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Purpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US)., Patients and Methods: The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI)., Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88)., Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication., Competing Interests: Edeltraut Garbe has been chairwoman of the Department of Clinical Epidemiology at the Leibniz Institute for Prevention Research and Epidemiology – BIPS and in this function occasionally performed studies for pharmaceutical industries. The pharmaceutical companies included Byk-Gulden, Nycomed, Bayer, Celgene, GlaxoSmithKline, Mundipharma, Novartis, Sanofi-Aventis, Sanofi Pasteur MSD, and STADA. She has been a consultant to Bayer-Schering, Nycomed, GlaxoSmithKline, Schwabe, Teva, and Novartis, as well as to AstraZeneca (including this study). Per Arkhammar, Marie Carlholm, Eileen O Dareng, Harald Fjällbrant, and Stefan Franzén are employees and shareholders of AstraZeneca. Atul Kumar is an employee of AstraZeneca. Tore Persson is an AstraZeneca contractor and shareholder. Cecilia Hedlund is an AstraZeneca contractor. Gunnar Johansson has served on advisory boards arranged by AstraZeneca, Novartis, and Teva. Bianca Kollhorst, Wiebke Schäfer, and Tania Schink are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. These are post-authorization safety studies (PASS) requested by health authorities and performed in line with the ENCePP Code of Conduct. Fabian Hoti, Muriel Lobier, Aaro Salosensaari, Xu Qiao, and Vasili Mushnikov are employed by IQVIA, a contract research organization that conducts studies financed by the pharmaceutical industry. Nicholas Sicignano and Kristian Svendsen confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. The authors report no other conflicts of interest in this work., (© 2024 Garbe et al.)

The Vänersborg Bridge in southwest Sweden is a single-leaf bascule bridge carrying railway traffic over a canal. The load consists of passing commuter trains, occasional freight trains and leaf openings to allow ships to pass on the canal. The bridge constructed from 1914 to 1916 was built by riveted truss members in steel. Over the years, several assessments and maintenance actions have been performed to keep the bridge in service. During autumn 2021, a long-term monitoring campaign was initiated with the installation of sensors to register the load effect and possible changes in the behaviour. In March 2023, the cloud-based service employed detected an abrupt change of behaviour. An emergency inspection revealed a large crack in one of the truss members in the counter-weight part. The published dataset contains sensor data from 64 registered bridge openings, comprising accelerations, strains, inclinations, and weather conditions. Data from before the fracture, during, and after are provided. During the bridge opening events, the data was recorded continuously with a sampling rate of 200 Hz. The evidence of damage in a real case scenario makes the dataset valuable for testing and evaluation of data-driven routines for infrastructure surveillance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: Co-morbidities are common in chronic obstructive pulmonary disease (COPD) and are associated with increased morbidity and mortality. The aim of the present study was to explore the prevalence of several comorbid conditions in severe COPD, and to investigate and compare their associations with long-term mortality., Methods: In May 2011 to March 2012, 241 patients with COPD stage 3 or 4 were included in the study. Information was collected on sex, age, smoking history, weight and height, current pharmacological treatment, number of exacerbations the recent year and comorbid conditions. At December 31st, 2019, mortality data (all-cause and cause specific) were collected from the National Cause of Death Register. Data were analyzed using Cox-regression analysis with gender, age, previously established predictors of mortality and comorbid conditions as independent variables, and all-cause mortality and cardiac and respiratory mortality, respectively, as dependent variables., Results: Out of 241 patients, 155 (64%) were deceased at the end of the study period; 103 patients (66%) died of respiratory disease and 25 (16%) of cardiovascular disease. Impaired kidney function was the only comorbid condition independently associated with increased all-cause mortality (HR (95% CI) 3.41 (1.47-7.93) p=0.004) and respiratory mortality (HR (95%CI) 4.63 (1.61 to 13.4), p = 0.005). In addition, age ≥70, BMI <22 and lower FEV1 expressed as %predicted were significantly associated with increased all-cause and respiratory mortality., Conclusion: In addition to the risk factors high age, low BMI and poor lung function; impaired kidney function appears to be an important risk factor for mortality in the long term, which should be taken into account in the medical care of patients with severe COPD., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Cellobiohydrolases (CBHs) in the glycoside hydrolase family 7 (GH7) (EC3.2.1.176) are the major cellulose degrading enzymes both in industrial settings and in the context of carbon cycling in nature. Small carbohydrate conjugates such as p-nitrophenyl-β-d-cellobioside (pNPC), p-nitrophenyl-β-d-lactoside (pNPL) and methylumbelliferyl-β-d-cellobioside have commonly been used in colorimetric and fluorometric assays for analysing activity of these enzymes. Despite the similar nature of these compounds the kinetics of their enzymatic hydrolysis vary greatly between the different compounds as well as among different enzymes within the GH7 family. Through enzyme kinetics, crystallographic structure determination, molecular dynamics simulations, and fluorometric binding studies using the closely related compound o-nitrophenyl-β-d-cellobioside (oNPC), in this work we examine the different hydrolysis characteristics of these compounds on two model enzymes of this class, TrCel7A from Trichoderma reesei and PcCel7D from Phanerochaete chrysosporium. Protein crystal structures of the E212Q mutant of TrCel7A with pNPC and pNPL, and the wildtype TrCel7A with oNPC, reveal that non-productive binding at the product site is the dominating binding mode for these compounds. Enzyme kinetics results suggest the strength of non-productive binding is a key determinant for the activity characteristics on these substrates, with PcCel7D consistently showing higher turnover rates (k cat ) than TrCel7A, but higher Michaelis-Menten (K M ) constants as well. Furthermore, oNPC turned out to be useful as an active-site probe for fluorometric determination of the dissociation constant for cellobiose on TrCel7A but could not be utilized for the same purpose on PcCel7D, likely due to strong binding to an unknown site outside the active site., (© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Inorganic pyrophosphate (PPi) is a crucial extracellular mineralization regulator. Low plasma PPi concentrations underlie the soft tissue calcification present in several rare hereditary mineralization disorders as well as in more common conditions like chronic kidney disease and diabetes. Even though deregulated plasma PPi homeostasis is known to be linked to multiple human diseases, there is currently no reliable assay for its quantification. We here describe a PPi assay that employs the enzyme ATP sulfurylase to convert PPi into ATP. Generated ATP is subsequently quantified by firefly luciferase-based bioluminescence. An internal ATP standard was used to correct for sample-specific interference by matrix compounds on firefly luciferase activity. The assay was validated and shows excellent precision (< 3.5%) and accuracy (93-106%) of PPi spiked into human plasma samples. We found that of several anticoagulants tested only EDTA effectively blocked conversion of ATP into PPi in plasma after blood collection. Moreover, filtration over a 300,000-Da molecular weight cut-off membrane reduced variability of plasma PPi and removed ATP present in a membrane-enclosed compartment, possibly platelets. Applied to plasma samples of wild-type and Abcc6 -/- rats, an animal model with established low circulating levels of PPi, the new assay showed lower variability than the assay that was previously in routine use in our laboratory. In conclusion, we here report a new and robust assay to determine PPi concentrations in plasma, which outperforms currently available assays because of its high sensitivity, precision, and accuracy., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Sugars were derivatized with N,O-dimethylhydroxylamine (DMHA) using a simple procedure. The disaccharides lactose and chitobiose and the human milk tetrasaccharides lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) were used as examples. The β-glycosylamines were formed exclusively in good yields (80-84%). The derivatives were very well suited for RP-HPLC, giving rise to single peaks for each sugar, without the usual complications caused by mutarotation. The LNT- and LNnT-derivatives separated very well on an ordinary RP-HPLC column, despite their close structural similarity. Also, three human milk pentasaccharides (LNF I, II and III) were derivatized with DMHA. Again, good separation of these isomers was obtained. The DMHA derivatization was easily reversed. The free oligosaccharides were recovered quantitatively by mild acidic hydrolysis. To demonstrate usefulness on a preparative scale, an LNDI-rich human milk oligosaccharide fraction was derivatized, and three HPLC fractions (one major and two minor) were collected. Hydrolysis and desalting gave saccharides LNDI, LNnDII, and LNDII, the latter mixed with minor amounts of LNnDI., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with mild chronic obstructive pulmonary disease (COPD) account for more than half of the total COPD population but are often undiagnosed and sparsely studied. This real-world, longitudinal study compared the socioeconomic burden, clinical characteristics and treatment patterns in patients with mild COPD and age- and gender-matched controls., Patients and Methods: Our population included mild COPD patients (forced expiratory volume in one second ≥80% of predicted value) and reference controls from 52 Swedish primary care centres over 15 years (2000-2014). We linked electronic medical record (EMR) data to Sweden's National Health Registries. The outcomes analyzed were socioeconomic status including annual income from work, presence of comorbidities and the use of medications., Results: 844 patients with mild COPD were included in this study and matched with 844 reference controls. Compared with the reference controls, mild COPD patients had a significantly lower annual income from work (mean difference, men: 12,559€ and women: 7143€) and were significantly less likely to be married or employed. The presence of comorbidities, including cardiovascular disease, anxiety and depression (only women) was significantly higher in mild COPD patients. The use of medications, such as proton pump inhibitors, antidepressants, central painkillers and sleep medications, was significantly higher in the mild COPD group., Conclusion: Mild COPD presents a considerable socioeconomic and clinical burden compared with reference controls The findings suggest that COPD constitutes a condition that influences health status even in mild disease clearly demanding an increased need for early detection and treatment., Competing Interests: KLa has, during the last 5 years, on one or more occasions, served on an advisory board, served as a speaker, and/or participated in education activities arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, Chiesi, Orion and Teva. CJ reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, outside the submitted work. KLi reports personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKline and Chiesi, outside the submitted work. BS reports personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKline, Meda, Teva and Chiesi, outside the submitted work. GJ has participated on the steering committee organised by Novartis for this study and served on advisory boards arranged by AstraZeneca, Novo Nordisk and Takeda. FSG and KM are employees of Novartis Pharma AG. BKB, LJ and HK are employees of IQVIA and received remuneration in relation to statistical analyses. The authors report no other conflicts of interest in this work., (© 2022 Larsson et al.)

