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Instead of applying the commonly used parametric Almon or Beta lag distribution of MIDAS, Breitung and Roling (J Forecast 34:588–603, 2015) suggested a nonparametric smoothed least-squares shrinkage estimator (henceforth SLS 1 ) for estimating mixed-frequency models. This SLS 1 approach ensures a flexible smooth trending lag distribution. However, even if the biasing parameter in SLS 1 solves the overparameterization problem, the cost is a decreased goodness-of-fit. Therefore, we suggest a modification of this shrinkage regression into a two-parameter smoothed least-squares estimator ( SLS 2 ). This estimator solves the overparameterization problem, and it has superior properties since it ensures that the orthogonality assumption between residuals and the predicted dependent variable holds, which leads to an increased goodness-of-fit. Our theoretical comparisons, supported by simulations, demonstrate that the increase in goodness-of-fit of the proposed two-parameter estimator also leads to a decrease in the mean square error of SLS 2 , compared to that of SLS 1 . Empirical results, where the inflation rate is forecasted based on the oil returns, demonstrate that our proposed SLS 2 estimator for mixed-frequency models provides better estimates in terms of decreased MSE and improved R2, which in turn leads to better forecasts. [ABSTRACT FROM AUTHOR]

Background: Hirschsprung's disease (HD) may result in an impaired quality of life (QoL) due to bowel problems, postoperative complications and other health-related issues. The Hirschsprung and Anorectal Malformation Quality of Life (HAQL) questionnaire is a disease-specific instrument developed in the Netherlands to measure the QoL in patients with HD and anorectal malformations. The aim of this study was to translate, culturally adapt and validate HAQL in a Danish Hirschsprung population. Material and methods: Translation and cultural adaptation were performed according to international guidelines. Invitations to participate in the validation were sent to 401 patients operated for HD during the period from 1985 to 2012. A total of 156 patients completed the translated and culturally adapted Danish versions of HAQL and 35 parents of children and adolescents completed the corresponding parent questionnaire. Reliability was evaluated in terms of internal consistency using Cronbach's α and test–retest reliability using Intraclass Correlation Coefficient for the retest step. Known groups comparison was performed with comparison of mild HD (defined as recto-sigmoidal HD) and serious HD (defined as more proximal disease). Results: The internal consistency of the dimensions was overall satisfactory for adults and adolescents but more problematic for children, where Cronbach's α was less than 0.7 in 60% of the dimensions. For both children and adolescents, the α-value was unsatisfactory for social functioning, emotional functioning, and body image. The test–retest reliability was overall good. The known groups comparison was only able to demonstrate a significant difference between mild and severe HD within one dimension. Conclusions: The translated version of the HAQL questionnaires provides an overall reliable instrument for evaluating disease-specific QoL in a Danish HD population, but it is important to acknowledge the limitations of the questionnaire, especially in children and adolescents. [ABSTRACT FROM AUTHOR]

Aging is a major risk factor for many chronic diseases. This study aimed to examine the effects of antihypertensive, lipid-lowering, and antidiabetic drugs on biological aging. We included 672 participants and 2746 repeated measurements from the Swedish Adoption/Twin Study of Aging. Self-reported medicine uses were categorized into antidiabetic, antihypertensive, and lipid-lowering drugs. A total of 12 biomarkers for biological aging (BA biomarkers) were included as outcomes. Conditional generalized estimating equations were applied conditioning on individuals to estimate the drug effect on BA biomarker level within the same person when using or not using the drug. Chronological age, body mass index, smoking status, number of multiple medication uses, blood pressure, blood glucose level, and apoB/apoA ratio were adjusted for as covariates in the model. Overall, using antihypertensive drugs was associated with a decrease in one DNA-methylation age (PCGrimAge: beta = − 0.39, 95%CI = − 0.67 to − 0.12). When looking into drug subcategories, calcium channel blockers (CCBs) were associated with a decrease in several DNA-methylation ages (PCHorvathAge beta = − 1.28, 95%CI = − 2.34 to − 0.21; PCSkin&bloodAge beta = − 1.34, 95%CI = − 2.61 to − 0.07; PCPhenoAge beta = − 1.74, 95%CI = − 2.58 to − 0.89; PCGrimAge beta = − 0.57, 95%CI = − 0.96 to − 0.17) and in functional biological ages (functional age index beta = − 2.18, 95%CI = − 3.65 to − 0.71; frailty index beta = − 1.31, 95%CI = − 2.43 to − 0.18). However, the results within other drug subcategories were inconsistent. Calcium channel blockers may decrease biological aging captured by the BA biomarkers measured at epigenetic and functional level. Future studies are warranted to confirm these effects and understand the underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

In studies where the outcome is a change-score, it is often debated whether or not the analysis should adjust for the baseline score. When the aim is to make causal inference, it has been argued that the two analyses (adjusted vs. unadjusted) target different causal parameters, which may both be relevant. However, these arguments are not applicable when the aim is to make predictions rather than to estimate causal effects. When the scores are measured with error, there have been attempts to quantify the bias resulting from adjustment for the (mis-)measured baseline score or lack thereof. However, these bias results have been derived under an unrealistically simple model, and assuming that the target parameter is the unadjusted (for the true baseline score) association, thus dismissing the adjusted association as a possibly relevant target parameter. In this paper we address these limitations. We argue that, even if the aim is to make predictions, there are two possibly relevant target parameters; one adjusted for the baseline score and one unadjusted. We consider both the simple case when there are no measurement errors, and the more complex case when the scores are measured with error. For the latter case, we consider a more realistic model than previous authors. Under this model we derive analytic expressions for the biases that arise when adjusting or not adjusting for the (mis-)measured baseline score, with respect to the two possible target parameters. Finally, we use these expressions to discuss when adjustment is warranted in change-score analyses. [ABSTRACT FROM AUTHOR]

Background: Medical advances in the treatment of cancer have allowed the development of multiple approved treatments and prognostic and predictive biomarkers for many types of cancer. Identifying improved treatment strategies among approved treatment options, the study of which is termed comparative effectiveness, using predictive biomarkers is becoming more common. RCTs that incorporate predictive biomarkers into the study design, called prediction-driven RCTs, are needed to rigorously evaluate these treatment strategies. Although researched extensively in the experimental treatment setting, literature is lacking in providing guidance about prediction-driven RCTs in the comparative effectiveness setting. Methods: Realistic simulations with time-to-event endpoints are used to compare contrasts of clinical utility and provide examples of simulated prediction-driven RCTs in the comparative effectiveness setting. Results: Our proposed contrast for clinical utility accurately estimates the true clinical utility in the comparative effectiveness setting while in some scenarios, the contrast used in current literature does not. Discussion: It is important to properly define contrasts of interest according to the treatment setting. Realistic simulations should be used to choose and evaluate the RCT design(s) able to directly estimate that contrast. In the comparative effectiveness setting, our proposed contrast for clinical utility should be used. [ABSTRACT FROM AUTHOR]

