| 1. |
- Acharya, B. S., et al.
(author)
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Introducing the CTA concept
- 2013
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In: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 43, s. 3-18
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Journal article (other academic/artistic)abstract
- The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project. (C) 2013 Elsevier B.V. All rights reserved.
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| 2. |
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| 3. |
- Province, M. A., et al.
(author)
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CYP2D6 Genotype and Adjuvant Tamoxifen : Meta-Analysis of Heterogeneous Study Populations
- 2014
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In: Clinical Pharmacology and Therapeutics. - New York, USA : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 95:2, s. 216-227
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Journal article (peer-reviewed)abstract
- The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1), CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
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| 5. |
- Caudle, Kelly E, et al.
(author)
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Incorporation of Pharmacogenomics into Routine Clinical Practice : the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process
- 2014
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In: Current drug metabolism. - : Bentham Science Publishers Ltd.. - 1389-2002 .- 1875-5453. ; 15:2, s. 209-217
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Journal article (peer-reviewed)abstract
- The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
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| 6. |
- Heikkilä, HM, et al.
(author)
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Dietary associations with prediabetic states : the DR's EXTRA study (ISRCTN45977199)
- 2012
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In: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 0954-3007 .- 1476-5640. ; 66:7, s. 819-824
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Journal article (peer-reviewed)abstract
- Background/objectives: Impaired fasting plasma glucose (IFG) and impaired glucose tolerance (IGT) predict development of type 2 diabetes (T2D), but display different pathophysiology for T2D. We studied the association of selected food items and nutrients with IFG, IGT and combined IFG and IGT (IFG+IGT), independent of cardiorespiratory fitness (VO(2max)).Subjects/methods: In a population-based sample of 1261 individuals, aged 58-78 years, we identified 126 subjects with IFG, 97 with IGT and 49 with simultaneous IFG and IGT by an oral glucose tolerance test. Dietary intake was assessed by 4-day food records. Cardiorespiratory fitness was assessed by defining maximal oxygen uptake (VO(2max)) from respiratory gas analysis during a maximal symptom-limited exercise stress test on a bicycle ergometer.Results: Increased intake of saturated fat was associated with higher odds for IFG (OR 1.07; 1.01-1.14) after adjustment for age, gender, VO(2max) and energy misreporting variable. Consumption of additional whole-grain bread (50 g/1000 kcal) and intake of dietary fiber (g/1000 kcal) were inversely associated with IGT (OR 0.61; 0.41-0.92, OR 0.91; CI 0.85-0.97, respectively).Conclusion: Dietary fiber and sources of cereal fiber are negatively associated with IGT, and saturated fat intake is positively associated with IFG, but not with IGT. The present data give practical dietary means at the population level for the elimination of prediabetic conditions. European Journal of Clinical Nutrition advance online publication, 14 March 2012; doi:10.1038/ejcn.2012.23.
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| 7. |
- van der Worp, H. Bart, et al.
(author)
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EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke
- 2014
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In: International Journal of Stroke. - : SAGE Publications. - 1747-4949 .- 1747-4930. ; 9:5, s. 642-645
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Journal article (peer-reviewed)abstract
- Rationale Cooling reduced infarct size and improved neurological outcomes in animal studies modeling ischemic stroke, and also improved outcome in randomized clinical trials in patients with hypoxic-ischemic brain injury after cardiac arrest. Cooling awake patients with ischemic stroke has been shown feasible in phase II clinical trials. Primary aim To determine whether systemic cooling to a target body temperature between 34 center dot 0 and 35 center dot 0 degrees C, started within six-hours of symptom onset and maintained for 24h, improves functional outcome at three-months in patients with acute ischemic stroke. Design International, multicenter, phase III, randomized, open-label clinical trial with blinded outcome assessment in 1500 patients aged 18 years or older with acute ischemic stroke and a National Institutes of Health Stroke Scale score of 6 up to and including 18. In patients randomized to hypothermia, cooling to a target body temperature of 34-35 degrees C will be started within six-hours after symptom onset with rapid intravenous infusion of refrigerated normal saline or a surface cooling technique and maintained for 24h with a surface or endovascular technique. Patients randomized to hypothermia will receive pethidine and buspirone to prevent shivering and discomfort. Primary outcome Score on the modified Rankin Scale at 91 days, as analyzed with ordinal logistic regression and expressed as a common odds ratio. Discussion With 750 patients per intervention group, this trial has 90% power to detect 7% absolute improvement at the 5% significance level. The full trial protocol is available at http://www.eurohyp1.eu. ClinicalTrials.gov Identifier: NCT01833312.
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| 8. |
- Woo, Daniel, et al.
(author)
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Meta-Analysis of Genome-Wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:4, s. 511-521
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Journal article (peer-reviewed)abstract
- Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
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| 9. |
- Biffi, Alessandro, et al.