Objective: The ability to predict impending asthma exacerbations may allow better utilization of healthcare resources, prevention of hospitalization and improve patient outcomes. We aimed to develop models using machine learning to predict risk of exacerbations., Methods: Data from 29,396 asthma patients was collected from electronic medical records and national registers covering clinical and epidemiological factors (e.g. comorbidities, health care contacts), between 2000 and 2013. Machine-learning classifiers were used to create models to predict exacerbations within the next 15 days. Model selection was done using the mean cross validation score of area under precision-recall curve (AUPRC)., Results: The most important predictors of exacerbation were comorbidity burden and previous exacerbations. Model validation on test data yielded an AUPRC = 0.007 (95% CI: ± 0.0002), indicating that historic clinical information alone may not be sufficient to predict a near future risk of asthma exacerbation., Conclusions: Supplementation with additional data on environmental triggers, (e.g. weather, pollen count, air quality) and from wearables, might be necessary to improve performance of the short-term predictive model to develop a more clinically useful tool., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The aim of this study was to assess the association between exacerbation frequency and clinical and economic outcomes in patients with COPD., Patients and Methods: Electronic medical record data linked to National Health Registries were collected from COPD patients at 52 Swedish primary care centers (2000-2014). The outcomes analyzed were exacerbation rate, mortality, COPD treatments, lung function and healthcare costs during the follow-up period. Based on the exacerbation rate two years before index date, the patients were initially classified into three groups, either 0, 1 or ≥2 exacerbations per year. After the index date, the classification into exacerbation groups was updated each year based on the exacerbation rate during the last year of follow-up. A sensitivity analysis was conducted excluding patients with asthma diagnosis from the analysis., Results: In total 18,586 COPD patients were analyzed. A majority of the patients (60-70%) who either have had no exacerbation or frequent exacerbations (≥2/year) during the pre-index period remained in their group (ie, with 0 or ≥2 annual exacerbations) during up to 11 years of follow-up. Compared with having no exacerbation, mortality was higher in patients having 1 (HR; 2.06 [1.93-2.20]) and ≥2 (4.58 [4.33-4.84]) exacerbations at any time during the follow-up. Lung function decline was more rapid in patients with frequent exacerbations and there was an almost linear relationship between exacerbations frequency and mortality. Total healthcare costs were higher in the frequent exacerbation group (≥2/year) than in patients with no or one exacerbation annually (p<0.0001 for both). The results did not differ from the main analysis after exclusion of patients with a concurrent asthma diagnosis., Conclusion: In addition to faster lung function decline and increased mortality, frequent exacerbations in COPD patients imply a significant economic burden., Competing Interests: Kjell Larsson has, during the last 5 years, on one or more occasion served in an advisory board, served as a speaker and/or participated in education activities arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Sanofi, Novartis, Orion, and Teva. Christer Janson reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva, outside the submitted work. Karin Lisspers reports personal fees from AstraZeneca, Novartis, Boehringer-Ingelheim, Glaxo-Smith-Kline, and Chiesi, outside the submitted work. Björn Ställberg reports personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKleine Meda, Teva, and Chiesi, outside the submitted work. Gunnar Johansson has participated in the steering committee organized by Novartis for this study and served on advisory boards arranged by AstraZeneca, Novo Nordisk and Takeda. Florian S Gutzwiller and Karen Mezzi are employees of Novartis Pharma AG. Bine Kjoeller Bjerregaard and Leif Jorgensen are employees of IQVIA, and received remuneration from Novartis in relation to statistical analyses. The authors report no other conflicts of interest in this work., (© 2021 Larsson et al.)

Purpose: Chronic obstructive pulmonary disease (COPD) exacerbations can negatively impact disease severity, progression, mortality and lead to hospitalizations. We aimed to develop a model that predicts a patient's risk of hospitalization due to severe exacerbations (defined as COPD-related hospitalizations) of COPD, using Swedish patient level data., Patients and Methods: Patient level data for 7823 Swedish patients with COPD was collected from electronic medical records (EMRs) and national registries covering healthcare contacts, diagnoses, prescriptions, lab tests, hospitalizations and socioeconomic factors between 2000 and 2013. Models were created using machine-learning methods to predict risk of imminent exacerbation causing patient hospitalization due to COPD within the next 10 days. Exacerbations occurring within this period were considered as one event. Model performance was assessed using the Area under the Precision-Recall Curve (AUPRC). To compare performance with previous similar studies, the Area Under Receiver Operating Curve (AUROC) was also reported. The model with the highest mean cross validation AUPRC was selected as the final model and was in a final step trained on the entire training dataset., Results: The most important factors for predicting severe exacerbations were exacerbations in the previous six months and in whole history, number of COPD-related healthcare contacts and comorbidity burden. Validation on test data yielded an AUROC of 0.86 and AUPRC of 0.08, which was high in comparison to previously published attempts to predict COPD exacerbation., Conclusion: Our work suggests that clinically available information on patient history collected via automated retrieval from EMRs and national registries or directly during patient consultation can form the basis for future clinical tools to predict risk of severe COPD exacerbations., Competing Interests: B.S. has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Meda, Novartis and Teva, and has served on advisory boards arranged by AstraZeneca, Novartis, Meda, GlaxoSmithKline, Teva and Boehringer Ingelheim, and has participated in the steering committee by Novartis for this study. K.Li. has received payments for educational activities and lectures from AstraZeneca, Chiesi, Novartis and Boehringer Ingelheim, served on advisory boards arranged by Novartis, Boehringer Ingelheim, GlaxoSmithKline and AstraZeneca, and has participated in the steering committee by Novartis for this study. K.La. has, during the last 5 years, on one or more occasion served in an advisory board and/or served as speaker and/or participated in education arranged by AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Orion, Mylan, Novartis, and TEVA, and has participated in the steering committee by Novartis for this study. C.J. has received honoraria for educational activities and lectures from Novartis, AstraZeneca, GlaxoSmithKline, TEVA and Boehringer Ingelheim outside the submitted work, and has participated in the steering committee by Novartis for this study. M.M., M. Ł. and B.K.B. are employed by IQVIA. G.B., B. H., and P.G. are employed by Novartis Pharma AG, Basel, Switzerland. G.J. has participated in the steering committee by Novartis for this study and served on advisory boards arranged by AstraZeneca, Novo Nordisk, and Takeda, and has participated in the steering committee by Novartis for this study. The authors report no other conflicts of interest in this work., (© 2021 Ställberg et al.)

The effect of inhaled corticosteroids (ICS) on the risk of osteoporosis and fracture in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to assess this risk in patients with COPD.Electronic medical record data linked to National Health Registries were collected from COPD patients and matched reference controls at 52 Swedish primary care centres from 2000 to 2014. The outcomes analysed were the effect of ICS on all fractures, fractures typically related to osteoporosis, recorded osteoporosis diagnosis, prescriptions of drugs for osteoporosis and a combined measure of any osteoporosis-related event. The COPD patients were stratified by the level of ICS exposure.A total of 9651 patients with COPD and 59 454 matched reference controls were analysed. During the follow-up, 19.9% of COPD patients had at least one osteoporosis-related event compared with 12.9% of reference controls (p<0.0001). Multivariate analysis in the COPD population demonstrated a dose-effect relationship, with high-dose ICS being significantly associated with any osteoporosis-related event (risk ratio 1.52 (95% CI 1.24-1.62)), while the corresponding estimate for low-dose ICS was 1.27 (95% CI 1.13-1.56) compared with COPD patients not using ICS. A similar dose-related adverse effect was found for all four of the specific osteoporosis-related events: all fractures, fractures typically related to osteoporosis, prescriptions of drugs for osteoporosis and diagnosis of osteoporosis.We conclude that patients with COPD have a greater risk of bone fractures and osteoporosis, and high-dose ICS use increased this risk further., Competing Interests: Conflict of interest: C. Janson reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, outside the submitted work. Conflict of interest: K. Lisspers reports personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKline and Chiesi, outside the submitted work. Conflict of interest: B. Ställberg reports personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKline, Meda, Teva and Chiesi, outside the submitted work. Conflict of interest: G. Johansson has nothing to disclose. Conflict of interest: F.S. Gutzwiller is an employee of Novartis Pharma AG. Conflict of interest: K. Mezzi is an employee of Novartis Pharma AG. Conflict of interest: L. Mindeholm is a consultant to Novartis, and shareholder of Novartis, Alcon and Novo-Nordisk. Conflict of interest: B.K. Bjerregaard is an employee of IQVIA and received remuneration in relation to statistical analyses. Conflict of interest: L. Jörgensen is an employee of IQVIA. Conflict of interest: K. Larsson has, during the last 5 years, on one or more occasion served in an advisory board, served as a speaker and/or participated in education activities arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, Chiesi, Orion and Teva., (Copyright ©ERS 2021.)

