airway microbiota is currently unknown. Aim: To examine the relative contribution of microbiota, eosinophilic inflammation and mast cell changes to AHR to mannitol in subjects with asthma. Methods: In 20 steroid-free, non-smoking subjects with asthma, AHR to mannitol was examined and bacterial DNA was extracted from broncheo-alveolar lavage (BAL) and subjected to Illumina MiSeq sequencing of the 16S rDNA V4 region. Eosinophils and mast cells (tryptase+/chymase- and trytase+/chymase+) were quantified by immunohistochemistry and computerized image analysis. Results: The relative abundance of Bacteroidetes was lower in asthmatics with AHR to mannitol compared to those without (median [IQR]: 18.4% [7.4] vs. 30.3% [16.8], p=0.006), whereas the relative abundance of Proteobacteria was higher (32.7% [11.4] vs. 24.8% [11.4], p=0.018). The degree of AHR to mannitol negatively correlated with the proportion of Bacteroidetes, rho(s): -0.61, p=0.002 and positively correlated with the proportion of Proteobacteria, rho(s): 0.54, p=0.008. The level of Bacteroidetes alone could explain 57% of the variation in AHR to mannitol independently of eosinophilic inflammation or mast cell phenotype. Conclusion: AHR to mannitol is associated with changes in the airway microbiota, independently of eosinophilic inflammation and mast cell phenotype, suggesting that the airway microbiota may constitute a driver of AHR in asthma.

Rationale: Although COPD is regarded as a non-eosinophilic and Th2-low disease, a significant proportion of the patients display elevated blood and sputum eosinophils. The nature of the eosinophilia in COPD and presence of basophils in lung tissues remains unexplored. Objectives: This study maps eosinophil and basophil tissue infiltration and associated Th2 immunity in major lung compartments across COPD severities. Methods: Eosinophils, basophils and GATA3+ cells were investigated in lung tissues and lymph nodes obtained from 30 COPD patients divided into GOLD I, II-III, and IV categories. Never-smoking and smoking non-COPD subjects (n=15) served as controls. Bronchi, bronchioles, pulmonary vessels, alveolar regions, and lymph nodes from > 140 tissue blocks underwent automated immunohistochemical staining and quantitative image analysis. Results: In COPD, the overall tissue density of eosinophils and basophils were increased (p 0.0001) and co-localization studies revealed a strong regional spatial relationship between eosinophils, basophils as well as GATA3+ cells. Conclusions: This study reveals that a surprisingly large proportion of COPD patients have focal lung infiltrations of eosinophils and basophils, which are likely caused by highly regionalized and still unexplored Th2 responses.

Rationale: Whether antigen presenting dendritic cell (DC) subsets are differently altered across asthma phenotypes remains unknown. This study explores multiple DC subsets in bronchial and alveolar tissues from patients with different phenotypes of asthma. Methods: Endobronchial biopsies (n=185) were obtained from healthy controls (n=8), patients with mild-moderate controlled (n=12) or uncontrolled (n=12) atopic asthma, and severe asthma (n=25). Transbronchial biopsies (n = 160) were obtained from healthy controls and mild-moderate asthmatics. Automatized immunohistochemistry was used for visualizing DC identification markers (CD1a, langerin, CD11c, BDCA2), confounding non-DCs (CD68, CD163), and DC phenotype markers (S-100, CD83 and RUNX3). Analysis was performed by tissue slide scanning techniques and computerized image analysis. Results: In healthy controls, langerin+ and CD11c+CD68-CD163- DCs were the most frequent DC populations within the bronchi. Epithelial langerin+ DCs decreased in severe asthmatics compared with controls (p Conclusions: This study shows that DC subsets are differentially altered in asthmatic patients and where severe asthma is associated with a particularly marked DC reduction which is likely caused by the high doses of steroids in this patient group.

Rationale: IL-17A plays a crucial role in lung inflammation. However, the major source for IL-17 in lung diseases remains unknown. The aim of this study is to identify major IL-17A expressing cell populations in healthy and diseased lungs. Methods: Surgical resections as well as nasal, bronchial and transbronchial biopsies were used to explore IL-17 in healthy controls(n=18), COPD(n=40), cystic fibrosis(n=5), allergic rhinitis(n=12), and asthma(n=40). Simultaneous visualization of IL17A and cell identification markers was performed by triple immunofluorescencetechniques. IL-17A+ cells were identified and levels of IL-17 were quantified in individual cells by combined virtual microscopy and computerized image analysis. Results: T-cells, mast cells and neutrophils were identified as IL-17A+ cells. Irrespective of disease, mast cells displayed significantly higher expression levels compared to neutrophils(p