Background: People with major neurocognitive disorder might be susceptible to drug-induced QT interval prolongation due to the presence of a number of concomitant risk factors. Objective: The aim of this study was to investigate the prevalence of QT-prolonging drugs and QT-prolonging drug–drug interactions and associated factors among older people with major neurocognitive disorder. Methods: In this register-based study, we obtained information regarding QT-prolonging drug use in a large population of older people with major neurocognitive disorder, through record linkage between the Swedish registry for cognitive/dementia disorders, and the Swedish Prescribed Drug Register. QT-prolonging drugs were identified according to the CredibleMeds online database and interactions using the Janusmed interaction database. Drug use was defined as one or more filled prescriptions during a 6-month timeframe, July 01 to December 31, 2017. Associations between people with a QT-prolonging drug and the factors of age and gender were analysed through multiple logistic regression. Results: Of 35,212 people included in the study, 41.6% had one or more QT-prolonging drug prescribed. The most commonly prescribed drug was donepezil, with a prevalence of 25.0%, followed by citalopram and escitalopram, representing 14.5% and 3.9% of prescriptions in the study population, respectively. Significant associations were found between QT-prolonging drug use and the factors of younger age and female gender. The most prevalent interaction was between citalopram and donepezil (2.7%), followed by the combination of escitalopram and donepezil (0.7%). Conclusions: In this population of older people with major neurocognitive disorder, QT-prolonging drugs and interactions that increase the risk of torsade de pointes were prevalent. Due to the presence of many risk factors in this population, it is important to continuously evaluate current QT-prolonging drugs and concomitant drug treatment in each individual. [ABSTRACT FROM AUTHOR]

In stochastic frontier analysis, the conventional estimation of unit inefficiency is based on the mean/mode of the inefficiency, conditioned on the composite error. It is known that the conditional mean of inefficiency shrinks towards the mean rather than towards the unit inefficiency. In this paper, we analytically prove that the conditional mode cannot accurately estimate unit inefficiency, either. We propose regularized estimators of unit inefficiency that restrict the unit inefficiency estimators to satisfy some a priori assumptions, and derive the closed form regularized conditional mode estimators for the three most commonly used inefficiency densities. Extensive simulations show that, under common empirical situations, e.g., regarding sample size and signal-to-noise ratio, the regularized estimators outperform the conventional (unregularized) estimators when the inefficiency is greater than its mean/mode. Based on real data from the electricity distribution sector in Sweden, we demonstrate that the conventional conditional estimators and our regularized conditional estimators provide substantially different results for highly inefficient companies. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to investigate how potentially inappropriate medication usage and anti-dementia drug use change from 3 years prior to, up until 3 years post-diagnosis of major neurocognitive disorders among older people living in Sweden. Methods: People registered in the Swedish registry for cognitive/dementia disorders from 1 July, 2008 to 31 December, 2017, and aged 68 years or older at diagnosis, were included (n = 67,226). Data were combined with the Swedish Prescribed Drug Registry to obtain information about drugs collected in 6-month periods at Swedish pharmacies from 3 years pre-diagnosis until 3 years post-diagnosis. Potentially inappropriate medications were identified according to Swedish national guidelines. A generalised estimating equation regression model and estimated marginal means were used. Results: Of the 67,226 people included in the study population, 59.2% were women and the mean age ± standard deviation was 81.5 ± 6.4 years, 47.0% lived together with a spouse or partner, and 88.9% were living at home at the time of diagnosis. The proportions of people using potentially inappropriate medications continuously decreased pre- and post-diagnosis, except for antipsychotic drug use, which continuously increased both pre- and post-diagnosis. Moreover, anticholinergic drug use increased pre-diagnosis and declined post-diagnosis. When comparing the periods pre- and post-diagnosis date, the adjusted proportion of people using potentially inappropriate medications was significantly lower post-diagnosis compared with pre-diagnosis, except for the adjusted proportion using antipsychotics, which was significantly higher post-diagnosis, 10.6%, compared with the period before, 3.1% (adjusted odds ratio 3.71; 95% confidence interval 3.59–3.83). The adjusted proportion of people using anticholinergic drugs was significantly lower post-diagnosis, 7.2%, compared with the pre-diagnosis period, 8.9% (adjusted odds ratio 0.80; 95% confidence interval 0.78–0.82). Anti-dementia drug use was significantly higher post-diagnosis, 52.6%, when compared with the pre-diagnosis period, 3.5% (adjusted odds ratio 30.13; 95% confidence interval 29.19–31.10). Conclusions: Overall, the prevalence of people using potentially inappropriate medications decreased and was significantly lower post-diagnosis of major neurocognitive disorders, except for antipsychotics. This indicates that potentially inappropriate medication use should be noticed and reviewed among all older people. The small decrease in the prevalence of anticholinergic drug users and the increasing proportions of people using antipsychotic drugs post-diagnosis are of special concern because of the adverse drug reactions associated with these types of potentially inappropriate medications. Consequently, it is important to identify and regularly question anticholinergic and antipsychotic drug treatment to prevent unnecessary and serious adverse drug reactions among a vulnerable group of people. [ABSTRACT FROM AUTHOR]

Purpose: To describe and compare self-reported medication adherence assessed with the 5-item version of Medication Adherence Report Scale (MARS-5) and pharmacy refill adherence based on data from the Swedish Prescribed Drug Register (SPDR) among persons with ischemic stroke, and to investigate independent predictors associated with respective assessments. Methods: A study questionnaire was sent to persons with ischemic stroke registered in the Swedish Stroke Register between Dec 2011 and March 2012, and who lived at home 3 months after discharge. The primary outcome was dichotomized to adherent/non-adherent based on MARS-5 and SPDR and analyzed with multivariable logistic regression. Adherence according to MARS-5 was defined as score 23 or higher (out of 25). Adherence according to SPDR was defined as at least one filled statin prescription recorded in SPDR in each 6-month interval during 2 years of follow-up. Results: Of 420 participants, 367 (87%) and 329 (78%) were adherent according to MARS-5 and SPDR, respectively, and 294 (70%) participants were adherent according to both assessments. A significant association was shown between medication adherence according to the two assessments (p = 0.020). Independent predictors associated with medication adherence according to MARS-5 were female sex, while factors associated with SPDR were male sex and being younger. Conclusions: The majority of participants were classified as adherent, 87% according to MARS-5 and 78% based on data from SPDR. However, only 70% were adherent according to both MARS-5 and SPDR, and different predictors were associated with the different measurements, suggesting that these assessments are measuring different aspects of adherence. [ABSTRACT FROM AUTHOR]