(author)
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APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study
- 2011
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In: Lancet Neurology. - 1474-4465. ; 10:8, s. 702-709
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Journal article (peer-reviewed)abstract
- Background Carriers of APOE epsilon 2 and epsilon 4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. Methods We investigated the association of APOE epsilon 2 and epsilon 4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE epsilon 4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. Findings For patients with lobar ICH, carriers of the APOE epsilon 2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2. 5x10(-5)), in both replication phases (p=0.008 in Europeans and p=0.016 in African-Americans), and in the meta-analysis (p=3.2x10(-8)). In the meta-analysis, each copy of APOE epsilon 2 increased haematoma size by a mean of 5.3 mL (95% CI 4.7-5.9; p=0.004). Carriers of APOE epsilon 2 had increased mortality (odds ratio [OR] 1.50, 95% CI 1.23-1.82; p=2.45x10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1-52, 1.25-1.85; p=1.74x10(-5)) compared with non-carriers after lobar ICH. APOE epsilon 4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1.08,0.86-1.36; p=0.52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Interpretation Vasculopathic changes associated with the APOE epsilon 2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the epsilon 2 variant might allow identification of those at increased risk of mortality and poor functional outcomes.
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| 12. |
- Gorini, C., et al.
(author)
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Non-Abelian gauge fields in the gradient expansion : generalized Boltzmann and Eilenberger equations
- 2010
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In: Physical Review B Condensed Matter. - 0163-1829 .- 1095-3795. ; 82:19
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Journal article (peer-reviewed)abstract
- We present a microscopic derivation of the generalized Boltzmann and Eilenberger equations in the presence of non-Abelian gauges for the case of a nonrelativistic disordered Fermi gas. A unified and symmetric treatment of the charge [U(1)] and spin [SU(2)] degrees of freedom is achieved. Within this framework, just as the U(1) Lorentz force generates the Hall effect, so does its SU(2)counterpart gives rise to the spin Hall effect. Considering elastic and spin-independent disorder we obtain diffusion equations for charge and spin densities and show how the interplay between an in-plane magnetic field and a time-dependent Rashba term generates in-plane charge currents.
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| 13. |
- Heikkila, H. M., et al.
(author)
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Combined low-saturated fat intake and high fitness may counterbalance diabetogenic effects of obesity : the DR's EXTRA Study
- 2013
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In: European Journal of Clinical Nutrition. - : Nature Publishing Group. - 0954-3007 .- 1476-5640. ; 67:9, s. 1000-1002
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Journal article (peer-reviewed)abstract
- We report associations of saturated fat (SF) intake with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), concurrent IFG+IGT and type 2 diabetes (T2DM) at different levels of cardiorespiratory fitness and body mass index (BMI). In a population-based sample (n = 1261, age 58-78 years), oral glucose tolerance, 4-day food intake and maximal oxygen uptake were measured. High intake of SF (>11.4 E%) was associated with elevated risk for IFG (4.36; 1.93-9.88), concurrent IFG+IGT (6.03; 1.25-29.20) and T2DM (4.77; 1.93-11.82) in the category of high BMI (>26.5) and high fitness, whereas there was no significantly elevated risk in individuals reporting low intake of SF. Concurrent high BMI and low fitness were associated with elevated risks. In general, SF intake and fitness did not differentiate the risk of abnormal glucose metabolism among subjects with low BMI. Limited intake of SF may protect from diabetogenic effects of adiposity, but only in individuals with high level of fitness.
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| 14. |
- Macleod, Malcolm R., et al.
(author)
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Hypothermia for Stroke: call to action 2010
- 2010
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In: International Journal of Stroke. - : SAGE Publications. - 1747-4949 .- 1747-4930. ; 5:6, s. 489-492
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Journal article (peer-reviewed)abstract
- The European Hypothermia Stroke Research Workshop was held in January 2010, in response to the alarming prospects of a significant increase of stroke expected in the coming years globally. Considering that a minority of patients (around 10%) are currently eligible for thrombolytic treatment, there is a need for an efficacious, cost-effective novel therapy that can be implemented broadly within European health care systems. Accordingly, the primary objective of the workshop was the definition of a research agenda aiming to assess the therapeutic benefits of hypothermia in patients with acute ischaemic stroke. The meeting was organised by the European Stroke Research Network for Hypothermia(EuroHyp) and attended by the representatives of World Stroke Organisation, European Stroke Organisation, Stroke Alliance for Europe, Society for Cryobiology and other organisations - specifically the European Space Agency, and small-and medium-sized enterprises based in EU member states. The participants adopted the 'Hypothermia for Stroke - Call to Action 2010', a declaration specifying the priorities for hypothermia research in acute ischaemic stroke. The research programme outlined - a clinical study programme designed to identify and validate therapeutic cooling as a novel treatment providing benefit to a large number of stroke patients-contains a well-integrated series of Phase II studies aiming to refine the intervention (depth, duration, and mode of cooling; antishivering strategy; patient selection) and a pivotal Phase III clinical trial. The proposed integrated Phase II and III clinical study programme would test the effectiveness of this optimised intervention, and would allow the development of evidence-based Clinical Practice Guidelines describing the optimal use of therapeutic hypothermia as a treatment strategy for stroke.
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