Leupeptin is a naturally occurring inhibitor of various proteases, in particular serine proteases. Following its discovery, the inhibitory properties of several other peptidyl argininals have been studied. The specificity of leupeptin is most likely due to the Leu-Leu-Argininal sequence, and its C-terminal aldehyde group has been suggested to enhance the binding efficiency and to be essential for function. The terminal aldehyde group makes the structure less vulnerable to carboxypeptidases. Here, we investigated whether the inhibitory function of leupeptin toward serine proteases is retained after oxidation or reduction of the aldehyde group. The oxidized form, which corresponds to the natural precursor, was shown to be superior to the reduced form in terms of inhibitory properties. However, the original leupeptin possessed enhanced inhibitory properties as compared with the oxidized form. Based on these results, new synthetic leupeptin analogues, 6-aminohexanoic acid (Ahx)-Phe-Leu-Arg-COOH and Ahx-Leu-Leu-Arg-COOH, were prepared by solid-phase peptide synthesis using the Fmoc strategy. In these analogues, the N-terminal capping acetyl group was replaced with a 6-aminohexanoyl group to allow conjugation. The structures of the modified leupeptin and the synthetic peptides were confirmed by mass spectrometry. Determination of the inhibitory properties against trypsin (IEC 3.4.21.4, Chymotrypsin IEC 3.4.21.1) revealed that these further modified tripeptides were tight binding inhibitors to their target enzyme, similar to the naturally occurring leupeptin, with K i values generally in the micromolar range. The Ahx-Phe-Leu-Arg-COOH analogue was selected for conjugation to inorganic oxide nanoparticles and agarose gel beads. All conjugates exhibited inhibitory activity in the same range as for the free peptides., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

This study reports the association of ICS use and the risk of type 2 diabetes mellitus (T2DM) in Swedish patients with COPD using data from real-world, primary care settings. A total of 7078 patients with COPD were included in this analysis and the 5-year cumulative incidence rate per 100,000 person years was 1506.9. The yearly incidence rate per 100,000 person years ranged from 850 to 1919. Use of ICS especially at a high dose in patients with COPD was related to an increased risk of T2DM.

Background: Life expectancy is significantly shorter for patients with chronic obstructive pulmonary disease (COPD) than the general population. Concurrent diseases are known to infer an increased mortality risk in those with COPD, but the effects of pharmacological treatments on survival are less established. This study aimed to examine any associations between commonly used drugs, comorbidities and mortality in Swedish real-world primary care COPD patients., Methods: Patients with physician-diagnosed COPD from a large primary care population were observed retrospectively, utilizing primary care records and mandatory Swedish national registers. The time to all-cause death was assessed in a stepwise multiple Cox proportional hazards regression model including demography, socioeconomic factors, exacerbations, comorbidities and medication., Results: During the observation period (1999-2009) 5776 (32.5%) of 17,745 included COPD patients died. Heart failure (hazard ratio [HR]: 1.88, 95% confidence interval [CI]: 1.74-2.04), stroke (HR: 1.52, 95% CI: 1.40-1.64) and myocardial infarction (HR: 1.40, 95% CI: 1.24-1.58) were associated with an increased risk of death. Use of inhaled corticosteroids (ICS; HR: 0.79, 95% CI: 0.66-0.94), beta-blockers (HR: 0.86, 95% CI: 0.76-0.97) and acetylsalicylic acid (ASA; HR: 0.87, 95% CI: 0.77-0.98) was dose-dependently associated with a decreased risk of death, whereas use of long-acting muscarinic antagonists (LAMA; HR: 1.33, 95% CI: 1.14-1.55) and N-acetylcysteine (NAC; HR: 1.26, 95% CI: 1.08-1.48) were dose-dependently associated with an increased risk of death in COPD patients., Conclusion: This large, retrospective, observational study of Swedish real-world primary care COPD patients indicates that coexisting heart failure, stroke and myocardial infarction were the strongest predictors of death, underscoring the importance of timely recognition and treatment of comorbidities. A decreased risk of death associated with the use of ICS, beta-blockers and ASA, and an increased risk associated with the use of LAMA and NAC, was also found., Competing Interests: JE has received honoraria for lectures from AstraZeneca, Novartis and Teva and has served on advisory boards arranged by Novartis. GJ has served on advisory boards arranged by AstraZeneca, Novartis and Teva. KjL has, during the last five years, on one or more occasion served as an advisory board member and/or served as speaker and/or participated in education activities arranged by AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Orion, Novartis, Teva and Takeda. KaL has received honoraria for educational activities from Novartis, AstraZeneca, Chiesi, Teva and Boehringer Ingelheim and served on advisory boards arranged by Novartis and GlaxoSmithKline. AM has no conflicts of interest to declare with regard to the topic of the present study. BS has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Meda and Teva, and has served on advisory boards arranged by AstraZeneca, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Meda and Teva. MT has received personal fees from AstraZeneca, during the conduct of the study. CJ has received honoraria for educational activities from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis and Teva, and has served on advisory boards arranged by AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva. The authors report no other conflicts of interest in this work., (© 2020 Ellingsen et al.)

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH -mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1 , EGFR , and RTEL1 were associated with IDH -wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH ), LRIG1 , PHLDB1 , ETFA , MAML2 and ZBTB16 were associated with IDH -mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

The present study aimed to generate real-world evidence regarding gender differences among chronic obstructive pulmonary disease (COPD) patients, especially as regards the diagnosis and outcomes in order to identify areas for improvement and management and optimize the associated healthcare resource allocation. ARCTIC is a large, real-world, retrospective cohort study conducted in Swedish COPD patients and a matched reference population from 52 primary care centers in 2000-2014. The incidence of COPD, prevalence of asthma and other comorbidities, risk of exacerbations, mortality rate, COPD drug prescriptions, and healthcare resource utilization were analyzed. In total, 17,479 patients with COPD were included in the study. During the study period, COPD was more frequent among women (53.8%) and women with COPD experienced more exacerbations vs. men (6.66 vs. 4.66). However, the overall mortality rate was higher in men compared with women (45% vs. 38%), but no difference for mortality due to COPD was seen between genders over the study period. Women seemed to have a greater susceptibility to asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, depression, and anxiety, but appeared less likely to have diabetes, kidney diseases, and cardiovascular diseases. Furthermore, women had a greater risk of COPD-related hospitalization and were likely to receive a significantly higher number of COPD drug prescriptions compared with men. These results support the need to reduce disease burden among women with COPD and highlight the role of healthcare professionals in primary care who should consider all these parameters in order to properly diagnose and treat women with COPD.

A serine protease inhibitor was extracted from potato tubers. The inhibitor was conjugated to soluble, prefractionated dextran and titanium dioxide and zinc oxide nanoparticles. Conjugation to dextran was achieved by periodate oxidation of the dextran, followed by Schiff base coupling to inhibitor amino groups, and finally reduction, whereas the conjugation to the oxide particles was carried out by aminosilanization and carbonyldiimidazole activation. The inhibitory effect of the conjugated inhibitor was compared to that of free inhibitor in solution and with gelatin gel as a direct substrate. A certain degree of inhibitory activity was retained for both the dextran-conjugated and particle-conjugated inhibitors. In particular, the apparent K i value of the dextran-conjugated inhibitor was found to be in the same range as that for free inhibitor. The dextran conjugate retained a higher activity than the free inhibitor after 1 month of storage at room temperature., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

