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Matthews A.,London School of Hygiene and Tropical Medicine | Herrett E.,London School of Hygiene and Tropical Medicine | Gasparrini A.,London School of Hygiene and Tropical Medicine | Van Staa T.,Health eResearch Centre | | And 4 more authors.
BMJ (Online) | Year: 2016

Objective: To quantify how a period of intense media coverage of controversy over the risk:benefit balance of statins affected their use. Design: Interrupted time series analysis of prospectively collected electronic data from primary care. Setting: Clinical Practice Research Datalink (CPRD) in the United Kingdom. Participants: Patients newly eligible for or currently taking statins for primary and secondary cardiovascular disease prevention in each month in January 2011-March 2015. Main outcome measures: Adjusted odds ratios for starting/stopping taking statins after the media coverage (October 2013-March 2014). Results: There was no evidence that the period of high media coverage was associated with changes in statin initiation among patients with a high recorded risk score for cardiovascular disease (primary prevention) or a recent cardiovascular event (secondary prevention) (odds ratio 0.99 (95% confidence interval 0.87 to 1.13; P=0.92) and 1.04 (0.92 to 1.18; P=0.54), respectively), though there was a decrease in the overall proportion of patients with a recorded risk score. Patients already taking statins were more likely to stop taking them for both primary and secondary prevention after the high media coverage period (1.11 (1.05 to 1.18; P<0.001) and 1.12 (1.04 to 1.21; P=0.003), respectively). Stratified analyses showed that older patients and those with a longer continuous prescription were more likely to stop taking statins after the media coverage. In post hoc analyses, the increased rates of cessation were no longer observed after six months. Conclusions: A period of intense public discussion over the risks: benefit balance of statins, covered widely in the media, was followed by a transient rise in the proportion of people who stopped taking statins. This research highlights the potential for widely covered health stories in the lay media to impact on healthcare related behaviour. © 2016 BMJ Publishing Group Ltd.

Heitland I.,University Utrecht | Heitland I.,Helmholtz Research Institute | Groenink L.,Utrecht Institute of Pharmaceutical science | van Gool J.M.,University Utrecht | And 4 more authors.
Genes, Brain and Behavior | Year: 2016

We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears. Potentiated-conditioned fear responses are dependent on genetic variability in CRHR1 (rs878886) across two large human samples. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Lalmohamed A.,Utrecht Institute of Pharmaceutical science | Lalmohamed A.,University Utrecht | Vestergaard P.,University of Aalborg | Jansen P.A.F.,University Utrecht | And 9 more authors.
Journal of Thrombosis and Haemostasis | Year: 2013

Background: Long-term risk of venous thromboembolism (VTE) following total hip or knee replacement (THR/TKR) compared with controls has not been studied extensively, and the long-term influence of outpatient anticoagulant use on VTE risk remains unknown. The objectives were to evaluate long-term VTE risk following THR/TKR compared with matched controls, and to investigate effect modification by prolonged outpatient vitamin K antagonist use. Methods: A Danish retrospective nationwide cohort study was conducted. All patients undergoing primary THR/TKR (n = 95,227) between 1998 and 2007 were selected, each matched by age, sex and region with three controls (no THR/TKR). Patients were stratified by prolonged outpatient vitamin K antagonist use in the previous 3 months (in a time-dependent manner). All subjects were followed for VTE, and Cox models were used to calculate disease and medication history adjusted hazard ratios (HRs). Results: Within 6 weeks following surgery, a 13-fold increased risk of VTE was found for THR (adj. HR 12.9; 95% CI 11.2-14.7), and a 14-fold elevated risk for TKR (adj. HR 13.6; 95% CI 11.0-16.7), compared with matched controls. The risk remained substantially increased for at least 4 months following THR/TKR. Within this period, prolonged outpatient vitamin K antagonist use reduced the increase in VTE risk by 69% for THR and 54% for TKR. Conclusion: The risk of VTE remains substantially elevated for at least 4 months following THR/TKR; this is well beyond the recommended duration of anticoagulant use. The increase in VTE risk is less pronounced in prolonged outpatient vitamin K antagonist users. © 2013 International Society on Thrombosis and Haemostasis.