Sibling comparison studies have the attractive feature of being able to control for unmeasured confounding by factors that are shared within families. However, there is sometimes a concern that these studies may have poor generalizability (external validity) due to the implicit restriction to families that are covariate-discordant, i.e., those families where at least two siblings have different levels of at least one of the covariates (exposure or confounders) under investigation. Even if this selection mechanism has been noted by many authors, previous accounts of the problem tend to be brief. The purpose of this paper is to provide a formal discussion of the implicit restriction to covariate-discordant families in sibling comparison studies. We discuss when and how this restriction may impair the generalizability of the study, and we show that a similar generalizability problem may in fact arise even when all families are covariate-discordant, e.g. even if the exposure is continuous so that all siblings have different exposure levels. We show how this problem can be solved by using a so-called marginal between-within model for estimation of marginal exposure effects. Finally, we illustrate the theoretical conclusions with a simulation study. [ABSTRACT FROM AUTHOR]

Aim: Psychotropic medications include many drugs that may be inappropriate for older individuals with cognitive impairment. In Sweden, many people become registered in the Swedish Dementia Registry when they are diagnosed with major neurocognitive disorder (NCD). In this study, we aim to describe psychotropic drug use and associated factors among older Swedish people with major NCD. Methods: This study included 38,251 people ≥ 65 years from the Swedish registry for cognitive/dementia disorders diagnosed during 2007–2017. Drug use was defined as one or more filled prescription(s) recorded in the Swedish Prescribed Drug Register during 1 July to 31 December 2017. Associations between psychotropics and age, sex, diagnosis date, Mini-Mental State Examination score and major NCD subtype were analysed through multiple logistic regression. Results: We found that 12.0% of the individuals filled at least one prescription for antipsychotics, 22.0% for anxiolytics, 23.0% for sedatives or hypnotics, 43.2% for antidepressants and 56.7% for antidementia drugs. In brief, psychotropic use was associated with female sex, higher age, longer time since diagnosis and specific subtypes of major NCD; the strongest association was found between antipsychotics and Lewy body dementia (odds ratio 2.40, 95% confidence interval 2.04–2.82). Conclusion: Psychotropic drugs were frequently dispensed among older Swedish people with major NCD. The use of antipsychotics and medications with sedative properties warrants concern, especially among those with Lewy body dementia who are severely sensitive to antipsychotics. A more restrictive prescribing pattern regarding these medications might reduce the risk of drug-related problems in this vulnerable group of people. [ABSTRACT FROM AUTHOR]

Background: Despite intense research, the prognosis for patients with advanced colorectal cancer (CRC) remains poor. The prostaglandin D2 receptors DP1 and DP2 are explored here as potential therapeutic targets for advanced CRC.Methods: A CRC cohort was analysed to determine whether DP1 and DP2 receptor expression correlates with patient survival. Four colon cancer cell lines and a zebrafish metastasis model were used to explore how DP1/DP2 receptor expression correlates with CRC progression.Results: Analysis of the clinical CRC cohort revealed high DP2 expression in tumour tissue, whereas DP1 expression was low. High DP2 expression negatively correlated with overall survival. Other pathological indicators, such as TNM stage and metastasis, positively correlated with DP2 but not DP1 expression. In accordance, the in vitro results showed high DP2 expression in four CC-cell lines, but only one expressed DP1. DP2 stimulation resulted in increased proliferation, p-ERK1/2 and VEGF expression/secretion. DP2-stimulated cells exhibited increased migration in the zebrafish metastasis model.Conclusion: Our results support DP2 receptor expression and signalling as a therapeutic target in CRC progression based on its expression in CRC tissue correlating with poor patient survival and that it triggers proliferation, p-ERK1/2 and VEGF expression and release and increased metastatic activity in CC-cells. [ABSTRACT FROM AUTHOR]

Background and Objective: Pain is highly prevalent among older people, and treatment is complicated because of comorbidities and polypharmacy. Among people with major neurocognitive disorder additional difficulties might arise. The aim of this study was to describe analgesic drug use in 2012 and 2017 and associated factors among older people with major neurocognitive disorder. Methods: In this register-based study, the Swedish Dementia Registry and the Swedish Prescribed Drug Register were combined in order to obtain data regarding analgesic drug use among older people with major neurocognitive disorder. One or more filled prescriptions during the timeframe of 6 months (1 July–31 December 2012 and 1 July–31 December 2017) defined drug use during the respective period. A comparison between 2012 and 2017 was made, including a total of 56,101 people (20,889 and 35,212 respectively) with a mean age of 81.9 and 82.7 years, respectively. Results: The overall use of analgesic drugs increased significantly from 41.6% of individuals to 46.0% between the years 2012 and 2017. Users of opioid analgesics (15.2% vs 17.3%) and paracetamol (37.0% vs 42.3%) increased, while the users of non-steroidal anti-inflammatory drugs (4.9% vs 2.7%) declined between the two data collections. Multiple logistic regression analyses were performed for different drugs and drug classes, and it was found that the use of opioids and paracetamol was associated with older age and a longer time since diagnosis. In contrast, non-steroidal anti-inflammatory drugs were associated with younger age and a shorter time since diagnosis. Conclusions: The results indicate that on a population level, pharmacological drug treatment has changed in line with guidelines between 2012 and 2017, with an increase in paracetamol and strong opioids and a decrease in non-steroidal anti-inflammatory drugs and tramadol. The relatively high prevalence of opioids warrants concern given the significant risk of adverse effects among older people with major neurocognitive disorder. [ABSTRACT FROM AUTHOR]

Background: Mammographic microcalcifications are considered early signs of breast cancer (BC). We examined the association between microcalcification clusters and the risk of overall and subtype-specific BC. Furthermore, we studied how mammographic density (MD) influences the association between microcalcification clusters and BC risk.Methods: We used a prospective cohort (n = 53,273) of Swedish women with comprehensive information on BC risk factors and mammograms. The total number of microcalcification clusters and MD were measured using a computer-aided detection system and the STRATUS method, respectively. Cox regressions and logistic regressions were used to analyse the data.Results: Overall, 676 women were diagnosed with BC. Women with ≥3 microcalcification clusters had a hazard ratio [HR] of 2.17 (95% confidence interval [CI] = 1.57-3.01) compared to women with no clusters. The estimated risk was more pronounced in premenopausal women (HR = 2.93; 95% CI = 1.67-5.16). For postmenopausal women, microcalcification clusters and MD had a similar influence on BC risk. No interaction was observed between microcalcification clusters and MD. Microcalcification clusters were significantly associated with in situ breast cancer (odds ratio: 2.03; 95% CI = 1.13-3.63).Conclusions: Microcalcification clusters are an independent risk factor for BC, with a higher estimated risk in premenopausal women. In postmenopausal women, microcalcification clusters have a similar association with BC as baseline MD. [ABSTRACT FROM AUTHOR]