The interaction between pancreatic proteases and a serine protease inhibitor purified from potato tubers was investigated by chromatography-coupled light scattering measurements. The molar mass distribution in the chromatogram was compared to theoretical values calculated for the different possible combinations of complexes and free components by three different approaches, namely section analyses of the chromatograms, full mass average determination and mass distribution analysis. This revealed that the inhibitor was able to bind trypsin in a 2:1 complex, whereas the data for chymotrypsin clearly showed a limitation to 1:1 complex regardless of the molar ratio in the injected samples. The same experiment carried out with elastase and the potato inhibitor gave only weak indications of complex formation under the conditions used., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objective:  Despite improved asthma and chronic obstructive pulmonary disease (COPD) management, treatment remains inadequate in many patients. Understanding the impact of current treatment in settings outside of controlled trials would add important clinical decision-making information. This study evaluated costs and outcomes associated with budesonide+formoterol (BF) Spiromax® initiation among real-world Swedish patients with asthma and/or COPD. Methods: In this retrospective observational analysis of Swedish patients with asthma and/or COPD, data were collected from the National Patient Register, National Dispensed Drug Register, and Cause of Death Register 1 year before and after initiating BF Spiromax (index date). Outcomes included exacerbation occurrence, treatment patterns, inpatient care, and healthcare costs. Results: The study included 576 patients (asthma: 51.6%; COPD: 32.8%; and asthma and COPD: 15.6%). Following BF Spiromax initiation in asthma patients, there were significant decreases in exacerbations (41.1% to 30.0%; P < 0.001), mean comorbidity-related inpatient visits (0.5 to 0.2; P < 0.001), and inpatient days (1.9 to 0.6; P = 0.006), and a trend toward fewer asthma-related inpatient visits (mean, 0.2 to 0.1; P = 0.056) and asthma-related inpatient days (mean, 0.7 to 0.3; P = 0.060). Increased inpatient utilization was observed in patients with COPD or both diagnoses. All-cause and asthma-/COPD-related medication costs decreased in all groups. Conclusions: After switching to BF Spiromax, asthma patients had fewer exacerbations and hospital visits versus the prior year and COPD patients showed an increase in all-cause and COPD-related healthcare resource utilization. All-cause and asthma-/COPD-related medication costs decreased in all groups after switching to BF Spiromax., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Purpose: Assess the clinical and economic consequences associated with an early versus late diagnosis in patients with COPD. Patients and methods: In a retrospective, observational cohort study, electronic medical record data (2000-2014) were collected from Swedish primary care patients with COPD. COPD indicators (pneumonia, other respiratory diseases, oral corticosteroids, antibiotics for respiratory infections, prescribed drugs for respiratory symptoms, lung function measurement) registered prior to diagnosis were applied to categorize patients into those receiving early (2 or less indicators) or late diagnosis (3 or more indicators registered >90 days preceding a COPD diagnosis). Outcome measures included annual rate of and time to first exacerbation, mortality risk, prevalence of comorbidities and health care utilization. Results: More patients with late diagnosis (n=8827) than with early diagnosis (n=3870) had a recent comorbid diagnosis of asthma (22.0% vs 3.9%; P <0.0001). Compared with early diagnosis, patients with late diagnosis had a higher exacerbation rate (hazard ratio [HR] 1.89, 95% confidence interval [CI]: 1.83-1.96; P <0.0001) and shorter time to first exacerbation (HR 1.61, 95% CI: 1.54-1.69; P <0.0001). Mortality was not different between groups overall but higher for late versus early diagnosis, after excluding patients with past asthma diagnosis (HR 1.10, 95% CI: 1.02-1.18; P =0.0095). Late diagnosis was also associated with higher direct costs than early diagnosis. Conclusion: Late COPD diagnosis is associated with higher exacerbation rate and increased comorbidities and costs compared with early diagnosis. The study highlights the need for accurate diagnosis of COPD in primary care in order to reduce exacerbations and the economic burden of COPD., Competing Interests: KjL has, during the last 5 years, on one or more occasion served in an advisory board and/or served as speaker and/or participated in education arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Orion, Takeda, Novartis, Chiesi and TEVA. CJ has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis and TEVA, and has served on advisory boards arranged by AstraZeneca, TEVA and Boehringer Ingelheim. BS has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, MEDA and TEVA, and has served on advisory boards arranged by AstraZeneca, Novartis, GlaxoSmithKline and Boehringer Ingelheim. KL has participated in the steering committee by Novartis for this study and received honoraria for educational activities and lectures from AstraZeneca, GlaxoSmithKline, Novartis, MEDA and TEVA and has served on advisory boards arranged by MEDA and Novartis. FSG and JBG are employees of Novartis Pharma AG. PO is an employee of Novartis AB. MU and LJ are employees of IQVIA, who received remuneration in relation to statistical analysis. GJ has participated in the steering committee by Novartis for this study and served on advisory boards arranged by AstraZeneca, Novo Nordisk and Takeda. BS reports personal fees from Novartis, during the conduct of the study; received personal fees from AstraZeneca, Novartis, Meda, Teva, Boehringer Ingelheim, and GlaxosSmithKline, outside the submitted work; KL reports personal fees from Novartis, during the conduct of the study; received personal fees from AstraZeneca, Novartis, Chiesi, TEVA, GlaxoSmithKline, and Boerhringer Ingelheim, outside the submitted work; KK was an employee of Novartis, the sponsor of the study, at the time of conduct of this analysis and until 31.10.2018. He is now affiliated with Respiratory Medicine Department, University of Ioannina, Ioannina, Greece. KK has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GlaxoSmithKline, MSD, Novartis, Takeda, and UCB, and has served on advisory boards arranged by AstraZeneca, Chiesi, ELPEN, Novartis and Takeda prior to 2015. The authors report no other conflicts of interest in this work.

Purpose: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown., Methods: rLTL was measured by qPCR in a Swedish population-based glioma case-control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification., Results: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02-1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex., Conclusions: In this Swedish glioma case-control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.

Objective: Polymorphisms in the CYP2R1 gene encoding Vitamin D 25-hydroxylase have been reported to correlate with circulating levels of 25-OH vitamin D3 (25(OH)D). It is unknown whether these variations also affect overall bone metabolism. In order to elucidate the overall associations of polymorphisms in the CYP2R1, we studied haplotype tagging single nucleotide polymorphisms (SNPs) in the gene and serum levels of 25(OH)D, calcium, phosphate, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23), as well as bone mineral density (BMD)., Methods: Baseline data on serum parameters and BMD from MrOS Sweden, a prospective population-based cohort study of elderly men (mean age 75 years, range 69-81), were analyzed. Genotyping was performed for eight SNPs covering the CYP2R1 gene in 2868 men with available samples of DNA. Subjects were followed up concerning incidence of fracture during five years., Results: There was a significant genetic association with circulating levels of 25(OH)D (4.6-18.5% difference in mean values between SNP alleles), but there were no correlations with levels of calcium, phosphate, PTH or FGF23 for any genetic variant. No differences were found in fracture incidence between the variants. There was an inverse relationship between lower BMD and concomitant higher 25(OH)D for three of the haplotypes (p < 0.005)., Conclusions: Common variants in the CYP2R1 gene encoding Vitamin D 25-hydroxylase correlate with levels of circulating 25(OH)D but do not otherwise associate with measures of calcium and phosphate homeostasis. Presence of the specific haplotypes may be an indicator of risk for low 25(OH)D levels, and may in addition be correlated to bone mineral density., Competing Interests: The authors have declared that no competing interests exist.

Objective: To assess the incidence of cardiovascular diseases (CVD) and type-2-diabetes in patients with psychiatric disorders., Methods: A population-based study was conducted using the Swedish national health registries. Patients were identified from the Electronic Medical Records (EMR) in 20 primary care centers and were categorized in four diagnosis cohorts according to their first psychiatric diagnosis: bipolar disorder, schizophrenia, major depressive disorder, or other mood disorder. A control cohort of patients with no psychiatric disorders followed in the same primary care centers was also identified. Incident CVD and type-2-diabetes were defined as the presence of a diagnosis of CVD or diabetes during the follow-up period in patients without prior event., Results: The age and sex standardized incidence rate of CVD was 13.5 per 1000 patient-year in the patients with any psychiatric disorder versus 6.3 per 1000 patient-year in the controls. A similar trend was observed for incident diabetes (5.7 versus 3.4 per 1000 patient-year, respectively). The bipolar disorder and the schizophrenia cohorts showed the highest standardized incidence rates., Conclusion: Incidence of CVD and to a lesser extent type-2-diabetes was particularly high in patients with psychiatric disorders. This carries strong clinical implications for the prevention of CVD and type-2-diabetes in these patients.

Background: Inhaled corticosteroids (ICS) are associated with an increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). Other factors such as severity of airflow limitation and concurrent asthma may further raise the possibility of developing pneumonia. This study assessed the risk of pneumonia associated with ICS in patients with COPD., Methods: Electronic Medical Record data linked to National Health Registries were collected from COPD patients and matched reference controls in 52 Swedish primary care centers (2000-2014). Levels of ICS treatment (high, low, no ICS) and associated comorbidities were assessed. Patients were categorized by airflow limitation severity., Results: A total of 6623 patients with COPD and 48,566 controls were analyzed. Patients with COPD had a more than 4-fold increase in pneumonia versus reference controls (hazard ratio [HR] 4.76, 95% confidence interval [CI]: 4.48-5.06). ICS use increased the risk of pneumonia by 20-30% in patients with COPD with forced expiratory volume in 1 s ≥ 50% versus patients not using ICS. Asthma was an independent risk factor for pneumonia in the COPD population. Multivariate analysis identified independent predictors of pneumonia in the overall population. The highest risk of pneumonia was associated with high dose ICS (HR 1.41, 95% CI: 1.23-1.62)., Conclusions: Patients with COPD have a greater risk of pneumonia versus reference controls; ICS use and concurrent asthma increased the risk of pneumonia further.

