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ABSTRACTWithin cut-to-length forwarding, a theoretical semi-autonomous teleoperation concept called tele-extraction, with automation of crane work and teleoperation of driving, was modeled and simulated. Both configurations modeled had greater potential for cost reduction than a previously studied alternative where the driving was automated, and crane work was teleoperated. Teledrive with teleoperated driving empty, driving loaded, and driving between log piles while loading, showed a reduced cost of 10% for five operators on ten forwarders, whereas teledrive with both loading and driving while loading automated showed a reduced cost of 18% at four operators. In both configurations, the lowest cost was reached at about 10% lower productivity compared to standard forwarding. Increased extraction distance had a negative impact on potential for cost reduction since the driving was teleoperated while terminal activities were autonomous.

ABSTRACTThe mechanization of roundwood harvesting in Sweden has historically cut costs rapidly. However, machinery and work methods have conceptually stayed the same since the introduction of the single-grip harvester. Current trends indicate that the next major wave of development will be based on automation, and that teleoperation is a step in this direction. This study aims to evaluate the economic potential of semi-automated tele-extraction compared to standard forwarding within the Nordic CTL two-machine harvesting system. The initial scenario examined autonomous terrain transportation with teleoperation during loading and unloading. A Discrete Event Simulation was implemented in the AnyLogic software. Input data included 1100 Swedish harvest sites, with in total 1.6 million m3and extraction distances from 20 to 1500 m. Scenarios with different numbers of teleoperators for a fleet of ten forwarders were tested. The optimum number of operators was seven per ten forwarders, resulting in a potential extraction cost reduction of 7% compared to standard forwarding. Extraction distances further than 500 m enabled use of five or six teleoperators, resulting in potential cost reductions of up to 15%. The highest potential cost reductions were linked to increased time used for autonomous driving, increasing the teleoperator availability for other machines. The simulation model provides a framework for further evaluation of new scenarios of automation and teleoperation of forwarders.

During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements.

ABSTRACTGlobally, almost 2 billion cubic meters of industrial roundwood are harvested yearly. Two of the most common methods of harvest and extraction are cut-to-length (CTL) and full-tree or tree-length (FT/TL). The aim of this study was to compile data on annual volumes of industrial roundwood harvested by the main methods in forestry countries. To quantify the effect of potential explanatory variables, the data were subjected to linear regression analysis, using shares of roundwood volumes harvested by fully mechanized CTL and/or FT/TL as response variables. Generally, high diesel price and Gross Domestic Product appear to favor CTL, while high shares of steep terrain (>20°) in forest land decrease the leve l of both mechanization and CTL, and low Social Security Rate (SSR) favor FT/TL. Two models were created for CTL, one with an R2of 0.64 and another more complex with an R2of 0.75. A separate model for mechanization (CTL and FT/TL together) showed an R20.57. The CTL models could potentially be used to predict shares of roundwood volumes harvested by CTL in countries not included in this study. Predictions for countries with large harvested volumes, e.g. China and India, are presented here, but they require validation, as does the model’s applicability for countries with small harvested volumes. Countries with less than 10% of steep slope forests are almost exclusively mechanized according to the model. For FT/TL, the proposed model is probably not sufficiently robust for prediction, but it highlights SSR as one important explanatory variable.

The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.

Purpose: Lesson Study is a model for advancing knowledge about how teachers can enhance teaching through collaboration in schools. This study aims to focus on two learning situations for students in Grades 1–3: elementary school (the first years of school) and school-age educare (activities for students before and after school while their parents are working or studying). The case study aims to describe how teachers use Lesson Study to enhance students' mathematical learning in the two learning situations. The objectives were to describe teachers' perceptions of Lesson Study activities and collaboration and students' knowledge before and after lessons. Design/methodology/approach: Data were collected as a narrative case study using audio-recorded conversations between researchers and teachers in the different learning contexts. A questionnaire comprising five open-ended questions was used to map students' knowledge of the subject. Findings: Teachers found it advantageous to cooperate with each other across the different learning situations. Mapping students' knowledge before and after a teaching session helped them understand how to create a teaching situation that benefits their students. They saw the value of continued collaboration and called for implementation of the Lesson Study method throughout the school. Research limitations/implications: An important limitation of this case study is that it was conducted in a very specific context, and the findings cannot, therefore, be generalized to other situations. However, there is a need for similar case studies to be conducted in different contexts, both in Sweden and in other countries, to pay attention to ways in which elementary schools and school-age educare can develop supplementary teaching situations. Originality/value: The originality of this case lies in planning and reporting a Lesson Study in two different learning situations in the same school, and the conclusion that educators identify and develop collaborative links in different subjects.

