Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

<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&gt

The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

Abstract Background. Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to histology in two large, phase III NSCLC trials. Methods. One study tested pemetrexed versus docetaxel in previously treated patients (n = 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (n = 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions (THIs) for overall survival (OS) and progression-free survival (PFS). For each histologic subgroup, the Kaplan–Meier method was used to estimate unadjusted within-arm medians, and Cox models were used to estimate covariate-adjusted between-arm hazard ratios (HRs). Results. In both studies, treatment arms were well balanced for histology. THIs were statistically significant (p < .005) for both OS and PFS. Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84, respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23, respectively). Whereas the efficacy of pemetrexed regimens differed according to histology, it did not differ for docetaxel or for cisplatin plus gemcitabine. Pemetrexed was well tolerated across histologic groups. Conclusions. The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology. These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma, but, because of efficacy and safety advantages, pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC

Effect of pulsed delivery and bouillon base on saltiness and bitterness perceptions of salt delivery profiles partially substituted with KCl

Reducing salt levels in processed food is an important target for a growing numbers of food manufacturers. The effects of pulsed delivery (Dynataste) and bouillon base on saltiness and bitterness perception of partially substituted solutions (KCl) were investigated. Pulsed delivery did not enhance salt perception and resulted in greater Overall Bitterness Scores for the same level of substitution with KCl. The presence of the bouillon base masked to a certain extent the loss of saltiness induced by the substitution and resulted in lower Overall Bitterness Scores of the substituted profiles

Protostellar Outflow Evolution in Turbulent Environments

The link between turbulence in star formatting environments and protostellar jets remains controversial. To explore issues of turbulence and fossil cavities driven by young stellar outflows we present a series of numerical simulations tracking the evolution of transient protostellar jets driven into a turbulent medium. Our simulations show both the effect of turbulence on outflow structures and, conversely, the effect of outflows on the ambient turbulence. We demonstrate how turbulence will lead to strong modifications in jet morphology. More importantly, we demonstrate that individual transient outflows have the capacity to re-energize decaying turbulence. Our simulations support a scenario in which the directed energy/momentum associated with cavities is randomized as the cavities are disrupted by dynamical instabilities seeded by the ambient turbulence. Consideration of the energy power spectra of the simulations reveals that the disruption of the cavities powers an energy cascade consistent with Burgers'-type turbulence and produces a driving scale-length associated with the cavity propagation length. We conclude that fossil cavities interacting either with a turbulent medium or with other cavities have the capacity to sustain or create turbulent flows in star forming environments. In the last section we contrast our work and its conclusions with previous studies which claim that jets can not be the source of turbulence.Comment: 24 pages, submitted to the Astrophysical Journa

An Improved Upper Bound for the Ring Loading Problem

The Ring Loading Problem emerged in the 1990s to model an important special case of telecommunication networks (SONET rings) which gained attention from practitioners and theorists alike. Given an undirected cycle on $n$ nodes together with non-negative demands between any pair of nodes, the Ring Loading Problem asks for an unsplittable routing of the demands such that the maximum cumulated demand on any edge is minimized. Let $L$ be the value of such a solution. In the relaxed version of the problem, each demand can be split into two parts where the first part is routed clockwise while the second part is routed counter-clockwise. Denote with $L^*$ the maximum load of a minimum split routing solution. In a landmark paper, Schrijver, Seymour and Winkler [SSW98] showed that $L \leq L^* + 1.5D$, where $D$ is the maximum demand value. They also found (implicitly) an instance of the Ring Loading Problem with $L = L^* + 1.01D$. Recently, Skutella [Sku16] improved these bounds by showing that $L \leq L^* + \frac{19}{14}D$, and there exists an instance with $L = L^* + 1.1D$. We contribute to this line of research by showing that $L \leq L^* + 1.3D$. We also take a first step towards lower and upper bounds for small instances

Sensory Measurements: Coordination and Standardization

Do sensory measurements deserve the label of “measurement”? We argue that they do. They fit with an epistemological view of measurement held in current philosophy of science, and they face the same kinds of epistemological challenges as physical measurements do: the problem of coordination and the problem of standardization. These problems are addressed through the process of “epistemic iteration,” for all measurements. We also argue for distinguishing the problem of standardization from the problem of coordination. To exemplify our claims, we draw on olfactory performance tests, especially studies linking olfactory decline to neurodegenerative disorders

Belowground DNA-based techniques: untangling the network of plant root interactions

Contains fulltext : 91591.pdf (publisher's version ) (Closed access)7 p

Improved Land Management in the Lake Victoria Basin: Annual Technical Report, July 2000 to June 2001

ICRAF and the Kenyan Ministry of Agriculture and Rural Development (MOARD) are implementing a project on “Improved Land Management in the Lake Victoria Basin.” The project began in 1999 – 2000 with a one-year startup year of activities under the Sida-sponsored National Soil and Water Conservation Programme (NSWCP). The collaborative project of ICRAF and MOARD has now been continued for another three years under the National Agriculture and Livestock Extension Programme (NALEP). This paper summarizes achievements and findings for the project for the year 2000 / 2001. The Swedish International Development Agency (SIDA) supports “Improved Land Management in the Lake Victoria Basin” through NALEP. Additional financial support for the activities reported herein was also provided by the Rockefeller Foundation, ICRAF core funds, Danida, the University of Florida and the USAID. Research conducted during 2000 / 2001 addressed a range of issues across a large tract of Western Kenya. A coarse resolution assessment of soil erosion risk conducted for the entire Lake Victoria Basin identified the Nzoia / Yala and Kagera river basins as those with the greatest percentage of land at risk. Biophysical research on land management problem domains has quantified the widespread spatial extent of soil physical and chemical degradation in the Nyando river basin and illustrated four contrasting biophysical problem domains within the basin. District-level data on population density, poverty and agricultural production available from secondary sources have been complemented with baseline household and community survey data collected in 9 villages around the Nyando river basin. The overall picture that is emerging is that while much of the Nyando river basin has experienced some physical and chemical land degradation, there are pockets of severe poverty, severe environmental degradation and extremely low agricultural production. Different approaches to extension, investment and policy may be needed to address poverty – environment – agricultural problems in different parts of the river basin. Reversing trends in environmental deterioration will require interventions on farmers fields and in the many areas between farms that publicly-used, although usually privately-owned. Farmers have demonstrated their willingness to adopt recommended conservation practices on their individual family fields, but the intensity of adoption depends upon the potential returns to investments, their cultural grouping, and the approach that extension providers take to the provision of information and mobilization of community participation. Adoption of improved practices and investments on publicly-used areas between farms requires the mobilization of collective action among small, medium and large groups. Collective action in the Nyando River basin is most likely to be effective where it harnesses local institutional arrangements (e.g. sub-clan affiliations among the Luo) and advances common interests in the provision of high quality water and the generation of additional cash income. Among other opportunities, there appears to be good prospects for market-oriented agroforestry for production of fruit, fuelwood and timber. Changes in local and national policies would help to ensure good returns for smallholder farmers. This report begins with a presentation of a number of major findings, implications of those findings for extension and investment and implications for policy. A summary of progress by activity is then presented, followed by lists of personnel involved, presentations and publications. An annex presents detailed accomplishments by activity