This study aimed to generate real-world evidence to assess the burden of comorbidities in COPD patients, to effectively manage these patients and optimize the associated healthcare resource allocation. ARCTIC is a large, real-world, retrospective cohort study conducted in Swedish COPD patients using electronic medical record data collected between 2000 and 2014. These patients were studied for prevalence of various comorbidities and for association of these comorbidities with exacerbations, mortality, and healthcare costs compared with an age-, sex-, and comorbidities-matched non-COPD reference population. A total of 17,479 patients with COPD were compared with 84,514 non-COPD reference population. A significantly higher prevalence of various comorbidities was observed in COPD patients 2 years post-diagnosis vs. reference population, with the highest percentage increase observed for cardiovascular diseases (81.8% vs. 30.7%). Among the selected comorbidities, lung cancer was relatively more prevalent in COPD patients vs. reference population (relative risk, RR = 5.97, p < 0.0001). Ischemic heart disease, hypertension, depression, anxiety, sleep disorders, osteoporosis, osteoarthritis, and asthma caused increased mortality rates in COPD patients. Comorbidities that were observed to be significantly associated with increased number of severe exacerbations in COPD patients included heart failure, ischemic heart disease, depression/anxiety, sleep disorders, osteoporosis, lung cancer, and stroke. The cumulative healthcare costs associated with comorbidities over 2 years after the index date were observed to be significantly higher in COPD patients (€27,692) vs. reference population (€5141) (p < 0.0001). The data support the need for patient-centered treatment strategies and targeted healthcare resource allocation to reduce the humanistic and economic burden associated with COPD comorbidities.

Background: Patients with severe uncontrolled asthma may receive oral corticosteroid (OCS) treatment regularly. The present study investigated the health care resource utilization and cost in regularly OCS treated Swedish asthma patients., Methods: Primary care medical records data were linked to data from Swedish national health registries. Patients ≥18 years with a drug claim for obstructive pulmonary diseases during 2007-2009 (index date) and a prior asthma diagnosis, were classified by their OCS claims during the 12-months' post index period: regular OCS equals ≥5 mg per day; periodic OCS less than 5 mg per day; or non-OCS users. Cost of asthma- and OCS-morbidity-related health care resource utilization were calculated., Results: A total of 15,437 asthma patients (mean age 47.8, female 62.6%), whereof 223 (1.44%) were regular OCS users, 3054 (19.7%) were periodic, and 12,160 (78.7%) were non-OCS users. Regular OCS users were older and more often females, had lower lung function, greater eosinophil count and more co-morbidities at baseline compared with the other groups. Age-adjusted annual total health care cost was three-times greater in the regular OCS group (€5615) compared with the non-OCS users (€1980) and twice as high as in the periodic OCS group (€2948). The major cost driver in the non-OCS and periodic OCS groups were primary care consultations, whereas inpatient costs were the major cost driver in the regular OCS group. The asthma related costs represented 10-12% of the total cost in all three groups., Conclusion: In this real-life asthma study in Sweden, the total yearly cost of health care resource utilization for a regular OCS user was three times greater than for a patient with no OCS use, indicating substantial economic and health care burden for asthma patients on regular oral steroid treatment.

Objectives To translate and evaluate the psychometric properties of the Venous Insufficiency Epidemiological and Economic Studies (VEINES) questionnaire, divided into two subscales; symptoms (VEINES-Sym) and quality of life (VEINES-QOL), in a Swedish cohort of patients with venous disease. Methods The original questionnaire was translated into Swedish with forward-backward translation and administered to 112 patients who were consecutively recruited and had varying degrees of chronic venous disease. Mean age was 54.5 ± 15.2 years (range: 19-83) and 75% of the participants were female. All patients completed the RAND 36-item health survey and the VEINES-QOL/Sym. Results The results showed excellent internal consistency for both VEINES-QOL (Cronbach's alpha (α) = 0.93) and VEINES-Sym (α = 0.89). Both the VEINES-QOL and VEINES-Sym correlated well to all the RAND-36 domains, demonstrating good construct validity. Exploratory factor analysis confirmed both subscales of the VEINES-QOL/Sym. Conclusions The Swedish VEINES-QOL/Sym is a valid health-related quality of life instrument for chronic venous disease, both for research purposes and for clinical evaluation.

The aim of the study was to investigate the prevalence, management and characteristics of asthma patients with frequent exacerbations.Data from asthma patients (aged ≥18 years) identified in primary care medical records were linked to Swedish national health registries. Exacerbations were defined as hospitalisations, emergency visits and/or collection of oral steroids. Frequent exacerbations were defined as two or more exacerbations per year during the 3-year observation period.Of 18 724 asthma patients, 81.49% had no exacerbations and 6.3% had frequent exacerbations in the year prior to the index date. Frequent exacerbations were observed yearly for 1.8% of the patients. Frequent exacerbators were older, more often females, and had increased eosinophil and neutrophil counts, lower lung function, and more comorbidities than patients without exacerbations. There was a slight increase in asthma medication claims and a slight decrease in physician visits compared with baseline, both in the group with and the group without frequent exacerbations.Patients with frequent exacerbations were characterised by greater age, female predominance, high eosinophil and neutrophil counts, and high prevalence of comorbidities. This study indicates that the Swedish healthcare system lacks efficiency to adjust treatment and management for this patient group. With new treatment options targeting severe asthma available, identification of these patients should be in focus to ensure reduction of exacerbations., Competing Interests: Conflict of interest: C. Janson reports payment for lectures, including service on speaker's bureaus from AstraZeneca, Teva and Novartis, outside the submitted work. K. Lisspers reports personal fees for membership of the steering committee, during the conduct of this work; and payment for lectures, including service on speaker's bureaus from AstraZeneca, Novartis and Teva, and payment for manuscript preparation from Meda, outside the submitted work. B. Ställberg reports personal fees from AstraZeneca for participation in the study steering committee, during the conduct of this work; and personal fees for advisory board work from AstraZeneca, Boehringer Ingelheim, Novartis and Meda, payment for lectures, including service on speaker's bureaus from AstraZeneca, Novartis, Meda and Teva, and payment for development of educational presentations from AstraZeneca and Teva, outside the submitted work. M. Thuresson reports fees for statistical consultations, both during the conduct of this work and outside the submitted work. G. Telg is a full-time employee of AstraZeneca, the study sponsor. K. Larsson reports personal fees for advisory board work from AstraZeneca, Boehringer Ingelheim, Novartis and Chiesi, and payment for lectures, including service on speaker's bureaus from AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Orion and Takeda, outside the submitted work., (Copyright ©ERS 2018.)

Background: The risk of dying of lung cancer is up to eightfold higher in patients with COPD than in age- and gender-matched controls. The aim of this study was to investigate the factors associated with lung cancer in a large cohort of COPD patients from primary care centers., Methods: To analyze whether age, gender, socioeconomic factors, comorbidity, and medication affect the risk of lung cancer in COPD, we used a COPD cohort of primary care patients. Data from primary care medical records and mandatory Swedish national registers were collected and linked in this population-based, retrospective observational registry study (NCT01146392)., Results: Of the total cohort, 19,894 patients were included in the study. Five hundred and ninety-four lung cancer cases were diagnosed, corresponding to 3.0% of the studied population. In a multivariate analysis, the risk of lung cancer was lower if the COPD patients had a concurrent asthma diagnosis (HR: 0.54, CI: 0.41-0.71), while the risk of lung cancer increased with increasing age. A decreased lung cancer risk was observed in an exposure-dependent manner in patients who were prescribed inhaled corticosteroids (HR: 0.52, CI: 0.37-0.73), while the opposite was found for the use of acetylsalicylic acid (HR: 1.58, CI: 1.15-2.16)., Conclusion: In this large population-based cohort, a concurrent asthma diagnosis and use of inhaled corticosteroids were independently related to decreased risk of lung cancer in COPD patients, while the use of acetylsalicylic acid was associated with an increased risk. The findings of the present study should be seen as hypothesis generating and need to be confirmed in prospective studies., Competing Interests: Disclosure Martin Sandelin has received honoraria for lectures from AstraZeneca, Novartis, Boehringer Ingelheim, and Amirall and has received grants from the Professor John Naeslunds Stipendiefond, Ture Stenholms Minnesfond and Uppsala County Association Against Heart and Lung Diseases. Karin Lisspers has received honoraria for educational activities and lectures from AstraZeneca, GlaxoSmithKline, Novartis, MEDA, and Takeda and has served on advisory boards arranged by MEDA and Novartis. Kjell Larsson has, during the last 5 years, on one or more occasion served on an advisory board, served as a speaker, and/or participated in education arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, Chiesi, Orion, and TEVA. Gunnar Johansson has served on advisory boards arranged by Astra Zeneca, Novo Nordisk, and Takeda. Christer Janson has received honoraria for educational activities and lectures from Novartis, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim outside the submitted work. Björn Ställberg has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, MEDA, and TEVA and has served on advisory boards arranged by AstraZeneca, Novartis, GSK, Boehringer Ingelheim, TEVA, and MEDA. The authors report no other conflicts of interest in this work.

