2,918 research outputs found
Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses
No full text<p><b>Background:</b> The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.</p>
<p><b>Methods:</b> The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.</p>
<p><b>Results:</b> Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.</p>
<p><b>Conclusion:</b> With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.</p>
Genome-wide study of gene variants associated with differential cardiovascular event reduction by Pravastatin therapy
No full textStatin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P < 0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8x10(-7)). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins
Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk
No full text<p><b>Objective:</b> The goal of this study was to examine the association of the antiinflammatory interleukin-10 (IL-10) with risk of cardiovascular disease (CVD).</p>
<p><b>Methods and Results:</b> In the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) cohort, we related baseline concentrations of circulating IL-10 to risk of CVD events in a nested case (n=819)-control (n=1618) study of 3.2 years of follow-up. Circulating IL-10 showed few strong associations with classical risk factors but was positively correlated with IL-6 and C-reactive protein. IL-10 was positively associated with risk of CVD events (odds ratio [OR] 1.17, 95% CI 1.05 to 1.31 per unit increase in log IL-10) after adjusting for classical risk factors and C-reactive protein. Furthermore, IL-10 was associated more strongly with CVD risk among those with no previous history of CVD (OR 1.42, 95% CI 1.18 to 1.70), compared with those with previous CVD (OR 1.04, 95% CI 0.90 to 1.19; P=0.018). Overall, IL-10 showed a modest ability to add discrimination to classical risk factors (C-statistic +0.005, P=0.002).</p>
<p><b>Conclusion:</b> Baseline circulating levels of the antiinflammatory IL-10 are positively associated with risk of CVD among the elderly without prior CVD events, although the association is less evident in those with a history of CVD. Additional epidemiological and mechanistic studies investigating the role of IL-10 in CVD are warranted.</p>
Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importnace of Lp(a)
No full textWe carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 x 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 x 10(-16) and rs4420638; P = 1.01 x 10(-11)) that are proxies for the epsilon 2 and epsilon 4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response.jlr Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).-Deshmukh, H. A., H. M. Colhoun, T. Johnson, P. M. McKeigue, D. J. Betteridge, P. N. Durrington, J. H. Fuller, S. Livingstone, V. Charlton-Menys, A. Neil, N. Poulter, P. Sever, D. C. Shields, A. V. Stanton, A. Chatterjee, C. Hyde, R. A. Calle, D. A. DeMicco, S. Trompet, I. Postmus, I. Ford, J. W. Jukema, M. Caulfield, and G. A. Hitman on behalf of the CARDS, ASCOT, and PROSPER investigators. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). J. Lipid Res. 2012. 53: 1000-1011
Heart 'omics' in AGEing (HOMAGE): design, research objectives and characteristics of the common database.
No full textHeart failure is common in older people and its prevalence is increasing. The Heart 'omics' in AGEing (HOMAGE) project aims to provide a biomarker approach that will improve the early diagnosis of heart failure. A large clinical database, based on (1) prospective population studies or (2) cross-sectional, prospective studies or randomized controlled trials (RCTs) of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising 'omics'-based biomarkers to identify the risk of developing heart failure and/or comorbidities. Population studies, patient cohorts and RCTs are eligible for inclusion in the common database, if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors. Currently, the HOMAGE database includes 43,065 subjects, from 20 studies in eight European countries, including healthy subjects from three population studies in France, Belgium and Italy (n = 7,124), patients with heart failure (n = 4,312) from four cohorts in the UK, Spain and Switzerland and patients at high risk for cardiovascular disease (n = 31,629) in 13 cohorts. It is anticipated that more partners will join the consortium and enlarge the pooled data. This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure
Discourse on formation of investigators’ competencies
No full textOne of the most important aims of law enforcement agencies is crime investigation and
prevention. Consequently, one of the main activities of the law enforcement agencies, especially in the
pre-trial investigation sphere, is to optimise the organisation of the pre-trial investigation in order to
save the experienced skilled and competent specialists. The author of this research offers a new
approach and analyses the qualification and competence of the pre-trial investigation subjects not only
in terms of personnel management, but all elements of the model of pre-trial investigation to make
pre-trial investigation organisation more effective. It should be noted that the content of an
investigators‘ qualification or levels of competence are still not determined or strictly regulated and
this is the reason for many discussions in this area. These discussions surround what qualification and level of competence the investigators should have in pre-trial investigation, what general and special
competencies they should acquire and how the content of the competencies should be determined. In the present article the author analyses the investigators‘ qualification and competence as a
presumption that it is an essential aspect of an effective pre-trial investigation. Analysing this question
the author compares other subjects such as the regulation of qualifications and levels of competence of
the prosecutors and pre-trial investigation judges. The author also identifies the problem of how to
define an investigators qualification and level of competence making recommendations to create a
Description of Investigators Competencies. Qualification requirements should be determined in this
legal act and general, occupational and special competencies should be identified with the content also
being determined within this framework. Formation of the Description of Investigators‘ Competencies
should determine not only the content of the investigators‘ required level of competence but also this
process should be consistent with the assessment and career development of investigators‘ including
the process of gaining the investigators‘ qualification. The aim of this research is to identify the problems associated with defining an investigators‘
qualification and levels of competence and to propose recommendations on how this could be
achieved. The subject of this research is limited to only looking at investigators‘ qualification and
level of competence. The author is using a qualitative method for this research based upon the contents of documents.