The cellular thermal shift assay (CETSA) was introduced in 2013 to investigate drug–target engagement inside live cells and tissues. As with all thermal shift assays, the response measured by CETSA is not simply governed by ligand affinity to the investigated target protein, but the thermodynamics and kinetics of ligand binding and protein unfolding also contribute to the observed protein stabilization. This limitation is commonly neglected in current applications of the method to validate the target of small-molecule probes. Instead, there is an eagerness to make direct comparisons of CETSA measurements with functional and phenotypic readouts from cells at 37 °C. Here, we present a perspective of the early CETSA literature and put the accumulated data into a quantitative context. The analysis includes annotation of ~270 peer-reviewed papers, the majority of which do not consider the underlying biophysical basis of CETSA. We also detail what future technology developments are needed to enable CETSA-based optimization of structure–activity relationships and more appropriate comparisons of these data with functional or phenotypic responses. Finally, we describe ongoing developments in assay formats that allow for CETSA measurements at single-cell resolution, with the aspiration to allow differentiation in cellular target engagement between cells in co-cultures and more complex models, such as organoids and potentially even tissue.

The cellular thermal shift assay (CETSA) was introduced in 2013 to investigate drug–target engagement inside live cells and tissues. As with all thermal shift assays, the response measured by CETSA is not simply governed by ligand affinity to the investigated target protein, but the thermodynamics and kinetics of ligand binding and protein unfolding also contribute to the observed protein stabilization. This limitation is commonly neglected in current applications of the method to validate the target of small-molecule probes. Instead, there is an eagerness to make direct comparisons of CETSA measurements with functional and phenotypic readouts from cells at 37 °C. Here, we present a perspective of the early CETSA literature and put the accumulated data into a quantitative context. The analysis includes annotation of ~270 peer-reviewed papers, the majority of which do not consider the underlying biophysical basis of CETSA. We also detail what future technology developments are needed to enable CETSA-based optimization of structure–activity relationships and more appropriate comparisons of these data with functional or phenotypic responses. Finally, we describe ongoing developments in assay formats that allow for CETSA measurements at single-cell resolution, with the aspiration to allow differentiation in cellular target engagement between cells in co-cultures and more complex models, such as organoids and potentially even tissue.

Demonstration of target binding is a key requirement for understanding the mode of action of new therapeutics. The cellular thermal shift assay (CETSA) has been introduced as a powerful label-free method to assess target engagement in physiological environments. Here, we present the application of live-cell CETSA to different classes of integral multipass transmembrane proteins using three case studies, the first showing a large and robust stabilization of the outer mitochondrial five-pass transmembrane protein TSPO, the second being a modest stabilization of SERCA2, and the last describing an atypical compound-driven stabilization of the GPCR PAR2. Our data demonstrated that using modified protocols with detergent extraction after the heating step, CETSA can reliably be applied to several membrane proteins of different complexity. By showing examples with distinct CETSA behaviors, we aim to provide the scientific community with an overview of different scenarios to expect during CETSA experiments, especially for challenging, membrane bound targets.

One of the major challenges with the powder bed fusion process (PBF) and formation of bulk metallic glass (BMG) is the development of process parameters for a stable process and a defect-free component. The focus of this study is to predict formation of a crystalline phase in the glass forming alloy AMZ4 during PBF. The approach combines a thermal finite element model for prediction of the temperature field and a phase model for prediction of crystallization and devitrification. The challenge to simulate the complexity of the heat source has been addressed by utilizing temporal reduction in a layer-by-layer fashion by a simplified heat source model. The heat source model considers the laser power, penetration depth and hatch spacing and is represented by a volumetric heat density equation in one dimension. The phase model is developed and calibrated to DSC measurements at varying heating rates. It can predict the formation of crystalline phase during the non-isothermal process. Results indicate that a critical location for devitrification is located a few layers beneath the top surface. The peak is four layers down where the crystalline volume fraction reaches 4.8% when 50 layers are built.

High density components of an AlCoCrFeNi alloy, often described as a high-entropy alloy, were manufactured by binder jetting followed by sintering. Thermodynamic calculations using the CALPHAD approach show that the high-entropy alloy is only stable as a single phase in a narrow temperature range below the melting point. At all other temperatures, the alloy will form a mixture of phases, including a sigma phase, which can strongly influence the mechanical properties. The phase stabilities in built AlCoCrFeNi components were investigated by comparing the as-sintered samples with the post-sintering annealed samples at temperatures between 900 °C and 1300 °C. The as-sintered material shows a dominant B2/bcc structure with additional fcc phase in the grain boundaries and sigma phase precipitating in the grain interior. Annealing experiments between 1000 °C and 1100 °C inhibit the sigma phase and only a B2/bcc phase with a fcc phase is observed. Increasing the temperature further suppresses the fcc phase in favor for the B2/bcc phases. The mechanical properties are, as expected, dependent on the annealing temperature, with the higher annealing temperature giving an increase in yield strength from 1203 MPa to 1461 MPa and fracture strength from 1996 MPa to 2272 MPa. This can be explained by a hierarchical microstructure with nano-sized precipitates at higher annealing temperatures. The results enlighten the importance of microstructure control, which can be utilized in order to tune the mechanical properties of these alloys. Furthermore, an excellent oxidation resistance was observed with oxide layers with a thickness of less than 5 μm after 20 h annealing at 1200 °C, which would be of great importance for industrial applications.

