TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Use of an Atrial Lead with Very Short Tip-To-Ring Spacing Avoids Oversensing of Far-Field R-Wave

The AVOID-FFS (Avoidance of Far-Field R-wave Sensing) study aimed to investigate whether an atrial lead with a very short tip-to-ring spacing without optimization of pacemaker settings shows equally low incidence of far-field R-wave sensing (FFS) when compared to a conventional atrial lead in combination with optimization of the programming.Patients receiving a dual chamber pacemaker were randomly assigned to receive an atrial lead with a tip-to-ring spacing of 1.1 mm or a lead with a conventional tip-to-ring spacing of 10 mm. Postventricular atrial blanking (PVAB) was programmed to the shortest possible value of 60 ms in the study group, and to an individually determined optimized value in the control group. Atrial sensing threshold was programmed to 0.3 mV in both groups. False positive mode switch caused by FFS was evaluated at one and three months post implantation.A total of 204 patients (121 male; age 73±10 years) were included in the study. False positive mode switch caused by FFS was detected in one (1%) patient of the study group and two (2%) patients of the control group (p = 0.62).The use of an atrial electrode with a very short tip-to-ring spacing avoids inappropriate mode switch caused by FFS without the need for individual PVAB optimization.ClinicalTrials.gov NCT00512915

An enterprise engineering approach for the alignment of business and information technology strategy

Information systems and information technology (IS/IT, hereafter just IT) strategies usually depend on a business strategy. The alignment of both strategies improves their strategic plans. From an external perspective, business and IT alignment is the extent to which the IT strategy enables and drives the business strategy. This article reviews strategic alignment between business and IT, and proposes the use of enterprise engineering (EE) to achieve this alignment. The EE approach facilitates the definition of a formal dialog in the alignment design. In relation to this, new building blocks and life-cycle phases have been defined for their use in an enterprise architecture context. This proposal has been adopted in a critical process of a ceramic tile company for the purpose of aligning a strategic business plan and IT strategy, which are essential to support this process. © 2011 Taylor & Francis.Cuenca, L.; Boza, A.; Ortiz, A. (2011). 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Standards on enterprise integration and engineering—state of the art. International Journal of Computer Integrated Manufacturing, 17(3), 235-253. doi:10.1080/09511920310001607087Chen, D., Doumeingts, G., & Vernadat, F. (2008). Architectures for enterprise integration and interoperability: Past, present and future. Computers in Industry, 59(7), 647-659. doi:10.1016/j.compind.2007.12.016Chen, H.-M., Kazman, R., & Garg, A. (2005). BITAM: An engineering-principled method for managing misalignments between business and IT architectures. Science of Computer Programming, 57(1), 5-26. doi:10.1016/j.scico.2004.10.002Cuenca, L., Ortiz, A., & Vernadat, F. (2006). From UML or DFD models to CIMOSA partial models and enterprise components. International Journal of Computer Integrated Manufacturing, 19(3), 248-263. doi:10.1080/03081070500065841Davis, G. B. (2000). Information Systems Conceptual Foundations: Looking Backward and Forward. IFIP Advances in Information and Communication Technology, 61-82. doi:10.1007/978-0-387-35505-4_5Gindy, N., Morcos, M., Cerit, B., & Hodgson, A. (2008). Strategic technology alignment roadmapping STAR® aligning R&D investments with business needs. International Journal of Computer Integrated Manufacturing, 21(8), 957-970. doi:10.1080/09511920801927148Goethals, F. G., Lemahieu, W., Snoeck, M., & Vandenbulcke, J. A. (2007). The data building blocks of the enterprise architect. Future Generation Computer Systems, 23(2), 269-274. doi:10.1016/j.future.2006.05.004Greefhorst, D., Koning, H., & Vliet, H. van. (2006). The many faces of architectural descriptions. Information Systems Frontiers, 8(2), 103-113. doi:10.1007/s10796-006-7975-xGregor, S., Hart, D., & Martin, N. (2007). Enterprise architectures: enablers of business strategy and IS/IT alignment in government. Information Technology & People, 20(2), 96-120. doi:10.1108/09593840710758031Hartono, E., Lederer, A. L., Sethi, V., & Zhuang, Y. (2003). Key predictors of the implementation of strategic information systems plans. ACM SIGMIS Database, 34(3), 41-53. doi:10.1145/937742.937747Henderson, J. C., & Venkatraman, H. (1993). Strategic alignment: Leveraging information technology for transforming organizations. IBM Systems Journal, 32(1), 472-484. doi:10.1147/sj.382.0472Hirschheim, R., & Sabherwal, R. (2001). Detours in the Path toward Strategic Information Systems Alignment. California Management Review, 44(1), 87-108. doi:10.2307/41166112Hoogervorst, J. A. P. (2009). Enterprise Governance and Enterprise Engineering. doi:10.1007/978-3-540-92671-9Johnson, A. M., & Lederer, A. L. (2010). CEO/CIO mutual understanding, strategic alignment, and the contribution of IS to the organization. Information & Management, 47(3), 138-149. doi:10.1016/j.im.2010.01.002JONKERS, H., LANKHORST, M., VAN BUUREN, R., HOPPENBROUWERS, S., BONSANGUE, M., & VAN DER TORRE, L. (2004). 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Review: Information Technology and Organizational Performance: An Integrative Model of IT Business Value. MIS Quarterly, 28(2), 283. doi:10.2307/25148636Newkirk, H. E., & Lederer, A. L. (2006). Incremental and Comprehensive Strategic Information Systems Planning in an Uncertain Environment. IEEE Transactions on Engineering Management, 53(3), 380-394. doi:10.1109/tem.2006.877446Noran, O. (2003). An analysis of the Zachman framework for enterprise architecture from the GERAM perspective. Annual Reviews in Control, 27(2), 163-183. doi:10.1016/j.arcontrol.2003.09.002Noran, O. (2005). A systematic evaluation of the C4ISR AF using ISO15704 Annex A (GERAM). Computers in Industry, 56(5), 407-427. doi:10.1016/j.compind.2004.12.005Ortiz, A., Lario, F., & Ros, L. (1999). Enterprise Integration—Business Processes Integrated Management: a proposal for a methodology to develop Enterprise Integration Programs. 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Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007

Stability and change in political attitudes: Observed, recalled, and “explained”

Using data from a panel survey of members of two generations, this study explores observed change in policy opinions across a 9-year span and respondents' recollections and explanations of their self-perceived attitude shifts. In general, remembrances corresponded poorly to opinions as originally expressed, with respondents perceiving that they were more attitudinally stable than was actually observed. When attempting to reconstruct their past political attitudes, individuals appeared to rely on simple rules of thumb such as one might employ to account for another's behavior. Finally, respondents readily supplied “explanations” for their self-perceived attitude history, even when those perceptions directly contradicted observed opinion change. It is argued that these results are not artifacts of survey measurement problems. Instead, they indicate that policy attitudes generally do not have strong cognitive representations, are eminently changeable, and once they are changed, an individual's cognitive autobiography is revised so as to render the changes invisible.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45497/1/11109_2004_Article_BF00987591.pd