Development of Hepatitis C virus (HCV) resistance against direct-acting antivirals (DAAs), including NS5A inhibitors, is an obstacle to successful treatment of HCV when DAAs are used in sub-optimal combinations. Furthermore, it has been shown that baseline (pre-existing) resistance against DAAs is present in treatment naive-patients and this will potentially complicate future treatment strategies in different HCV genotypes (GTs). Thus the aim was to detect low levels of NS5A resistant associated variants (RAVs) in a limited sample set of treatment-naive patients of HCV GT1a and 3a, since such polymorphisms can display in vitro resistance as high as 60000 fold. Ultra-deep single molecule real time (SMRT) sequencing with the Pacific Biosciences (PacBio) RSII instrument was used to detect these RAVs. The SMRT sequencing was conducted on ten samples; three of them positive with Sanger sequencing (GT1a Q30H and Y93N, and GT3a Y93H), five GT1a samples, and two GT3a non-positive samples. The same methods were applied to the HCV GT1a H77-plasmid in a dilution series, in order to determine the error rates of replication, which in turn was used to determine the limit of detection (LOD), as defined by mean + 3SD, of minority variants down to 0.24%. We found important baseline NS5A RAVs at levels between 0.24 and 0.5%, which could potentially have clinical relevance. This new method with low level detection of baseline RAVs could be useful in predicting the most cost-efficient combination of DAA treatment, and reduce the treatment duration for an HCV infected individual.

Fire-related fatalities and injuries have become a growing governmental concern in Sweden, and a national vision zero strategy has been adopted stating that nobody should get killed or seriously injured from fires. There is considerable uncertainty, however, regarding the numbers of both deaths and injuries due to fires. Different national sources present different numbers, even on deaths, which obstructs reliable surveillance of the problem over time. We assume the situation is similar in other countries. This study seeks to assess the true number of fire-related deaths in Sweden by combining sources, and to verify the coverage of each individual source. By doing so, we also wish to demonstrate the possibilities of improved surveillance practices.Data from three national sources were collected and matched; a special database on fatal fires held by The Swedish Contingencies Agency (nationally responsible for fire prevention), a database on forensic medical examinations held by the National Board of Forensic Medicine, and the cause of death register held by the Swedish National Board of Health and Welfare.The results disclose considerable underreporting in the single sources. The national database on fatal fires, serving as the principal source for policy making on fire prevention matters, underestimates the true situation by 20%. Its coverage of residential fires appears to be better than other fires.Systematic safety work and informed policy-making presuppose access to correct and reliable numbers. By combining several different sources, as suggested in this study, the national database on fatal fires is now considerably improved and includes regular matching with complementary sources.

Field concentrations of polychlorinated biphenyls (PCBs) were measured in sediment and nine marine soft bottom invertebrate species. Lipid- and organic carbon normalised biota-sediment accumulation factors (BSAFs) were determined for 29 nonplanar and 11 coplanar congeners. To investigate whether the bioaccumulation was in thermodynamic equilibrium with the sediment, the determined BSAFs were compared to theoretically calculated ones to obtain a BSAFdet./BSAFtheor-ratio. Large interspecific variations were found: one suspension feeding and one deposit feeding species of brittle stars (Amphiura filiformis and A. chiajei), and one predatory polychaete (Glycera rouxii) had ratios>1 for congeners with logKow>6.5. In these species there was also a linear relationship between logKow and BSAF, both for coplanar and for planar congeners but with lower values for coplanar ones. For other species the pattern was more scattered. Only the deposit feeding polychaete Melinna cristata had BSAFdet./BSAFtheor-ratios

Semipermeable membrane devices (SPMD) represent a passive sampling technology that is becoming widely used for monitoring of surface waters pollution. While "classic" procedures employ dialysis to recover target compounds from exposed SPMDs, in the present study analytes were isolated from cut membrane together with sequestering medium (triolein) using hexane as an extraction solvent. This approach allowed us to reduce the time needed for accomplishment of isolation step from 48 h to only 1 h. Automated gel permeation chromatography (GPC) clean-up is employed in the following step to separate triolein from analytes fraction. Musk compounds (MCs), polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs) and several other persistent organochlorine compounds (OCs) were determined in the respective fraction by GC method employing selective detectors (MSD, ECD). As shown in a series of analyses of SPMDs deployed in various aquatic ecosystems, high recoveries and good repeatability of results together with a possibility to obtain the information on the pollution of sampling site at the day of sample arrival to laboratory make this newly implemented procedure an interesting alternative to time consuming dialysis.