There is a widespread myth that we have to be careful about what we eat so that we do not cause protein deficiency. We know today that it is virtually impossible to design a calorie-sufficient diet, whether it is based on meat, fish, eggs, various vegetarian diets or even unprocessed whole natural plant foods, which is lacking in protein and any of the amino acids. The body is capable of taking incomplete proteins and making them complete by utilizing the amino acid recycling mechanism. The majority of amino acids absorbed from the intestinal tract are derived from recycled body protein. Research shows that high levels of animal protein intake may significantly increase the risk of premature mortality from all causes, among them cardiovascular diseases, cancer and type 2 diabetes.

A model based on gelatin for protease activity studies was designed. The model is also extended to study the efficiency of inhibitors in a separate protective layer covering the layer containing the target substrate. A good correlation between protease concentration and the size of erosion wells formed in a plain gelatin layer was observed. Similarly, increased concentration of inhibitors gave a systematic decrease in well area. Kinetic analyses of the two-layer model in a spectrophotometric plate reader with a fixed concentration of substrate in the bottom layer displayed a strict dependence of both inhibitor concentration and thickness of the top "protective" layer. An apparent, but weaker inhibition effect was also observed without inhibitors due to diffusional and erosion delay of enzyme transport to the substrate-containing layer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Asthma is often associated with other diseases. To identify and manage comorbidities is important, as these conditions may increase the disease burden., Objective: To describe the prevalence of comorbidities, disease burden and mortality across age groups in a large Swedish primary care real-life asthma population., Methods: Observational cohort study of asthma patients, all ages, identified from electronic medical records by ICD-10-CM code, data from 36 primary care centers. Data were linked to national mandatory Swedish health registers. Comorbidities were identified by ICD-10-CM codes and collected from electronic medical records and the National Patient Registers, mortality data from the Cause of Death Register. Exacerbations were defined as hospitalizations due to asthma, and/or emergency visits at hospital and/or prescription claims of oral steroids., Results: In total 33,468 patients (58% women) were included. The most prevalent comorbidities were acute upper respiratory tract infection (53%), rhinitis (25%), acute lower respiratory tract infection (25%), hypertension (21%), anxiety and depression (20%). The comorbidities associated with highest risk for an exacerbation were COPD OR 1.98 (95%CI: 1.80-2.19), nasal polyps OR 1.75 (95%CI: 1.49-2.05) and rhinitis OR 1.52 (95%CI: 1.41-1.63). All-cause mortality was similar to the Swedish population, 1011 deaths per 100,000 person/year compared with 1058 deaths (standardized risk = 0.99 [95%CI:0.95-1.04]). The pulmonary related death rate was greater in the study population versus the Swedish population (122 versus 72 per 100,000person/year)., Conclusion: Comorbid disease was frequent in this large real-life asthma population with an impact on exacerbations. To identify and treat comorbidities with impact on asthma outcomes are essential to improve asthma care., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mass spectrometry-based proteomics benefits from efficient digestion of protein samples. In this study, trypsin was immobilized on nanoporous anodized alumina membranes to create an enzyme reactor suitable for peptide mass fingerprinting. The membranes were derivatized with 3-aminopropyltriethoxysilane and the amino groups were activated with carbonyldiimidazole to allow coupling of porcine trypsin via ε-amino groups. The function was assessed using the artificial substrate Nα-Benzoyl-L-arginine 4-nitroanilide hydrochloride, bovine ribonuclease A and a human plasma sample. A 10-membrane flow-through reactor was used for fragmentation and MS analysis after a single pass of substrate both by collection of product and subsequent off-line analysis, and by coupling on-line to the instrument. The peptide pattern allowed correct identification of the single target protein in both cases, and of >70 plasma proteins in single pass mode followed by LC-MS analysis. The reactor retained 76% of the initial activity after 14days of storage and repeated use at room temperature., Significance: This manuscript describes the design of a stable enzyme reactor that allows efficient and fast digestion with negligible leakage of enzyme and enzyme fragments. The high stability facilitates the use in an online-setup with MS detection since it allows the processing of multiple samples within an extended period of time without replacement., (Copyright © 2017. Published by Elsevier B.V.)

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are an important measure of disease severity in terms of impaired disease progression, increased recovery time, healthcare resource utilization, overall morbidity and mortality. We aimed to quantify exacerbation and healthcare resource utilization rates among COPD patients in Sweden with respect to baseline treatments, exacerbation history, and comorbidities., Methods: Patients with a COPD or chronic bronchitis (CB) diagnosis in secondary care at age of ≥40 years on 1.7.2009 were identified and followed until 1.7.2010 or death. Severe exacerbations were defined as hospitalizations due to respiratory disease, and healthcare resource utilization was measured by all-cause hospitalizations and secondary care visits. Poisson regression was used adjusting for age, gender, time since COPD/CB diagnosis, and Charlson comorbidity index., Results: In 88,548 patients (54% females, mean age 72 years), previous respiratory hospitalizations and current high use of COPD medication (double or triple therapy) predicted an 8.3-fold increase in severe exacerbation rates and 1.8-fold increase in healthcare resource utilization rates in the following year, compared to patients without combination treatment and/or history of severe exacerbations., Conclusions: COPD/CB patients with history of severe exacerbations and high use of COPD medication experienced a significantly increased rate of severe exacerbations and healthcare resource utilization during the one-year follow-up.

Background: Severe and uncontrolled asthma is associated with increased risk of exacerbations and death. A substantial proportion of asthma patients have poor asthma control, and a concurrent COPD diagnosis often increases disease burden. The objective of the study was to describe the prevalence and managemant of severe asthma in a Swedish asthma popuöation., Methods: In this observational cohort study, primary care medical records data (2006-2013) from 36 primary health care centers were linked to data from national mandatory Swedish health registries. The studied population (>18 years) had a record of drug collection for obstructive pulmonary disease (ATC code R03) during 2011-2012, and a physician diagnosed asthma (ICD-10 code J45-J46) prior to drug collection. Severe asthma was classified as collection of high dose inhaled steroid (> 800 budesonide or equivalent per day) and leukotriene receptor antagonist and/or long-acting beta-agonist. Poor asthma control was defined as either collection of ≥600 doses of short-acting beta-agonists, and/or ≥1 exacerbation(s) during the year post index date., Results: A total of 18,724 asthma patients (mean 49 years, 62.8% women) were included, of whom 17,934 (95.8%) had mild to moderate and 790 (4.2%) had severe asthma. Exacerbations were more prevalent in severe asthma (2.59 [2.41-2.79], Relative Risk [95% confidence interval]; p < 0.001). Poor asthma control was observed for 28.2% of the patients with mild to moderate asthma and for more than half (53.6%) of the patients with severe asthma (<0.001). Prior to index, one in five severe asthma patients had had a contact with secondary care and one third with primary care. A concurrent COPD diagnosis increased disease burden., Conclusion: Severe asthma was found in 4.2% of asthma patients in Sweden, more than half of them had poor asthma control, and most patients had no regular health care contacts.

Background: We assessed direct and indirect costs associated with COPD in Sweden and examined how these costs vary across time, age, and disease stage in a cohort of patients with COPD and matched controls in a real-world, primary care (PC) setting., Patients and Methods: Data from electronic medical records linked to the mandatory national health registers were collected for COPD patients and a matched reference population in 52 PC centers from 2000 to 2014. Direct health care costs (drug, outpatient or inpatient, PC, both COPD related and not COPD related) and indirect health care costs (loss of income, absenteeism, loss of productivity) were assessed., Results: A total of 17,479 patients with COPD and 84,514 reference controls were analyzed. During 2013, direct costs were considerably higher among the COPD patient population (€13,179) versus the reference population (€2,716), largely due to hospital nights unrelated to COPD. Direct costs increased with increasing disease severity and increasing age and were driven by higher respiratory drug costs and non-COPD-related hospital nights. Indirect costs (~€28,000 per patient) were the largest economic burden in COPD patients of working age during 2013., Conclusion: As non-COPD-related hospital nights represent the largest direct cost, management of comorbidities in COPD would offer clinical benefits and relieve the financial burden of disease., Competing Interests: Disclosure Karin Lisspers has received honoraria for educational activities and lectures from AstraZeneca, GlaxoSmithKline, Novartis, MEDA, and Takeda and has served on advisory boards arranged by MEDA and Novartis. She has also participated in the steering committee for this study funded by Novartis. Kjell Larsson has, during the last 5 years, on one or more occasion served in an advisory board, served as a speaker, and/or participated in education arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, Chiesi, Orion and Teva. Gunnar Johansson has participated in the steering committee organized by Novartis for this study and served on advisory boards arranged by Astra Zeneca, Novo Nordisk, and Takeda. Christer Janson has received honoraria for educational activities and lectures from Novartis, AstraZeneca, Glaxo-SmithKline, and Boehringer Ingelheim outside the submitted work. Björn Ställberg has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, MEDA, and TEVA and has served on advisory boards arranged by AstraZeneca, Novartis, GSK, Boehringer Ingelheim and MEDA. Florian S Gutzwiller, and Jean-Bernard Gruenberger are employees of Novartis Pharma AG. Madlaina Costa-Scharplatz is an employee of Novartis AB. Milica Uhde and Leif Jorgensen are employees of IQVIA, who received remuneration in relation to statistical analysis. The authors report no other conflicts of interest in this work.