Purpose: The anorectic effect of PYY3–36 makes it a potential pharmacological weight loss treatment. Modifications of the endogenous peptide to obtain commercially attractive pharmacological and biophysical stability properties are examined. Methods: Half-life extended PYY3–36 analogues were prepared and examined regarding Y2-receptor potency as well as biophysical and stability properties. Results: Deamidation of asparagine in position 18 and 29 was observed upon incubation at 37°C. Asparagine in position 18 – but not position 29 – could be substituted to glutamine without detrimental effects on Y2-receptor potency. Covalent dimers were formed via the phenol impurity benzoquinone reacting with two N-terminal residues (Isoleucine-Lysine). Both residues had to be modified to suppress dimerization, which could be done without negatively affecting Y2-receptor potency or other stability/biophysical properties. Introduction of half-life extending modifications in position 30 and 35 eliminated aggregation at 37°C without negatively affecting other stability properties. Placement of a protracting moiety (fatty acid) in the receptor-binding C-terminal region reduced Y2-receptor potency substantially, whereas only minor effects of protractor position were observed on structural, biophysical or stability properties. Lipidated PYY3–36 analogues formed oligomers of various sizes depending on primary structure and solution conditions. Conclusions: By rational design, a chemically and physically stable Y2-receptor selective, half-life extended PYY3–36 peptide has been developed. [ABSTRACT FROM AUTHOR]

We thank Sander Greenland and Albert Hofman (hereafter abbreviated GH) for their comments [[1]] on our paper [[2]], and the Editor for giving us the opportunity to respond. They proceeded by fitting a hierarchical model, in which the food coefficients were modeled as HT ht Graph where HT ht is a vector of fixed parameters and HT ht is a random error term, assumed to have a normal distribution with mean 0 and fixed assumed variance HT ht . If, in addition, the variance of HT ht is small, then the food coefficients are prevented from varying within this subspace, which will further increase the shrinkage. In this case, the dimensions of HT ht and HT ht are identical, and there will be no shrinkage, regardless of the assumed variance of HT ht . [Extracted from the article]

Background This project is part of the prospective quasi experimental proof-of-concept investigation of clinical pharmacist intervention study to reduce drug-related problems among people admitted to a ward in a rural hospital in northern Sweden. Objective To explore doctors' and nurses' perceptions and expectations of having a ward-based pharmacist providing clinical pharmacy services. Setting Medical ward in a rural hospital in northern Sweden. Method Eighteen face-to-face semi-structured interviews were conducted with a purposive sample of doctors and nurses working on the ward where the clinical pharmacy service was due to be implemented. Semi-structured interviews were digitally recorded, transcribed and analysed using thematic analysis. Main outcome measure Perceptions and expectations of nurses and doctors. Results Doctors and nurses had limited experience of working with pharmacists. Most had a vague idea of what pharmacists can contribute within a ward setting. Participants, mainly nurses, suggested inventory and drug distribution roles, but few were aware of the pharmacists' skills and clinical competence. Different views were expressed on whether the new clinical pharmacy service would have an impact on workload. However, most participants took a positive view of having a ward-based pharmacist. Conclusion This study provided an opportunity to explore doctors' and nurses' expectations of the role of clinical pharmacists before a clinical pharmacy service was implemented. To successfully implement a clinical pharmacy service, roles, clinical competence and responsibilities should be clearly described. Furthermore, it is important to focus on collaborative working relationships between doctors, nurses and pharmacists. [ABSTRACT FROM AUTHOR]

Multiple tests arise frequently in epidemiologic research. However, the issue of multiplicity adjustment is surrounded by confusion and controversy, and there is no uniform agreement on whether or when adjustment is warranted. In this paper we compare frequentist and Bayesian frameworks for multiple testing. We argue that the frequentist framework leads to logical difficulties, and is unable to distinguish between relevant and irrelevant multiplicity adjustments. We further argue that these logical difficulties resolve within the Bayesian framework, and that the Bayesian framework makes a clear and coherent distinction between relevant and irrelevant adjustments. We use Directed Acyclic Graphs to illustrate the differences between the two frameworks, and to motivate our arguments. [ABSTRACT FROM AUTHOR]

Heritability is the most commonly used measure of genetic contribution to disease outcomes. Being the fraction of the variance of latent trait liability attributable to genetic factors, heritability of binary traits is a difficult technical concept that is sometimes misinterpreted as the more-easily understandable concept of attributable fraction. In this paper we use the liability threshold model to describe the analytical relationship between heritability and attributable fraction. Towards this end, we consider a hypothetical intervention that is aimed to reduce the genetic risk of the disease for a specified target group of the population. We show how the relation between the heritability and the attributable fraction depends on the disease prevalence, the intervention effect and the size of the target group. We use two real examples to illustrate the practical implications of our theoretical results. [ABSTRACT FROM AUTHOR]

Purpose: Increased numbers of drugs and changes in pharmacokinetic and pharmacodynamic parameters among elderly people contribute to increased prevalence of adverse drug reactions. Drug-drug interactions (DDIs) are an important reason for admission to hospital and elderly people with dementia are particularly vulnerable. The aims of the present study were to assess the occurrence and characteristics of clinically relevant DDIs and to investigate potential risk factors associated with DDIs among elderly people with dementia.Methods: People ≥ 65 years with dementia, admitted to two hospitals in Northern Sweden, were included. The medical records of 458 patients were reviewed. Clinically relevant DDIs were identified using the Janusmed interactions database. Pharmacological classification was conducted using Stockley’s classification system.Results: A total of 401 DDIs were identified among 43.2% of the study population, of which 98.5% had interactions that may require dose adjustment and 7.6% had drug combinations that should be avoided. Pharmacodynamic interactions were most common, of which furosemide-citalopram (n = 35) were most frequently observed. Omeprazol-citalopram (n = 25) was the most common drug combination among pharmacokinetic interactions. Citalopram and warfarin were the most commonly involved drug substances. An association was found between a higher number of medications being prescribed and having at least one DDI.Conclusion: Clinically relevant drug-drug interactions are prevalent among elderly people with dementia living in Northern Sweden. Drug-drug interactions should be identified in order to manage and prevent adverse outcomes. This is particularly important among this group of people especially when multiple medications are being prescribed. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the association between shift work and incident dementia in two population-based cohorts from the Swedish Twin Registry (STR). The STR-1973 sample included 13,283 participants born 1926-1943 who received a mailed questionnaire in 1973 that asked about status (ever/never) and duration (years) of shift work employment. The Screening Across the Lifespan Twin (SALT) sample included 41,199 participants born 1900-1958 who participated in a telephone interview in 1998-2002 that asked about night work status and duration. Dementia diagnoses came from Swedish patient registers. Cox proportional-hazards regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Potential confounders such as age, sex, education, diabetes, cardiovascular disease and stroke were included in adjusted models. In genotyped subsamples (n = 2977 in STR-1973; n = 10,366 in SALT), APOE ε4 status was considered in models. A total of 983 (7.4%) and 1979 (4.8%) dementia cases were identified after a median of 41.2 and 14.1 years follow-up in the STR-1973 and SALT sample, respectively. Ever shift work (HR 1.36, 95% CI 1.15-1.60) and night work (HR 1.12, 95% CI 1.01-1.23) were associated with higher dementia incidence. Modest dose-response associations were observed, where longer duration shift work and night work predicted increased dementia risk. Among APOE ε4 carriers, individuals exposed to ≥ 20 years of shift work and night work had increased dementia risk compared to day workers. Findings indicate that shift work, including night shift work, compared to non-shift jobs is associated with increased dementia incidence. Confirmation of findings is needed. [ABSTRACT FROM AUTHOR]