Diamond-Blackfan anemia (DBA) is a bone marrow failure syndrome caused by mutations in ribosomal protein genes. Pathogenic mechanisms are poorly understood but involve severely reduced proliferation of erythroid precursors. Because current DBA therapies are ineffective and associated with severe side effects, disease-specific therapies are urgently needed. We hypothesized that druggable molecular pathways underlying the defect can be revealed through phenotypic small-molecule screens. Accordingly, a screening assay was developed using c-kit+ fetal liver erythroid progenitors from a doxycycline-inducible DBA mouse model. The addition of doxycycline to the culture medium induces the phenotype and reduces proliferation to <10% of normal, such that rescue of proliferation can be used as a simple readout for screening. Here, we describe the assay rationale and efforts toward validation of a microtiter plate–compatible assay and its application in a pilot screen of 3871 annotated compounds. Ten hits demonstrated concentration-dependent activity, and we report a brief follow-up of one of these compounds. In conclusion, we established a robust scalable assay for screening molecules that rescue erythropoiesis in DBA.

Diamond-Blackfan anemia (DBA) is a bone marrow failure syndrome caused by mutations in ribosomal protein genes. Pathogenic mechanisms are poorly understood but involve severely reduced proliferation of erythroid precursors. Because current DBA therapies are ineffective and associated with severe side effects, disease-specific therapies are urgently needed. We hypothesized that druggable molecular pathways underlying the defect can be revealed through phenotypic small-molecule screens. Accordingly, a screening assay was developed using c-kit+ fetal liver erythroid progenitors from a doxycycline-inducible DBA mouse model. The addition of doxycycline to the culture medium induces the phenotype and reduces proliferation to <10% of normal, such that rescue of proliferation can be used as a simple readout for screening. Here, we describe the assay rationale and efforts toward validation of a microtiter plate–compatible assay and its application in a pilot screen of 3871 annotated compounds. Ten hits demonstrated concentration-dependent activity, and we report a brief follow-up of one of these compounds. In conclusion, we established a robust scalable assay for screening molecules that rescue erythropoiesis in DBA.

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma.

Evidence of physical interaction with the target protein is essential in the development of chemical probes and drugs. The cellular thermal shift assay (CETSA) allows evaluation of drug binding in live cells but lacks a framework to support quantitative interpretations and comparisons with functional data. We outline an experimental platform for such analysis using human kinase p38α. Systematic variations to the assay’s characteristic heat challenge demonstrate an apparent loss of compound potency with an increase in duration or temperature, in line with expectations from the literature for thermal shift assays. Importantly, data for five structurally diverse inhibitors can be quantitatively explained using a simple model of linked equilibria and published binding parameters. The platform further distinguishes between ligand mechanisms and allows for quantitative comparisons of drug binding affinities and kinetics in live cells and lysates. We believe this work has broad implications in the appropriate use of the CETSA for target and compound validation.

Targeting the protein–protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is still limited. The arylmethylidenepyrazolinone SJ-172550 has been reported as a selective MDMX antagonist; yet, uncertainties about its mechanism of action have raised doubts about its use as a chemical probe. Here, we show that, in addition to its unclear mode of action, SJ-172550 is unstable in aqueous buffers, giving rise to side products of unknown biological activity. Using an SJ-172550-derived affinity probe, we observed promiscuous binding to cellular proteins whereas cellular thermal shift assays did not reveal a stabilizing effect on MDMX. Overall, our results raise further questions about the interpretation of data using SJ-172550 and related compounds to investigate cellular phenotypes.

A prerequisite for successful drugs is effective binding of the desired target protein in the complex environment of a living system. Drug–target engagement has typically been difficult to monitor in physiologically relevant models, and with current methods, especially, while maintaining spatial information. One recent technique for quantifying drug–target engagement is the cellular thermal shift assay (CETSA), in which ligand-induced protein stabilization is measured after a heat challenge. Here, we describe a CETSA protocol in live A431 cells for p38α (MAPK14), where remaining soluble protein is detected in situ, using high-content imaging in 384-well, microtiter plates. We validate this assay concept using a number of known p38α inhibitors and further demonstrate the potential of this technology for chemical probe and drug discovery purposes by performing a small pilot screen for novel p38α binders. Importantly, this protocol creates a workflow that is amenable to adherent cells in their native state and yields spatially resolved target engagement information measurable at the single-cell level.