Aims: To describe weight-change pathways in patients with type 2 diabetes (T2D) and associated healthcare costs using repeated BMI measurements and healthcare utilization data., Methods: Patients with newly-diagnosed T2D with body mass index (BMI, kg/m 2 ) at diagnosis and subsequent measures at year 1-3 were identified. Based on three-year BMI change, patients were assigned to one of 27 BMI change pathways defined by annual BMI change: BMI↗ (≥1 BMI unit increase), BMI→ (<1 BMI unit change), and BMI↘ (≥1 BMI unit decrease). Mean annual and three-year cumulative healthcare costs were estimated for each pathway by combining Swedish unit costs with resource use from primary care and national patient registers., Results: Cohort consisted of 15,819 patients; 44% women, mean age of 61 years, HbA1c of 6.7% (50mmol/mol), BMI of 30.6kg/m 2 . Most common BMI pathways (mean costs): BMI→→→ (€5,311), BMI↘→→ (€5,461), and BMI→→↘ (€6,281). General trends: BMI→→→ linked to lowest, BMI↗→↗ linked to highest costs., Conclusion: In patients with newly-diagnosed T2D, weight stability was the most common BMI change pattern over 3 years and associated with lowest healthcare costs. Relationship between weight change and healthcare costs appears complex warranting further investigation., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To compare long-term changes in healthcare utilization and costs for type 2 diabetes patients before and after insulin initiation, as well as healthcare costs after insulin versus non-insulin anti-diabetic (NIAD) initiation., Methods: Patients newly initiated on insulin (n=2823) were identified in primary health care records from 84 Swedish primary care centers, between 1999 to 2009. First, healthcare costs per patient were evaluated for primary care, hospitalizations and secondary outpatient care, before and up to seven years after insulin initiation. Second, patients prescribed insulin in second line were matched to patients prescribed NIAD in second line, and the healthcare costs of the matched groups were compared., Results: The total mean annual healthcare cost increased from €1656 per patient 2 years before insulin initiation to €3814 seven years after insulin initiation. The total cumulative mean healthcare cost per patient at year 5 after second-line treatment was €13,823 in the insulin group compared to €9989 in the NIAD group., Conclusions: Initiation of insulin in type 2 diabetes patients was followed by increased healthcare costs. The increases in costs were larger than those seen in a matched patient population initiated on NIAD treatment in second-line., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims and Objectives: To describe overweight persons' experiences with weight reduction and participation in the dietary advice on prescription., Background: Approximately 20% of overweight individuals are able to successfully lose weight. Experiences from earlier weight reduction programmes indicate that those who succeed typically manage to avoid overeating to handle stress and have high motivation to lose weight. Those who fail have low self-control and engage in negative health behaviours such as eating when experiencing negative emotions and stress., Design: The study used a descriptive qualitative design and was conducted at a Primary Health Care Centre in south-west Sweden., Methods: The first nineteen study participants who completed the weight reduction programme in two years responded in writing to five open questions about their experiences with the programme. Data were analysed using inductive content analysis., Results: The participants appreciated the face-to-face meetings with the nurse because they felt seen and listened to during these sessions. They also felt their life situations and self-discipline had an impact on how well they were able to follow the programme. Dietary advice on prescription advice was considered to be helpful for achieving behavioural changes and losing weight. People who succeeded in sustainably losing weight described the importance of support from partners or close friends., Conclusions: To achieve sustainable weight reduction, it is important to individualise the programme in order to address each person's life situation and the unique difficulties they may encounter., Relevance to Clinical Practice: Motivational interviewing appears to be a good technique for developing a successful relationship between the nurse and the patient. The dietary advice on prescription advice was perceived to be a good way to improve food habits and can easily be used at many Primary Health Care Centres. Patient's partners should also be offered the opportunity to participate in the programme., (© 2016 John Wiley & Sons Ltd.)

Introduction: Only a selected proportion of chronic obstructive pulmonary disease (COPD) patients are managed in secondary care. The aim of this study was to characterize disease severity, treatment and structure of secondary care for COPD in Sweden. Methods: Information was collected from 29 of 33 existing secondary care units of respiratory medicine in Sweden, using both individual data from 373 consecutively enrolled COPD patients with Global initiative on Obstructive Lung Disease (GOLD) stage III-IV and a structural questionnaire about available resources at the units. Patient data included exacerbations, health status assessed by COPD Assessment Test (CAT), lung function, comorbid conditions, pharmacological treatment and vaccinations. Structural data included available smoking cessation support, multidisciplinary rehabilitation, physical training, patient education and routine follow-up after exacerbations at the respective unit. All patients were reclassified according to the GOLD 2014 group A-D classification. Multiple linear regression investigated associations of available resources with number of exacerbations and CAT score. Results: According to GOLD 2014, 87% of the population were GOLD D and 13% were GOLD C. Triple inhaled therapy were prescribed in 88% of the patients. Over 75% of the units had resources for smoking cessation, multidisciplinary rehabilitation, physical training and patient education. Routine follow-up after exacerbations was available in 35% of the units. Being managed at units with access to structured patient education was associated with statistically significantly fewer exacerbations (adjusted regression coefficient (95% confidence interval) -0.79 (-1.39 to -0.19), p  = 0.010). Conclusion : Most stage III-IV COPD patients managed at secondary care respiratory units in Sweden have maximized inhaled therapy and high risk disease even when reclassified according to GOLD 2014. Most units have access to smoking cessation, rehabilitation and patient education. Patients managed at units with structured patient education have a lower exacerbation risk.

Background: In the development of new drugs for severe asthma, it is a challenge from an ethical point of view to randomize severe asthma patients to placebo, and to obtain long-term safety data due to discontinuations. The aim of this study was to evaluate the feasibility of using electronic health record (EHR) data to create a real-world reference population of uncontrolled asthmatic patients to supplement the concurrent control/placebo group in long-term studies of asthma., Methods: EHR data from 36 primary care centres and a University hospital in Sweden were linked to Swedish mandatory health registers (2005-2013), creating a population covering 33 890 asthma patients, including data on co-morbidities, risk factors and laboratory/respiratory measurements. A severe asthma EHR reference cohort was established. We used logistic regression to estimate the propensity score (probability) of each RCT or EHR patient existing in the EHR cohort given their covariates., Results: We created an EHR-derived reference cohort of 240 patients, matching the placebo group (N = 151) in an RCT of severe asthma. The exacerbation rate during follow-up in the EHR study population was 1.24 (weighted) compared to 0.9 in the RCT placebo group. Patients in the EHR cohort were of similar age as in the RCT placebo group, 50.6 years versus 50.1 years; had slightly higher body mass index 27.0 kg/m 2 versus 27.3 kg/m 2 ; and consisted of 40% versus 34% males., Conclusions: The results indicate that EHRs provide an opportunity to supplement the control group in RCTs of severe diseases.

Introduction: The aim of the present study was to use real-world data from Swedish primary-care and national registries to understand clinical outcomes in patients with Type 2 diabetes (T2D) treated with liraglutide in clinical practice, and to compare with data from those treated with sitagliptin., Methods: This was a non-interventional, retrospective study conducted between February 2014 and September 2014 using T2D patient data from Swedish primary-care centers and national healthcare registries. The primary objective was to assess the effectiveness of liraglutide in control of glycemia and body weight in clinical practice (stage 1). The secondary objective was to compare the clinical effectiveness of liraglutide with sitagliptin on glycemic control and body weight in clinical practice in a propensity-score-matched population (stage 2)., Results: In stage 1 (n = 402), 39.4% of patients treated with liraglutide achieved ≥1.0% (10.9 mmol/mol) reduction in glycated hemoglobin (HbA1c) after 180 days of treatment and 54.9% achieved the target HbA1c of <7.0% (53.0 mmol/mol). Moreover, compared with baseline, 22.5% of patients treated with liraglutide achieved both ≥1.0% reduction in HbA1c and ≥3.0% reduction in body weight. In stage 2, a significantly greater proportion of patients receiving liraglutide (n = 180) than sitagliptin (n = 208) achieved ≥1.0% reduction in HbA1c [52.9% vs 33.5%, respectively (P = 0.0002)]. Mean body-weight loss was also significantly greater in patients receiving liraglutide vs sitagliptin [-3.5 vs -1.3 kg, respectively (P < 0.0001)]., Conclusion: This study provides real-world evidence from Sweden corroborating previous clinical trials that demonstrate greater efficacy of liraglutide over sitagliptin on glycemic control and body-weight reduction in patients with T2D., Funding: Novo Nordisk A/S., Trial Registration: ClinicalTrials.gov identifier NCT02077946.