Measures of causal effects play a central role in epidemiology. A wide range of measures exist, which are designed to give relevant answers to substantive epidemiological research questions. However, due to mathematical convenience and software limitations most studies only report odds ratios for binary outcomes and hazard ratios for time-to-event outcomes. In this paper we show how logistic regression models and Cox proportional hazards regression models can be used to estimate a wide range of causal effect measures, with the R-package stdReg. For illustration we focus on the attributable fraction, the number needed to treat and the relative excess risk due to interaction. We use two publicly available data sets, so that the reader can easily replicate and elaborate on the analyses. The first dataset includes information on 487 births among 188 women, and the second dataset includes information on 2982 women diagnosed with primary breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether comprehensive medication reviews conducted by clinical pharmacists as part of a healthcare team reduce drug-related hospital readmission rates among people with dementia or cognitive impairment. Methods: This randomized controlled trial was carried out between January 9, 2012, and December 2, 2014. Patients aged ≥65 years with dementia or cognitive impairment admitted to three wards at two hospitals located in Northern Sweden were included. Results: Of the 473 deemed eligible for participation, 230 were randomized to intervention and 230 to control group by block randomization. The primary outcome, risk of drug-related hospital readmissions, was assessed at 180 days of follow-up by intention-to-treat analysis. During the 180 days of follow-up, 18.9% (40/212) of patients in the intervention group and 23.0% (50/217) of those in the control group were readmitted for drug-related reasons (HR = 0.80, 95% CI = 0.53-1.21, p = 0.28, univariable Cox regression). Heart failure was significantly more common in the intervention group. After adjustment for heart failure as a potential confounder and an interaction term, multiple Cox regression analysis indicated that pharmacist participation significantly reduced the risk of drug-related readmissions (HR = 0.49, 95% CI = 0.27-0.90, p = 0.02). A post-hoc analysis showed a significantly reduced risk of 30-day readmissions due to drug-related problems in the total sample (without adjustment for heart failure). Conclusion: Participation of clinical pharmacists in healthcare team conducting comprehensive medication reviews did not significantly reduce the risk of drug-related readmissions in patients with dementia or cognitive impairment; however, post-hoc and subgroup analyses indicated significant effects favoring the intervention. More research is needed. Trial registration: Clinical trials NCT01504672. [ABSTRACT FROM AUTHOR]

Purpose: As people get older, their sensitivity to drugs and adverse drug reactions can increase due to pharmacokinetic and pharmacodynamic changes. Older people with dementia are a particularly vulnerable group of people. They are at an increased risk of being prescribed potentially inappropriate medications, which may lead to harmful consequences. The aim of this study was to investigate the prevalence of potentially inappropriate medications among older patients with cognitive impairment. Methods: Medical records for patients aged ≥65 years admitted to two hospitals in Northern Sweden were reviewed. Potentially inappropriate medications were identified using the EU(7)-PIM list as an identification tool. Results: Of 428 patients included in the study, 40.9% had one or more potentially inappropriate medication prescribed. The most commonly represented potentially inappropriate medication classes were hypnotics and sedatives, cardiovascular drugs and laxatives. The most commonly involved potentially inappropriate medications were zopiclone, digoxin and sodium picosulfate. There was an association seen between having a higher number of medications prescribed and having one or more potentially inappropriate medication. Conclusion: Potentially inappropriate medications are prevalent among older people with cognitive impairment living in Northern Sweden. It is important to continuously evaluate the need for potentially inappropriate medications in this patient group, in order to prevent adverse drug reactions, especially among those who have a higher number of medications prescribed. [ABSTRACT FROM AUTHOR]

In this article we investigate if the Swedish consumer prices for electricity are adjusted equally fast regardless of whether the NordPool power market prices are decreased or increased. Due to relatively moderate variations in the variables, we have applied quantile regression, since it is mainly the large changes (above the median) that essentially tend to have a considerable effect on the consumer prices. Moreover, in order to adjust for stochastic- and deterministic trends, autocorrelation, structural breaks as well as to measure APT effects in the short- and in the medium-run, we apply a wavelet decomposition approach. Our results show evidence that significantly positive asymmetric price transmission (APT) effects exist in this market. More specifically, in the short-run (based on the wavelet decomposition D1 for 1-2 months cycles), we find that that there is a higher propensity to rapidly and systematically increase the consumer prices subsequently to an increase in the NordPool market price, compared with the propensity to decrease their customers prices subsequently to a corresponding drop in the NordPool market prices. However, no significant APT effects were detected in the medium- or in the long-run (i.e. the asymmetric price transmission effects are observed only in the short-run). In summary, we could isolate significant APT effects in the short-run (1-2 months decomposition cycles), and for large changes in the dependent variable (percentiles = 0.9). Therefore, only large changes in the NordPool prices lead to feedback effects in the form of asymmetric price transmission effects. Our evidence supports the notion of firms' downward stickiness of retail prices for maximizing profit, which are not expected to be found on a fully efficient market. Although our finding shows that the price inefficiency is short-lived, these large temporal inefficiencies are still costly for the consumers. It should be noted that blunt traditional powerless methods do not detect these APT effects, while our wavelet quantile methods are powerful and make a significant contribution in the literature by providing new empirical evidence. [ABSTRACT FROM AUTHOR]