The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP), which causes DNA damage through perturbation of DNA synthesis. Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment. Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR–Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient-derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.

The cellular thermal shift assay (CETSA) was introduced in 2013 as a means to assess drug binding in complex environments such as cell lysates, live cells, and even tissues. The assay principle relies on the well-proven biophysical concept of ligand-induced thermal stabilization of proteins, which in CETSA applications is measured as a persistent presence of soluble protein at elevated temperatures. Given its recent development, we have just started to learn about the benefits and pitfalls of the method as it is applied to a growing number of protein target classes, the majority of which are intracellular soluble proteins. One of the early technology developments concerned the transfer of the original assay procedure from PCR tubes and Western blot detection of soluble protein to a homogeneous assay in high-density microplates. A move to high-throughput formats is essential for a more systematic application in drug discovery settings, as well as in academic efforts for validating chemical probes through studies of structure–activity relationships. This perspective aims at providing an overview of knowledge gained in microplate formatting of CETSA and makes an attempt at forecasting future applications.

Health-care professionals have a responsibility to be attentive to patients’ adherence behavior but it could be difficult to identify poor adherence in the context of clinical practice. Assessment of personality could be used to identify individuals who are in need for support with their adherence behavior. To our knowledge, existing adherence questionnaires are not based on individuals reflecting asthmatics in the general population and there is limited research describing adherence with asthma medication in relation to personal goals with the treatment. The aim was to develop and validate an adherence questionnaire in adult individuals with asthma from the general population and to assess adherence in relation to personality traits and goals with the asthma medication using the developed questionnaire. The study was conducted in three phases: 1. A preliminary postal 46-item questionnaire was refined after psychometric testing (n= 157). 2. The questionnaire was validated (n= 104). 3. The developed adherence questionnaire was analyzed in relation to personality traits and achieved goals with the asthma medication. Adult respondents with physician diagnosed asthma using asthma medications were selected from the population-based West Sweden Asthma Study. The respondents completed the Neuroticism, Extraversion and Openness to Experience Five-Factor Inventory and the Medication Adherence Report Scale and stated their goals with the asthma medication. Data were analyzed using t-tests, correlations, multiple regression and principal component analysis. A final questionnaire was developed consisting of ten items organized in three subscales - “medication routines”, “self-adjusting the medication” and “concerns about side-effects”. Two of the subscales - “medication routines” and “self-adjusting the medication” – were associated with the Medication Adherence Report Scale. The subscale “medication routines” was associated with the personality traits – Conscientiousness and Neuroticism and unachieved goals with the asthma medication. The developed questionnaire appears to be useful for measuring adherence to asthma medication in adult individuals with asthma. The study suggests that both individual differences and personal treatment goals need to be addressed in efforts to promote adherence to asthma medication treatment.

•Approaches used in Computational Welding Mechanics are applicable for additive Manufacturing.•The model sizes pose additional challenges in case of simulating AM.•Models must couple microstructural and material behavior.

Smoking tobacco increases the risk of respiratory disease in adults and children, but communicating the magnitude of these effects in a scientific manner that is accessible and usable by the public and policymakers presents a challenge. We have therefore summarized scientific data on the impact of smoking on respiratory diseases to provide the content for a unique resource, SmokeHaz.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10−4). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7–2.3 for lung cancer (LC; P=4.0 × 10−4), chronic obstructive pulmonary disease (COPD; P=9.3 × 10−4), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10−4), COPD (OR=3.22, P=2.9 × 10−4), PAD (OR=3.47, P=9.2 × 10−3) and AAA (OR=6.44, P=6.3 × 10−3). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10−5), particularly for early-onset cases (P=2.1 × 10−7). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Angiotensin IV (Ang IV) and related peptide analogs, as well as nonpeptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocyclic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N terminus of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09, and of Ang IV in either the extended or γ-turn conformation at the C terminus to human IRAP were predicted by docking and molecular dynamics simulations. The binding free energies calculated with the linear interaction energy method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

The geometrical quality of a welded assembly is to some extent depending part positions before welding. Here, a design of experiment is set up in order to investigate this relation using physical tests in a controlled environment. Based on the experimental results it can be concluded that the influence of part position before welding is significant for geometrical deviation after welding. Furthermore, a working procedure for a completely virtual geometry assurance process for welded assemblies is outlined. In this process, part variations, assembly fixture variations and welding induced variations are important inputs when predicting the capability of the final assembly.

Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2–deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2–HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4–MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness.