Background and Objectives: Statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are unrelated. Many patients initiated on statins experience a paradoxical decrease in HDL-C. The aim of this study was to evaluate the association between a decrease in HDL-C and risk of major adverse cardiovascular events (MACE)., Methods: Data from 15,357 primary care patients initiated on statins during 2004-2009 were linked with data from mandatory national hospital, drug-dispensing, and cause-of-death registers, and were grouped according to HDL-C change: decreased ≥0.1 mmol/L, unchanged ±0.1 or ≥0.1 mmol/L increased. To evaluate the association between decrease in HDL-C and risk of MACE, a sample of propensity score-matched patients from the decreased and unchanged groups was created, using the latter group as reference. MACE was defined as myocardial infarction, unstable angina pectoris, ischaemic stroke, or cardiovascular mortality. Cox proportional hazards models were used to estimate relative risks., Results: HDL-C decreased in 20%, was unchanged in 58%, and increased in 22% of patients initiated on statin treatment (96% treated with simvastatin). The propensity score-matched sample comprised 5950 patients with mean baseline HDL-C and LDL-C of 1.69 and 4.53 mmol/L, respectively. HDL-C decrease was associated with 56% higher MACE risk (hazard ratio 1.56; 95% confidence interval 1.12-2.16; p < 0.01) compared with the unchanged HDL-C group., Conclusions: Paradoxical statin-induced reduction in HDL-C was relatively common and was associated with increased risk of MACE.

The etiologies of brain tumors are in the most cases unknown, but improvements in genetics and DNA screening have helped to identify a wide range of brain tumor predisposition disorders. In this review we are discussing some of the most common predisposition disorders, namely: neurofibromatosis type 1 and 2, schwannomatosis, rhabdoid tumor predisposition disorder, nevoid basal cell carcinoma syndrome (Gorlin), tuberous sclerosis complex, von Hippel-Lindau, Li-Fraumeni and Turcot syndromes. Recent findings from the GLIOGENE collaboration and the newly identified glioma causing gene POT1, will also be discussed. Genetics. We will describe these disorders from a genetic and clinical standpoint, focusing on the difference in clinical symptoms depending on the underlying gene or germline mutation. Central nervous system (CNS) tumors. Most of these disorders predispose the carriers to a wide range of symptoms. Herein, we will focus particularly on tumors affecting the CNS and discuss improvements of targeted therapy for the particular disorders.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas with minimal therapeutic opportunities. We observed that lipid droplets (LDs) accumulate in human MPNST cell lines and in primary human tumor samples. The goal of this study was to investigate the relevance of lipid metabolism to MPNST survival and as a possible therapeutic target., Methods: Based on preliminary findings that MPNSTs accumulate LDs, we hypothesized that a deregulated lipid metabolism supports MPNST cell survival/proliferation rate. To test this, we examined respiration, role of fatty acid oxidation (FAO), and the enzyme fatty acid synthase involved in de novo fatty acid synthesis in MPNSTs using both genetic and pharmacological tools., Results: We demonstrate that LDs accumulate in MPNST cell lines, primary human and mouse MPNST tumors, and neural crest cells. LDs from MPNST cells disappear on lipid deprivation, indicating that LDs can be oxidized as a source of energy. Inhibition of FAO decreased oxygen consumption and reduced MPNST survival, indicating that MPNST cells likely metabolize LDs through active FAO. FAO inhibition reduced oxygen consumption and survival even in the absence of exogenous lipids, indicating that lipids synthesized de novo can also be oxidized. Consequently, inhibition of de novo fatty acid synthesis, which is overexpressed in human MPNST cell lines, effectively reduced MPNST survival and delayed induction of tumor growth in vivo., Conclusion: Our results show that MPNSTs depend on lipid metabolic pathways and suggest that disrupting lipid metabolism could be a potential new strategy for the development of MPNST therapeutics., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Chronic bronchitis and previous exacerbations are both well-known risk factors for new exacerbations, impaired health-related quality of life, and increased mortality in COPD. The aim of the study was to characterize the phenotype of concurrent chronic bronchitis and frequent exacerbation in severe COPD., Methods: Information on patient characteristics, comorbidity, and exacerbations from the previous year (total number and number requiring hospitalization) was collected from 373 patients with stage III and IV COPD attending 27 secondary care respiratory units in Sweden. Logistic regression used chronic bronchitis and frequent exacerbations (≥2 exacerbations or ≥1 hospitalized exacerbations in the previous year) as response variables. Stratification and interaction analyses examined effect modification by sex., Results: Chronic bronchitis was associated with current smoking (adjusted odds ratio [OR] [95% CI], 2.75 [1.54-4.91]; P=0.001), frequent exacerbations (OR [95% CI], 1.93 [1.24-3.01]; P=0.004), and musculoskeletal symptoms (OR [95% CI], 1.74 [1.05-2.86]; P=0.031), while frequent exacerbations were associated with lung function (forced expiratory volume in 1 second as a percentage of predicted value [FEV1% pred]) (OR [95% CI] 0.96 [0.94-0.98]; P=0.001) and chronic bronchitis (OR [95% CI] 1.73 [1.11-2.68]; P=0.015). The phenotype with both chronic bronchitis and frequent exacerbations was associated with FEV1% pred (OR [95% CI] 0.95 [0.92-0.98]; P=0.002) and musculoskeletal symptoms (OR [95% CI] 2.55 [1.31-4.99]; P=0.006). The association of smoking with the phenotype of chronic bronchitis and exacerbations was stronger in women than in men (interaction, P=0.040)., Conclusion: Musculoskeletal symptoms and low lung function are associated with the phenotype of combined chronic bronchitis and frequent exacerbations in severe COPD. In women, current smoking is of specific importance for this phenotype. This should be considered in clinical COPD care.

Aims: To describe healthcare resource use patterns and estimate healthcare costs of newly diagnosed Type 2 diabetes mellitus (T2DM) patients in Sweden., Methods: Patients with a newly diagnosed T2DM between 1999 and 2009 were identified from 84 Swedish primary care centres. Healthcare resource use data, excluding pharmaceuticals, were extracted from electronic patient records and a national patient register, and reported as per patient mean number of primary care contacts, laboratory tests and hospitalizations. Per patient mean healthcare costs are reported as annual and cumulative costs., Results: During a median (maximum) of 4.6 (9.0) years follow-up; 38,956 patients (183,513 patient years) on average made 81 primary care contacts, was hospitalized 2.14 times, and took 31 laboratory tests. Mean per patient annual healthcare costs were €4128 (95% CI, 4054-4199) the first year after diagnosis, €2708 (95% CI, 2641-2776) the second year, and €3030 (95% CI, 2854-3204) in year 9 (2012 values). Mean per patient cumulative healthcare costs were €26,503 (95% CI, 26,025-26,970) at 9 years of follow-up. Hospitalizations accounted for the majority of healthcare costs., Conclusions: Although newly diagnosed T2DM patients require a substantial amount of healthcare services in primary care, hospitalizations account for the majority of healthcare costs., (Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Introduction: Our understanding of how comorbid diseases influence health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) is limited and in need of improvement. The aim of this study was to examine the associations between comorbidities and HRQL as measured by the instruments EuroQol-5 dimension (EQ-5D) and the COPD Assessment Test (CAT)., Methods: Information on patient characteristics, chronic bronchitis, cardiovascular disease, diabetes, renal impairment, musculoskeletal symptoms, osteoporosis, depression, and EQ-5D and CAT questionnaire results was collected from 373 patients with Forced Expiratory Volume in one second (FEV1) <50% of predicted value from 27 secondary care respiratory units in Sweden. Correlation analyses and multiple linear regression models were performed using EQ-5D index, EQ-5D visual analog scale (VAS), and CAT scores as response variables., Results: Having more comorbid conditions was associated with a worse HRQL as assessed by all instruments. Chronic bronchitis was significantly associated with a worse HRQL as assessed by EQ-5D index (adjusted regression coefficient [95% confidence interval] -0.07 [-0.13 to -0.02]), EQ-5D VAS (-5.17 [-9.42 to -0.92]), and CAT (3.78 [2.35 to 5.20]). Musculoskeletal symptoms were significantly associated with worse EQ-5D index (-0.08 [-0.14 to -0.02]), osteoporosis with worse EQ-5D VAS (-4.65 [-9.27 to -0.03]), and depression with worse EQ-5D index (-0.10 [-0.17 to -0.04]). In stratification analyses, the associations of musculoskeletal symptoms, osteoporosis, and depression with HRQL were limited to female patients., Conclusion: The instruments EQ-5D and CAT complement each other and emerge as useful for assessing HRQL in patients with COPD. Chronic bronchitis, musculoskeletal symptoms, osteoporosis, and depression were associated with worse HRQL. We conclude that comorbid conditions, in particular chronic bronchitis, depression, osteoporosis, and musculoskeletal symptoms, should be taken into account in the clinical management of patients with severe COPD.