The use of the multivariate Principal Response Curve (PRC) for community analysis: a case study on the effects of carbendazim on enchytraeids in Terrestrial Model Ecosystems (TME).

The effects of the fungicide carbendazim (formulation Derosal®) on enchytraeids were determined in Terrestrial Model Ecosystem (TME) tests. TMEs consisted of intact soil columns (diameter 17.5 cm; length 40 cm) taken from three grassland sites (Amsterdam (The Netherlands), Bangor (Wales, England) and Flörsheim (Germany)) or an arable site (Coimbra (Portugal)). Results for each TME site were evaluated using the multivariate Principal Response Curve (PRC) method. The resulting No-Observable Effect Concentrations (NOECs) for the community were compared with the NOECs generated by univariate statistical methods. Furthermore, the E

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Funding: Innovative Medicines Initiative and the Wellcome Trus

Measurement of the tau lepton lifetime with the three-dimensional impact parameter method.

A new method is presented for the measurement of the mean $\tau$ lepton lifetime using events in which $\tau$'s are pair-produced and both $\tau$'s decay to hadrons and $\nu_\tau$. Based on the correlation between the two $\tau$'s produced at a symmetric $e^+ e^-$ collider, the 3DIP method relies on the three-dimensional information from a double-sided vertex detector and on kinematic constraints for the precise measurement of the $\tau$ decay angles. Using the data collected from 1992 to 1994 with the ALEPH detector at LEP, a $\tau$ lifetime of $288.0 \pm 3.1 \pm 1.3$\fs is obtained from the sample in which both $\tau$'s decay to one charged track, and $292.8 \pm 5.6 \pm 3.0$\fs from the sample in which one $\tau$ decays to one prong and the other to three prongs. The results show small statistical correlations with those derived from other methods. When combined with the previously published ALEPH measurements, the resulting $\tau$ lifetime is $291.2 \pm 2.0 \pm 1.2$\fs

Measurement of the tau lepton lifetime with the three-dimensional impact parameter method.

A new method is presented for the measurement of the mean $\tau$ lepton lifetime using events in which $\tau$'s are pair-produced and both $\tau$'s decay to hadrons and $\nu_\tau$. Based on the correlation between the two $\tau$'s produced at a symmetric $e^+ e^-$ collider, the 3DIP method relies on the three-dimensional information from a double-sided vertex detector and on kinematic constraints for the precise measurement of the $\tau$ decay angles. Using the data collected from 1992 to 1994 with the ALEPH detector at LEP, a $\tau$ lifetime of $288.0 \pm 3.1 \pm 1.3$\fs is obtained from the sample in which both $\tau$'s decay to one charged track, and $292.8 \pm 5.6 \pm 3.0$\fs from the sample in which one $\tau$ decays to one prong and the other to three prongs. The results show small statistical correlations with those derived from other methods. When combined with the previously published ALEPH measurements, the resulting $\tau$ lifetime is $291.2 \pm 2.0 \pm 1.2$\fs

Measurement of the tau lepton lifetime with the three-dimensional impact parameter method.

A new method is presented for the measurement of the mean $\tau$ lepton lifetime using events in which $\tau$'s are pair-produced and both $\tau$'s decay to hadrons and $\nu_\tau$. Based on the correlation between the two $\tau$'s produced at a symmetric $e^+ e^-$ collider, the 3DIP method relies on the three-dimensional information from a double-sided vertex detector and on kinematic constraints for the precise measurement of the $\tau$ decay angles. Using the data collected from 1992 to 1994 with the ALEPH detector at LEP, a $\tau$ lifetime of $288.0 \pm 3.1 \pm 1.3$\fs is obtained from the sample in which both $\tau$'s decay to one charged track, and $292.8 \pm 5.6 \pm 3.0$\fs from the sample in which one $\tau$ decays to one prong and the other to three prongs. The results show small statistical correlations with those derived from other methods. When combined with the previously published ALEPH measurements, the resulting $\tau$ lifetime is $291.2 \pm 2.0 \pm 1.2$\fs

Measurement of the tau lepton lifetime with the three-dimensional impact parameter method.

A new method is presented for the measurement of the mean $\tau$ lepton lifetime using events in which $\tau$'s are pair-produced and both $\tau$'s decay to hadrons and $\nu_\tau$. Based on the correlation between the two $\tau$'s produced at a symmetric $e^+ e^-$ collider, the 3DIP method relies on the three-dimensional information from a double-sided vertex detector and on kinematic constraints for the precise measurement of the $\tau$ decay angles. Using the data collected from 1992 to 1994 with the ALEPH detector at LEP, a $\tau$ lifetime of $288.0 \pm 3.1 \pm 1.3$\fs is obtained from the sample in which both $\tau$'s decay to one charged track, and $292.8 \pm 5.6 \pm 3.0$\fs from the sample in which one $\tau$ decays to one prong and the other to three prongs. The results show small statistical correlations with those derived from other methods. When combined with the previously published ALEPH measurements, the resulting $\tau$ lifetime is $291.2 \pm 2.0 \pm 1.2$\fs

Measurement of the tau lepton lifetime with the three-dimensional impact parameter method.

A new method is presented for the measurement of the mean $\tau$ lepton lifetime using events in which $\tau$'s are pair-produced and both $\tau$'s decay to hadrons and $\nu_\tau$. Based on the correlation between the two $\tau$'s produced at a symmetric $e^+ e^-$ collider, the 3DIP method relies on the three-dimensional information from a double-sided vertex detector and on kinematic constraints for the precise measurement of the $\tau$ decay angles. Using the data collected from 1992 to 1994 with the ALEPH detector at LEP, a $\tau$ lifetime of $288.0 \pm 3.1 \pm 1.3$\fs is obtained from the sample in which both $\tau$'s decay to one charged track, and $292.8 \pm 5.6 \pm 3.0$\fs from the sample in which one $\tau$ decays to one prong and the other to three prongs. The results show small statistical correlations with those derived from other methods. When combined with the previously published ALEPH measurements, the resulting $\tau$ lifetime is $291.2 \pm 2.0 \pm 1.2$\fs