A questionnaire of respiratory symptoms and diseases completed by 6610 adults in 3 age cohorts (35–36 y; 50–51 y and 65–66 y) in northern Sweden was followed-up by interview and lung function testing of 1243 subjects with asthmatic or bronchitic symptoms and 263 subjects assessed from the postal questionnaire as being healthy. We report the results of this follow-up study.

Nutrition is a central factor influencing immunity and resistance to infection, but the extent to which nutrition during development affects adult responses to infections is poorly understood. Our study investigated how the nutritional composition of the larval diet affects the survival, pathogen load and food intake of adult fruit flies, Bactrocera tryoni, after septic bacterial infection. We found a sex-specific effect of larval diet composition on survival post-infection: survival rate was higher and bacterial load was lower for infected females raised on a sugar-rich larval diet than for females raised on a protein-rich larval diet, an effect that was absent in males. Both males and females were heavier when fed a balanced larval diet compared with a protein- or sugar-rich diet, while body lipid reserves were higher for those that had consumed the sugar-rich larval diet compared with other diets. Body protein reserves were lower for flies that had been raised on the sugar-rich larval diet compared with other diets in males, but not females. Both females and males shifted their nutrient intake to ingest a sugar-rich diet when infected compared with sham-infected flies without any effect of the larval diet, suggesting that sugar-rich diets can be beneficial to fight off bacterial infection as shown in previous literature. Overall, our findings show that nutrition during early life can shape individual fitness in adulthood.

Interaction between a drug and its protein target results in a shift in thermal stability of that protein. The cellular thermal shift assay–CETSA–exploits this to characterize intracellular drug-protein engagement.

Passive smoking, or environmental tobacco smoke (ETS), is a risk factor for lung cancer, cardiovascular disease, and childhood asthma, but a relationship with COPD has not been fully established. Our aim was to study ETS as a risk factor for COPD in never smokers.

Simulation of some, or all, steps in a manufacturing chain may be important for certain applications in order to determine the final achieved properties of the component. The paper discusses the additional challenges in this context.

ABSTRACTNew drugs for the treatment of human African trypanosomiasis are urgently needed. A number of 2-aminopyrazines/2-aminopyridines were identified as promising leads following a focused screen of 5,500 compounds for Trypanosoma bruceisubsp. bruceiviability. Described compounds are trypanotoxic in the submicromolar range and show comparably low cytotoxicity on representative mammalian cell lines. Specifically, 6-([6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)]oxy)-N-(piperidin-4-yl)pyrazin-2-amine (CBK201352) is trypanotoxic for T. bruceisubsp. brucei, T. bruceisubsp. gambiense, and T. bruceisubsp. rhodesienseand is nontoxic to mammalian cell lines, and in vitropreclinical assays predict promising pharmacokinetic parameters. Mice inoculated intraperitoneally (i.p.) with 25 mg/kg CBK201352 twice daily for 10 days, starting on the day of infection with T. bruceisubsp. brucei, show complete clearance of parasites for more than 90 days. Thus, CBK201352 and related analogs are promising leads for the development of novel treatments for human African trypanosomiasis.

Objectives. To assess the prevalence of bronchial hyperresponsiveness (BHR) in a population of north Finland among subjects with no previous diagnosis of asthma or chronic bronchitis by using histamine and methacholine challenges. The agreement between the methods was also evaluated.Study design.An epidemiological study assessing the prevalence of BHR measured with 2 direct dosimetric challenge methods.Methods.Seventy-nine randomly selected subjects (21–73 years) were studied; 67% had respiratory or allergic symptoms. The baseline spirometry was normal or showed mild obstruction. Bronchial challenges to methacholine and histamine were performed on each subject in a randomized order. Provocative doses inducing the decrease of FEV1 by 15% and 2 0% (PD15FEV1 and PD20FEV1) and dose response ratios (DDR) were calculated for both tests.Results.BHR with the methacholine test (PD20FEV1≤2.6 mg) was found in 20% and with the histamine test (PD15FEV1≤1.6 mg) in 28% of subjects; the agreement was 80% (kappa 0.45; 95% CI 0.23–0.68). In staging the severity of BHR the methods had a good agreement (weighted kappa 0.64; CI 95% 0.46-0.82). Prevalence of BHR fulfilling the criteria of the both methods was 14%.ConclusionsThe findings suggest that the prevalence of BHR in the population of north Finland with no previous diagnosis of asthma or chronic bronchitis is at least 14%, probably around 2 0%, assessed by histamine and methacholine challenge methods. The methods have a good agreement to be used for classifying the severity of BHR.

Most studies evaluating bronchodilation in flow-volume spirometry have been conducted in patients with obstructive airways diseases, but less is known about bronchodilation responses in the general population or in healthy subjects.