Bereszczak J.Z.,Utrecht Institute of Pharmaceutical science | Bereszczak J.Z.,Netherlands Proteomics Center | Watts N.R.,U.S. National Institutes of Health | Wingfield P.T.,U.S. National Institutes of Health | And 3 more authors.
Protein Science | Year: 2014

Hepatitis B virus core-antigen (capsid protein) and e-antigen (an immune regulator) have almost complete sequence identity, yet the dimeric proteins (termed Cp149d and Cp(210)149d, respectively) adopt quite distinct quaternary structures. Here we use hydrogen deuterium exchange-mass spectrometry (HDX-MS) to study their structural properties. We detect many regions that differ substantially in their HDX dynamics. Significantly, whilst all regions in Cp(210)149d exchange by EX2-type kinetics, a number of regions in Cp149d were shown to exhibit a mixture of EX2- and EX1-type kinetics, hinting at conformational heterogeneity in these regions. Comparison of the HDX of the free Cp149d with that in assembled capsids (Cp149c) indicated increased resistance to exchange at the C-terminus where the inter-dimer contacts occur. Furthermore, evidence of mixed exchange kinetics were not observed in Cp149c, implying a reduction in flexibility upon capsid formation. Cp(210)149d undergoes a drastic structural change when the intermolecular disulphide bridge is reduced, adopting a Cp149d-like structure, as evidenced by the detected HDX dynamics being more consistent with Cp149d in many, albeit not all, regions. These results demonstrate the highly dynamic nature of these similar proteins. To probe the effect of these structural differences on the resulting antigenicity, we investigated binding of the antibody fragment (Fab E1) that is known to bind a conformational epitope on the four-helix bundle. Whilst Fab E1 binds to Cp149c and Cp149d, it does not bind non-reduced and reduced Cp(210)149d, despite unhindered access to the epitope. These results imply a remarkable sensitivity of this epitope to its structural context. © 2014 The Protein Society.

Tjin A Tsoi S.L.N.M.,Utrecht Institute of Pharmaceutical science | Tjin A Tsoi S.L.N.M.,Netherlands Center for Post Academic Education in Pharmacy | De Boer A.,University Utrecht | Koster A.S.,Utrecht Institute of Pharmaceutical science
Journal of Continuing Education in the Health Professions | Year: 2016

Introduction: Continuing education (CE) can support health care professionals in maintaining and developing their knowledge and competencies. Although lack of motivation is one of the most important barriers of pharmacists' participation in CE, we know little about the quality or the quantity of motivation. We used the self-determination theory, which describes autonomous motivation (AM) as originating from within an individual and controlled motivation (CM) as originating from external factors, as a framework for this study. Our aim was to obtain insight into the quality and quantity of pharmacists' motivation for CE. Methods: The scores of 425 pharmacists on Academic Motivation Scale were subjected to K-means cluster analysis to generate motivational profiles. Results: We unraveled four motivational profiles: (1) good quality with high AM/low CM, (2) high quantity with high AM/high CM, (3) poor quality with low AM/high CM, and (4) low quantity with low AM/low CM. Female pharmacists, pharmacists working in a hospital pharmacy, pharmacists working for more than 10 years, and pharmacists not in training were highly represented in the good-quality profile. Pharmacists working in a community pharmacy, pharmacists working for less than 10 years, and pharmacists in training were highly represented in the high-quantity profile. Male pharmacists were more or less equally distributed over the four profiles. The highest percentage of pharmacy owners was shown in the low-quantity profile, and the highest percentage of the nonowners was shown in the good-quality profile. Discussion: Pharmacists exhibit different motivational profiles, which are associated with their background characteristics, such as gender, ownership of business, practice setting, and current training. Motivational profiles could be used to tailor CE courses for pharmacists. Copyright © 2016 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.

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