Background: Older people are more sensitive to drugs and adverse drug reactions than younger people because of age-related physiological changes such as impaired renal function. As people with dementia are particularly vulnerable to the effects of drugs, it is especially important to evaluate the dosages of renally cleared medications in this group. Objective: The aim of this study was to estimate the prevalence of impaired renal function and inappropriate prescriptions on the basis of renal function among older patients with dementia or cognitive impairment. Methods: The medical records of 428 patients aged ≥65 years who were admitted to two hospitals in northern Sweden were reviewed and renally cleared medications were identified. The Cockcroft-Gault equation was used to evaluate renal function. Doses were evaluated according to the Geriatric Dosage Handbook. Results: Renal function was impaired (estimated glomerular filtration rate <60 ml/min) in 65.4 % of the study population. Impaired renal function was associated with increasing age. Among 547 prescriptions identified as renally cleared medications, 9.1 % were inappropriate based on the patient's renal function; 13.5 % of the 326 patients prescribed renally cleared medications had inappropriate prescriptions. Inappropriate prescriptions were more common among patients living in nursing homes. Conclusions: Impaired renal function is common and inappropriate prescription is prevalent among old people with cognitive impairment in northern Sweden. Continuous consideration of renal function is important when prescribing medications to this group. [ABSTRACT FROM AUTHOR]

Background: Alteration in respiratory activity and mitochondrial DNA (mtDNA) transcription seems to be an important feature of cancer cells. Leukotriene D(4) (LTD(4)) is a proinflammatory mediator implicated in the pathology of chronic inflammation and cancer. We have shown earlier that LTD(4) causes translocation of beta-catenin both to the mitochondria, in which it associates with the survival protein Bcl-2 identifying a novel role for beta-catenin in cell survival, and to the nucleus in which it activates the TCF/LEF transcription machinery.Methods: Here we have used non-transformed intestinal epithelial Int 407 cells and Caco-2 colon cancer cells, transfected or not with wild type and mutated (S33Y) beta-catenin to analyse its effect on mitochondria activity. We have measured the ATP/ADP ratio, and transcription of the mtDNA genes ND2, ND6 and 16 s in these cells stimulated or not with LTD(4).Results: We have shown for the first time that LTD(4) triggers a cellular increase in NADPH dehydrogenase activity and ATP/ADP ratio. In addition, LTD(4) significantly increased the transcription of mtDNA genes. Overexpression of wild-type beta-catenin or a constitutively active beta-catenin mutant mimicked the effect of LTD(4) on ATP/ADP ratio and mtDNA transcription. These elevations in mitochondrial activity resulted in increased reactive oxygen species levels and subsequent activations of the p65 subunit of NF-kappaB.Conclusions: The present novel data show that LTD(4), presumably through beta-catenin accumulation in the mitochondria, affects mitochondrial activity, lending further credence to the idea that inflammatory signalling pathways are intrinsically linked with potential oncogenic signals. [ABSTRACT FROM AUTHOR]

Purpose: Drug treatment associated problems are common and are the cause of a large proportion of hospitalizations in old people. People with dementia are especially at risk of drug-related problems. The objectives of this study were to assess the occurrence and character of drug-related problems that lead to acute hospital admissions among old people (≥65 years) with dementia or cognitive impairment. Methods: This study was conducted in orthopedic and internal medicine wards in two hospitals in Northern Sweden. Information about acute admissions was collected from the medical records. A total of 458 people aged 65 years or older with dementia or cognitive impairment were included in the study. The contribution of drug-related problems to each hospitalization was assessed. Results: Of 458 acute hospital admissions, 189 (41.3 %) were determined to be drug-related. The most common drug-related problem (86/189; 45.5 %) was an adverse drug reaction. In total, 264 drugs were judged to be involved in 189 drug-related admissions, of which cardiovascular (29.5 %) and psychotropic (26.9 %) drugs were the most commonly involved drug classes. The relationship between the drug-related problem and the admission was judged certain in 25 cases, probable in 78 cases, and possible in 86 cases. Drug-related admissions were more common among people taking more drugs ( p = 0.035) and among younger patients ( p = 0.031). Conclusion: Drug-related problems appear to be responsible for a major proportion of hospitalizations among old people with dementia or cognitive impairment. Targeted interventions such as education and medication reviews may be warranted to reduce drug-related problems. [ABSTRACT FROM AUTHOR]

The attributable fraction (or attributable risk) is a widely used measure that quantifies the public health impact of an exposure on an outcome. Even though the theory for AF estimation is well developed, there has been a lack of up-to-date software implementations. The aim of this article is to present a new R package for AF estimation with binary exposures. The package AF allows for confounder-adjusted estimation of the AF for the three major study designs: cross-sectional, (possibly matched) case-control and cohort. The article is divided into theoretical sections and applied sections. In the theoretical sections we describe how the confounder-adjusted AF is estimated for each specific study design. These sections serve as a brief but self-consistent tutorial in AF estimation. In the applied sections we use real data examples to illustrate how the AF package is used. All datasets in these examples are publicly available and included in the AF package, so readers can easily replicate all analyses. [ABSTRACT FROM AUTHOR]

When studying the association between an exposure and an outcome, it is common to use regression models to adjust for measured confounders. The most common models in epidemiologic research are logistic regression and Cox regression, which estimate conditional (on the confounders) odds ratios and hazard ratios. When the model has been fitted, one can use regression standardization to estimate marginal measures of association. If the measured confounders are sufficient for confounding control, then the marginal association measures can be interpreted as poulation causal effects. In this paper we describe a new R package, stdReg, that carries out regression standardization with generalized linear models (e.g. logistic regression) and Cox regression models. We illustrate the package with several examples, using real data that are publicly available. [ABSTRACT FROM AUTHOR]

We examined associations of maternal age at childbearing (MAC) with gestational age and fetal growth (i.e., birth weight adjusting for gestational age), using two genetically informed designs (cousin and sibling comparisons) and data from two cohorts, a population-based Swedish sample and a nationally representative United States sample. We also conducted sensitivity analyses to test limitations of the designs. The findings were consistent across samples and suggested that, associations observed in the population between younger MAC and shorter gestational age were confounded by shared familial factors; however, associations of advanced MAC with shorter gestational age remained robust after accounting for shared familial factors. In contrast to the gestational age findings, neither early nor advanced MAC was associated with lower fetal growth after accounting for shared familial factors. Given certain assumptions, these findings provide support for a causal association between advanced MAC and shorter gestational age. The results also suggest that there are not causal associations between early MAC and shorter gestational age, between early MAC and lower fetal growth, and between advanced MAC and lower fetal growth. [ABSTRACT FROM AUTHOR]

Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes. [ABSTRACT FROM AUTHOR]

In this article we examine multicollinearity in the standard OLS interaction-term model-a problem often disregarded by practitioners and in previous research. As a remedy we propose a number of new shrinkage parameters based on the Liu (Commun Stat 22:393-402, ) estimator. Using Monte Carlo simulations, we evaluate the robustness of all models for different data-generating processes under varying conditions such as altered sample sizes and error distributions. In the simulation study it is demonstrated that the Liu estimator, which is robust to multicollinearity, systematically outperforms the traditionally applied OLS approach. The simple reason is that interaction models by definition always induce substantial multicollinearity, which in turn distorts the inference of OLS. Conversely, the Liu estimator is robust against multicollinearity in interaction-term models. The advantages of our Liu-based method are also demonstrated in practice when examining the efficiency of the Swedish power retailing market. By the use of this unique data set we find strong evidence of positive asymmetric price transmission effects. Increases in Nord Pool electricity wholesale spot prices lead to immediate and full increases in the electricity retail prices, but decreases in Nord Pool prices are not completely passed down or are delayed before being passed down to consumers. This finding suggests evidence of inefficient and unjust wealth transfers from consumers to retailers in the Swedish power market. [ABSTRACT FROM AUTHOR]

Background:Alcohol consumption has been suggested to increase risk of breast cancer through a mechanism that also increases mammographic density. Whether the association between alcohol consumption and mammographic density is modified by background breast cancer risk has, however, not been studied.Methods:We conducted a population-based cross-sectional study of 53 060 Swedish women aged 40-74 years. Alcohol consumption was assessed using a web-based self-administered questionnaire. Mammographic density was measured using the fully-automated volumetric Volpara method. The Tyrer-Cuzick prediction model was used to estimate risk of developing breast cancer in the next 10 years. Linear regression models were used to evaluate the association between alcohol consumption and volumetric mammographic density and the potential influence of Tyrer-Cuzick breast cancer risk.Results:Overall, increasing alcohol consumption was associated with higher absolute dense volume (cm3) and per cent dense volume (%). The association between alcohol consumption and absolute dense volume was most pronounced among women with the highest (⩾5%) Tyrer-Cuzick 10-year risk. Among high-risk women, women consuming 5.0-9.9, 10.0-19.9, 20.0-29.9, and 30.0-40.0 g of alcohol per day had 2.6 cm3 (95% confidence interval (CI), 0.2-4.9), 2.9 cm3 (95% CI, −0.6 to 6.3), 4.6 cm3 (95% CI, 1.5-7.7), and 10.8 cm3 (95% CI, 4.8-17.0) higher absolute dense volume, respectively, as compared with women abstaining from alcohol. A trend of increasing alcohol consumption and higher absolute dense volume was seen in women at low (⩽3%) risk, but not in women at moderate (3.0-4.9%) risk.Conclusion:Alcohol consumption may increase breast cancer risk through increasing mammographic density, particularly in women at high background risk of breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to investigate trends in the prevalence of potentially inappropriate drug use among old people living in geriatric care units in the county of Västerbotten between 2007 and 2013 using six national quality indicators and to assess the impact of medication reviews on those quality indicators. Methods: Data were collected concerning potentially inappropriate drug use, function in the activities of daily living (ADL) and cognitive function, using the Multi-Dimensional Dementia Assessment Scale (MDDAS). A comparison was made between the years 2007 and 2013, comprising 2772 and 1902 people, respectively, living in geriatric care in the county of Västerbotten, Sweden. We conducted a parallel investigation of a separate corresponding population in Västerbotten County from 2012, where potentially inappropriate drug use was measured before and after 895 medication reviews which involved a clinical pharmacist. Results: After controlling for age, sex, ADL and cognitive impairment, there was a significant improvement in five out of six quality indicators between 2007 and 2013. While 44 % of the people were exposed to one or more potentially inappropriate medications in 2007, this number had declined to 26 % by 2013. In the separate population from 2012, the frequency of potentially inappropriate drug use was significantly reduced amongst the people who had a medication review performed. Conclusion: The extent of potentially inappropriate drug use declined between 2007 and 2013 according to the quality indicators used. Medication reviews involving clinical pharmacists might be an important factor in reducing potentially inappropriate drug use and improving drug treatment among old people. [ABSTRACT FROM AUTHOR]

A common goal of epidemiologic research is to study how two exposures interact in causing a binary outcome. Sufficient-cause interaction is a special type of mechanistic interaction, which requires that two events (e.g. specific exposure levels from two risk factors) are necessary in order for the outcome to occur. Recently, tests have been derived to establish the presence of sufficient-cause interactions, for categorical exposures with at most three levels. In this paper we derive prevalence bounds, i.e. lower and upper bounds on the prevalence of subjects for which sufficient-cause interaction is present. The derived bounds hold for categorical exposures with arbitrary many levels. We apply the bounds to data from a study of gene-gene interaction in the development of Rheumatoid Arthritis. We provide an R-program to estimate the bounds from real data . [ABSTRACT FROM AUTHOR]

Purpose: Body mass index (BMI) is a modifiable lifestyle factor that has been associated with an increased risk of fatal prostate cancer and biochemical recurrence. The main purpose of the present study was to investigate the association between the exposure BMI at the time of a prostate cancer diagnosis and weight change after diagnosis, and the outcomes of prostate cancer progression and mortality in a large cohort study. Methods: Data from 4,376 men diagnosed with clinically localized prostate cancer between 1997 and 2002 were analyzed. BMI and weight change were self-reported in 2007. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated in complete-case analysis ( n = 3,214) using Cox proportional hazards models. Results: Progression was experienced among 639 (14.6 %) of the study participants, and in total, 450 (10.3 %) deaths of any cause and 134 (3.1 %) prostate cancer-specific deaths were recorded during follow-up. Obese men had a 47 % increased rate of overall mortality compared to normal weight men (HR 1.47, 95 % CI 1.03-2.10). No statistically significant associations were found for BMI and prostate cancer progression or prostate cancer-specific mortality. A weight loss >5 % after diagnosis almost doubled the rate of overall mortality compared to maintaining a stable weight (HR 1.94, 95 % CI 1.41-2.66), while a weight gain >5 % was associated with an almost doubled increased rate of prostate cancer-specific mortality (HR 1.93, 95 % CI 1.18-3.16). Conclusions: Being obese was associated with an increased rate of overall mortality, and gaining weight after a prostate cancer diagnosis was associated with an increased rate of prostate cancer-specific mortality. [ABSTRACT FROM AUTHOR]