Navigating a ship in following and stern quartering seas is well known to seafarers for the possible troublesome situations that may arise. The issue has also been addressed by many researchers during the last 50 years. In 1964 Du Cane and Goodrich presented one of the first systematic studies on ships in following seas together with a compilation of accounts on real occurrences of dangerous situations for ships in following and stern quartering seas. Later research has confirmed the possibility for occurrence of several types of allegedly capricious behaviour for a ship travelling at a course within one third of the compass card, i.e. between −60° and 60° relative to the waves. The research included in the references is covering many different types of ships from fishing boats to fast naval vessels and merchant ships. Despite the 51 years of research in the tradition pointed out by Du Cane and Goodrich’s work, there is still a lack of effective methodology within many of the areas connected to following and stern quartering seas. The present paper is mainly focusing on manoeuvring in following seas. Nevertheless, results included in the current paper, among others, show that ship motion in the horizontal plane has a major impact on the magnitude and timing of wave excitation in all degrees of freedom. Therefore the presented results are of importance for most of the seakeeping and safety issues related to navigation in following and stern quartering seas. The most significant results presented in the current paper come from semi-captive tests with a semi-planing ship model At these tests the surge force, sway force, roll moment and yaw moment were measured, while the ship model was free to heave and pitch. The test data are compared to computational data obtained by a strongly simplified hydrodynamic modelling. This comparison shows very encouraging results. The paper does also address criteria for safe manoeuvring in following and stern quartering seas, methodologies for full-scale tests and experiments with a free-running scale model.

When measuring the aerodynamic particle size distribution of pulmonary drug products, the commonly used instrument is a cascade impactor. For this type of analysis, a mass balance (MB) criterion, 85–115% of label claim, has been recommended by the U.S. Food and Drug Administration (FDA) to be included in the drug product specification. Using statistical model simulations, the effect of inherent product variability on the risk to fail the proposed criteria has been assessed and compared to the corresponding risk to fail the delivered dose uniformity (DDU) test. The results clearly show that the MB criterion is at odds with typical variability of orally inhaled products and seriously contributes to the risk that a typical batch would be rejected due to natural variability of the delivered dose of the product. The MB criterion is generally more difficult to comply with compared to the corresponding delivered dose uniformity (DDU) test, indicating that the proposed FDA MB specification overrules the DDU criteria as being that controlling the DDU.

This is a population-based study on the prevalence of respiratory symptoms assessed by a mail questionnaire. The objective was to examine if work in an iron mine increased the risk of airway symptoms or obstructive diseases. The exposed group consisted of 114 previous or current male miners. Referents, 2472 males from the province, had never been employed by the mining company or worked as miners. Age, smoking and a family history of asthma were considered as possible confounders. The miners had an increased risk for respiratory symptoms (OR=2.2, 95% CI=1.4–3.1) including recurrent wheeze (OR=2.4, 95% CI=1.5–3.9), longstanding cough (OR=1.8, 95% CI=1.0–3.2), and for physician-diagnosed chronic bronchitis (OR=2.2, 95% CI=1.0–4.5). Attacks of shortness of breath and asthma manifestations were similar between miners and referents. Higher risks in miners were found particularly among the non-smokers for physician-diagnosed chronic bronchitis (OR=9.2, 95% CI=3.0–28) and for symptoms as well. A family history of asthma was less common among miners (9.2% vs. 17%, p< 0.05). We conclude that miners in a modern underground iron mine had an increased risk of respiratory symptoms. In contrast to other studies, this increased risk was particularly found in non-smokers. A family history of asthma may be an important confounder in occupational studies of respiratory diseases.

Background: The clinical benefit of combining long-acting β2-agonists with inhaled corticosteroids rather than doubling the dose of corticosteroid has been well-documented. However, there are concerns that this might result in a masking of underlying airway inflammation. Objective: The aim of this study was to test the hypothesis that the addition of the long-acting β2-agonist salmeterol (SALM) to a low dose of the inhaled corticosteroid fluticasone propionate (FP) has a steroid-sparing effect and does not result in a worsening of bronchial inflammation compared to doubling the dose of inhaled corticosteroid. Methods: Fifty-six asthmatic subjects, previously not well-controlled on inhaled corticosteroids, were randomized to receive 3 months of treatment with inhaled FP 500 μg twice a day (FP 1000) or FP 200 μg twice a day plus SALM 50 μg twice a day (FP 400 + SALM). Fluticasone propionate 200 μg twice a day served as the control (FP400). Bronchial mucosal biopsy specimens, bronchial washings (BW), and bronchoalveolar lavage were obtained before and after treatment. The primary end points for the study were submucosal mast cell and eosinophil counts. Results: There was a significant improvement in FEV1in the FP400 + SALM group compared to both the FP400 and FP1000 groups. This was accompanied by a significant improvement in peak expiratory flow in the FP400 + SALM group in both the morning and evening compared to the FP1000 group. There were no significant between treatment differences in the change in the number of submucosal mast cells or eosinophils. However, in the FP400 + SALM group there was a significant decrease in submucosal mast cells after 12 weeks of treatment. The addition of SALM to FP was not associated with any increases in airway inflammation in the biopsy specimens, bronchoalveolar lavage, or bronchial washings. Conclusion: These findings confirm that addition of SALM to FP has clinical benefits but does not mask or exacerbate airway inflammation and suggest that long-acting β2-adrenoceptor agonists might influence mast cell numbers. (J Allergy Clin Immunol 2003;112:72-8.)