The author will analysis eight legal acts related to the qualification and competence of pre-trial
investigation and fifty different investigators‘ job descriptions.Straipsnyje nagrinėjama ikiteisminio tyrimo pareigūnų (tyrėjų) kvalifikacija ir kompetencija kaip viena iš veiksmingo ikiteisminio tyrimo organizavimo prielaidų. Analizuojant tyrėjų kvalifikacijos ir kompetencijos turinį ir jo reglamentavimą, lyginama kitų ikiteisminio tyrimo subjektų – prokurorų ir ikiteisminio tyrimo teisėjų – kvalifikacijos ir kompetencijos turinio reglamentavimo ypatumai, identifikuojamos tyrėjų kvalifikacijos ir kompetencijos apibrėžties problemos ir pateikiami sprendimo būdai – siūlomas ikiteisminio tyrimo pareigūnų (tyrėjų) kompetencijų aprašas, kuriame būtų tiksliai nustatyti tyrėjų kvalifikaciniai reikalavimai, identifikuotos bendrosios, profesinės ir specialiosios kompetencijos ir apibrėžtas šių kompetencijų turinys. Ikiteisminio tyrimo pareigūnų kompetencijų aprašo suformavimas sudarytų galimybę ne tik aiškiai apibrėžti tyrėjo kompetencijos turinį, bet ir šį procesą nuosekliai susieti su tyrėjo veiklos vertinimu, karjera ir kvalifikacijos tobulinimu. Straipsnį sudaro įvadas ir dvi dalys. Pirmoje dalyje nagrinėjama tyrėjo kvalifikacijos apibrėžties problematika, gretinama ikiteisminio tyrimo pareigūno, prokuroro ir teisėjo kvalifikacijos apibrėžtys. Šioje dalyje siūloma tiksliai nustatyti ir apibrėžti tyrėjo kvalifikacinius reikalavimus. Antrojoje dalyje analizuojama tyrėjo kompetencijos turinys. Nagrinėjant prokurorų, teisėjų kompetencijos turinį ir jo reglamentavimo ypatumus, siūloma sudaryti tyrėjo kompetencijų aprašą, kuriame būtų tiksliai apibrėžtas tyrėjo kompetencijos turinys
Sepsis-driven temporal variability in cytokine secretion and heart rate is potentiated by withdrawing vagal innervation: Evidence of higher order neuroimmunological communication via the cholinergic anti-inflammatory pathway in the ovine fetus near term
No full textFetal brain-gut communication is disrupted during sepsis and associated with a higher degree of intestinal inflammation: Implications for non-evasive monitoring
No full textInternet technologies relevant to private investigators’ working practices
No full textMuch has been written and discussed especially in the various US media and in legislative organs, about how the Internet is used illegally (hacking, stalking for instance), but hardly if any research has been done as to how the investigative industry employs the new medium to its benefit. The author described in this thesis how private investigators (PIs) execute their profession these days using the facilities the Internet avail them in contrast to the time before the dawn of the Internet. This contrast is also investigated in an international context, an important part of the thesis, drawn from the author's 32 years of international business experience and that of PIs worldwide. The availability of the various online facilities in different countries are compared. To better understand the new medium, and its facilities a short outline of the Internet’s history, it’s set up in general and for the use of PIs in particular is supplied. PIs also face limitations in their daily work, limitations originating from online, legal, educational, financial and international causes. The new medium not only helps PIs in their investigative, but also in their office work. Finally PIs' wishes for new tools to facilitate their daily investigative work and their outlook as to where the new medium will head are also discussed
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