The influence of solidification rate on the solution-treatment response has been investigated for an Al-7Si-0.3Mg alloy and an Al-8Si-3Cu-0.5Mg alloy. The concentrations of Mg, Cu, and Si in the matrix after different solution-treatment times were measured using a wavelength dispersive spectrometer. All Mg dissolves into the matrix for the Al-Si-Mg alloy when solution treated at 803 K (530 °C) because the π-Fe phase is unstable and transforms into short β-Fe plates which release Mg. The Q-AlMgCuSi phase do not dissolve completely at 768 K (495 °C) in the Al-Si-Cu-Mg alloy and the concentration in the matrix reached 0.22 to 0.25 wt pct Mg. The distance between π-Fe phases and AlCu phases was found to determine the solution-treatment time needed for dissolution and homogenization for the Al-Si-Mg alloy and Al-Si-Cu-Mg alloy, respectively. From the distance between the phases, a dimensionless diffusion time was calculated which can be used to estimate the solution-treatment times needed for different coarsenesses of the microstructure. A model was developed to describe the dissolution and homogenization processes. [ABSTRACT FROM AUTHOR]

The commonly accepted dogma of the bacterial GroE chaperonin system entails protein folding mediated by cycles of several ATP-dependent sequential steps where GroEL interacts with the folding client protein. In contrast, we herein report GroES-mediated dynamic remodeling (expansion and compression) of two different protein substrates during folding: the endogenous substrate MreB and carbonic anhydrase (HCAII), a well-characterized protein folding model. GroES was also found to influence GroEL binding induced unfolding and compression of the client protein underlining the synergistic activity of both chaperonins, even in the absence of ATP. This previously unidentified activity by GroES should have important implications for understanding the chaperonin mechanism and cellular stress response. Our findings necessitate a revision of the GroEL/ES mechanism. [ABSTRACT FROM AUTHOR]

Purpose: Since 2005, statins have been recommended to patients with ischaemic stroke. The objective of this study was to analyse how statin treatment has been disseminated in different patient groups (age, sex, socioeconomic status and country of birth) in Sweden between 2004 and 2009. Methods: The Swedish Stroke Register (Riks-Stroke) has been linked to the Longitudinal Integration Database for Health Insurance and Labour Market Studies. Approximately 85 % of stroke patients in Sweden are included in Riks-Stroke. Odds ratios for statin prescribing were calculated using a multivariable logistic regression model including age, sex, socioeconomic status and risk factors. Results: During the study period, 108,950 ischaemic stroke patients were discharged alive from hospital. The proportion with statins at discharge increased from 32.9 % in 2004 to 60.1 % in 2009. Patients with secondary school or university education had slightly higher odds [odds ratio (OR) 1.07, 95 % confidence interval (CI) 1.04-1.11 and OR 1.05, 95 % CI 1.01-1.10 respectively] than patients with primary school education. Patients on a high income were prescribed more statins than those on a low income (OR 1.24, 95 % CI 1.19-1.28). Compared with patients born in Sweden, patients born in other countries were prescribed more statins (Nordic countries excepting Sweden: OR 1.07, 95 % CI 1.01-1.14; Europe: OR 1.31, 95 % CI 1.22-1.40; Outside Europe: OR 1.20, 95 % CI 1.08-1.34). Conclusions: Statin prescribing after ischaemic stroke has increased from 2004 to 2009. Our results also show a social stratification in the dissemination of statins, with patients having a higher income and patients with higher education receiving statins more often than those with a lower income and education, and patients born in Sweden receiving statins less often than those born outside of Sweden. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation end-products (RAGE) has been implicated in several pathophysiological processes relevant to Alzheimer’s disease (AD), including transport and synaptotoxicity of AD-associated amyloid β (Aβ) peptides. A recent Chinese study (Li et al. in J Neural Transm 117:97–104, ) suggested an association between the 82S allele of the functional single nucleotide polymorphism (SNP) G82S (rs2070600) in the RAGE-encoding gene AGER and risk of AD. The present study aimed to investigate associations between AGER, AD diagnosis, cognitive scores and cerebrospinal fluid AD biomarkers in a European cohort of 316 neurochemically verified AD cases and 579 controls. Aside from G82S, three additional tag SNPs were analyzed to cover the common genetic variation in AGER. The 82S allele was associated with increased risk of AD ( Pc = 0.04, OR = 2.0, 95% CI 1.2–3.4). There was no genetic interaction between AGER 82S and APOE ε4 in producing increased risk of AD ( P = 0.4), and none of the AGER SNPs showed association with Aβ42, T-tau, P-tau181 or mini-mental state examination scores. The data speak for a weak, but significant effect of AGER on risk of AD. [ABSTRACT FROM AUTHOR]

The cysteinyl leukotriene1 (CysLT1) receptor (CysLT1R) enhances survival and proliferation of intestinal cells via distinct pathways. Here, we have demonstrated that there is significant endogenous production of CysLTs from both non-tumour- and tumour-derived intestinal epithelial cells. Treatment of two non-tumour cell lines, Int 407 and IEC-6, with CysLT1R antagonists led to shrinkage and detachment of cells, confirmed as apoptotic cell death, and a dose-dependent reduction in proliferation. However, in the tumour intestinal cell lines Caco-2, SW480, HCT-116 and HT-29, treatment with CysLT1R antagonists significantly reduced proliferation, but had no effect on apoptosis. A unique characteristic of intestinal cancer cells is the presence of nuclear CysLT1Rs, which are inaccessible to receptor antagonists. In these cells, inhibition of the endogenous production of CysLTs indirectly, by 5-lipoxygenase inhibition, impaired CysLT1R signalling throughout the cell, and resulted in apoptosis of the tumour cells. These data reveal the existence of constitutive CysLT1R signalling that mediates both survival and proliferation in intestinal cells. Importantly, we propose that tumour-derived intestinal cells are resistant to CysLT1R antagonist-induced apoptosis, a phenomena that could be explained by nuclear CysLT1R signalling.Oncogene (2006) 25, 6660–6665. doi:10.1038/sj.onc.1209666; published online 22 May 2006 [ABSTRACT FROM AUTHOR]

A number of commercial and high-purity non-heat-treatable aluminum alloys are investigated in this work. It is found that both magnesium and manganese in solid solution give a nearly linear concentration dependence of the strength at a given strain for commercial alloys. This deviates from high-purity AIMg binary alloys, where a parabolic concentration dependence is found. Mn in solid solution is (band to give a considerably higher strengthening effect per atom than Mg, both in terms of yield stress and initial work hardening rate. This strengthening effect is stronger comparing commercial grades to high-purity alloys. This enhanced strengthening is believed to be a synergy or clustering effect caused by interaction between Mn atoms and trace elements, probably silicon, in solid solution. [ABSTRACT FROM AUTHOR]