Background: Recently performed studies have found a number of limitations in the daily lives of asthmatics, and a large disparity between the perception of the sufferers and what health care professionals believe matters to asthmatics. Aim: What matters to Swedish asthma patients, what medicines do they use, and are they compliant with given prescriptions? A further aim was to compare perceptions about asthma and asthma management in asthmatics and among Swedish general practitioners (GP). Design: A structured telephone interview of a representative sample of Swedish asthmatics, and a mailed questionnaire survey among GPs from different parts of Sweden. Methods: Screening by telephone of a random sample of 10,350 subjects aged 18–45. Of those, 240 were subsequently selected for a detailed structured telephone interview about their asthma. A mailed structured questionnaire containing similar questions to those asked of the asthmatics was sent to 600 GPs, and 139 returned completed answers. Results: 16% of the asthmatics reported (asthma) symptoms occurring every day during the previous month. Nocturnal symptoms at least twice per week were reported by 19%. Both these were reported by considerably higher proportions of the asthmatics than the GPs had expected. A large majority classified their disease as mild or very mild, although great majority reported frequent symptoms. Activities or situations which caused symptoms of asthma often or “now and then” were physical exertion, 67%; bad weather, 59%; contact with animals/pets, 58%; and visits to cafés or restaurants, 36%; and several asthmatics avoided these activities due to their asthma. Conclusion: A great majority of asthmatics report a large number of symptoms and limitations in their daily living in proportions which were roughly expected by the GPs.

Objectives. Respiratory symptoms and obstructive pulmonary diseases experienced during exercise and in cold weather were analysed in a large postal questionnaire study of a general adult population living in a cold climate. The aim of this study was to assess the prevalence of shortness of breath (SOB) during exercise, or in cold weather, and to find out if the risks (odds ratio=OR) for asthma, chronic bronchitis, or SOB during exercise, or in cold weather, were affected by recreational cross-country skiing, or by outdoor work in a cold climate.Results. Of the 7937 invited persons, 84% responded; 876 of them were outdoor workers and 1497 were recreational cross-country skiers. Of the non-smoking responders, asthmatic subjects had the highest prevalence of SOB during exercise in cold weather (78%-82%), but allergic and bronchitic persons also had significantly higher prevalence rates (22%-38% and 27%-59%, respectively) than healthy persons (10%-19%). In all categories, the prevalence of SOB was significantly higher among current smokers than among ex-or non-smokers.Risk factor analysis revealed increased risks for respiratory conditions among those who had a family history of obstructive airway disease, or allergy. Skiers did not have a significantly increased risk for asthma, or respiratory symptoms. Among outdoor workers the risk for SOB during exercise in cold weather, OR 1.23 (CI 1.03–1.47), and for chronic bronchitis, OR 1.77 (CI 1.21–2.60), was higher than among indoor workers.Conclusions. In conclusion, the risk for chronic bronchitis and bronchitic symptoms was elevated among outdoor workers, but not among regular recreational cross-country skiers, and the risk for asthma was not significantly elevated by regular exercising, or by working in a cold climate.

COPD is a common and disabling disease that entails high costs for society. The objectives of this study were to measure the societal costs of COPD in Sweden, and to examine the relationship between severity of illness and costs.

Epidemiological studies indicate a lower prevalence of asthma in Eastern than Western Europe. This study of the prevalence of asthma, chronic bronchitis, and respiratory symptoms was performed in three different regions of Estonia, a state incorporated in the Soviet Union until 1991. A postal questionnaire was sent to a random sample of 24307 of the population aged 15–64 years. The response rate was 77·6%. The prevalence of physician-diagnosed asthma was 2·0% or considerably lower than in Northern and Western European countries. The prevalence of wheezing last 12 months, 21·7%, recurrent wheeze, 13·3%, and attacks of shortness of breath, 12·5%, were similar or even higher compared with prevalence rates found in the Nordic countries. The prevalence of physician-diagnosed chronic bronchitis was 10·7%, and was higher among women than in men, although the proportion of current smokers among men, 57%, was considerably greater than in women, 28%. A possible explanation to the high prevalence of respiratory symptoms also among non-smoking women may be exposure to environmental tobacco smoke in small, crowded Estonian homes. Diagnostic criteria based on the Soviet-time definitions is discussed as a possible explanation to the low prevalence of physician-diagnosed asthma and high prevalence of chronic bronchitis in Estonia compared with other Northern European countries.

To examine if exposure to environmental tobacco smoke (ETS) during childhood has an impact on asthma prevalence in adults, and to identify the amount of nuisance from ETS and other lower airway irritants (LAWIs) in a city population.

Background and aim: In epidemiological questionnaire studies results can be influenced by non-responder bias. However, in respiratory epidemiology this has been analysed in very few recently published papers. The aim of our paper is to assess if the results found in our previous postal questionnaire study in an adult population in Northern Finland were biased by non-response. Methods: A random sample of 385 persons from the 1284 non-responders in a previous postal questionnaire study was examined. The same questionnaire as in the original study was again mailed to these persons, and those still not answering were contacted by phone. Results: Totally 183 complete answers (48%) were collected. Lack of interest (56%) and forgetting to mail the response letter (22%) were the most common reasons to non-response. Typical non-responders were young men and current smokers who less frequently reported respiratory symptoms in exercise and asthma than the responders in the original study. Answers collected by phone gave for some questions higher prevalence rates than postal answers. Conclusion: Firstly, in this population the response rate (83.6%) in the original study was high enough to provide reliable results for respiratory symptoms and diseases, only the prevalence of current smoking was biased by non-response. Secondly, the methods used for collecting responses in a non-response study may influence the results.

Only limited data are available about the incidence of asthma based on longitudinal prospective studies. Further, the results from different studies on incidence vary considerably depending on the age composition of the cohorts under study, the used methods and the criteria for disease. Also among adults high incidence rates have been reported during recent years. The aim of this study was to examine to what extent the incidence of physician-diagnosed asthma could be explained by a real incidence of the disease, and to what extend by an increased diagnostic activity or altered diagnostic praxis. Another aim was to study risk factors for asthma based on incident cases. Three cross-sectional surveys have been performed in the same population sample living in the northern-most province of Sweden, Norrbotten. The first survey was performed in 1986, and 5698 subjects, 86% of those invited, responded to a postal questionnaire. Of these, 4754 subjects (83%) participated at the third survey in 1996. After exclusion of all subjects who had reported that they had asthma in 1986, or had been classified as having asthma in 1986, 68 men and 98 women (P=0·02) reported in 1996 that they had been diagnosed as having asthma by a physician. Thus, the cumulative incidence for the 10-year period was 3·2% among men and 4·5% among women. After correction for subjects who already in 1986 had reported symptoms common in asthma, or had been classified as having chronic bronchitis, 97 subjects with incident asthma remained, which corresponded to an annual incidence rate among men of 1·7 and among women of 2·9/1000 persons year⁻¹(P=0·01). Clinical examinations confirmed asthma in a large majority of these 97 subjects. Significant risk factors were family history of asthma, both ex- and current smoking, and female sex. The socio-economic groups manual workers and assistant non-manual employees were associated with incident asthma, although not significantly. The increasing prevalence of asthma among adults during recent 10–20 years may to a considerable extent be explained by an increased diagnostic activity or altered diagnostic praxis. Use of different methods when measuring incidence may in part explain the extremely diverging incidence rates of asthma found in different studies. Copyright 2001 Harcourt Publishers Ltd.

AbstractBackground:In previous studies we have found that subjects with bronchitis have a higher prevalence of ‘snoring as a problem’ than respiratory healthy subjects. Objectives:We aimed to study whether the high prevalence of snoring among subjects with bronchitis also represents a high prevalence of obstructive sleep apnoea (OSA). Method:Subjects in three age groups born 1919–1920, 1934–1935 and 1949–1950 had been identified as bronchitic in an earlier study (n = 471) and without respiratory symptoms (n = 108). Of the 91 subjects reporting snoring to be a problem, 70 were invited to participate in the study.Sleep investigation was performed in 52 of these 70 subjects. Results:‘Snoring as a problem’, predicted OSA to a similar degree in both bronchitic and respiratory healthy subjects. The estimated prevalence for obstructive sleep apnoea with an apnoea/hypopnoea index (AHI) 10 as the cut-off point and concomitant daytime symptoms such as daytime sleepiness or liability to nodding off during breaks in activity in the daytime, was 5.4% for bronchitic subjects and 2.3% for respiratory healthy subjects. Apnoea in addition to snoring predicted OSA better than did snoring alone. Age correlated significantly with AHI, and OSA was most common in the middle-aged group, 61–62 years old. Conclusion:OSA is twice as common in subjects with chronic bronchitis as in subjects free of pulmonary disease or symptoms.Copyright © 2001 S. Karger AG, Basel