Subgroup analysis and interpretation for phase 3 confirmatory trials: White paper of the EFSPI/PSI working group on subgroup analysis

Subgroup by treatment interaction assessments are routinely performed when analysing clinical trials and are particularly important for phase 3 trials where the results may affect regulatory labelling. Interpretation of such interactions is particularly difficult, as on one hand the subgroup finding can be due to chance, but equally such analyses are known to have a low chance of detecting differential treatment effects across subgroup levels, so may overlook important differences in therapeutic efficacy. EMA have therefore issued draft guidance on the use of subgroup analyses in this setting. Although this guidance provided clear proposals on the importance of pre‐specification of likely subgroup effects and how to use this when interpreting trial results, it is less clear which analysis methods would be reasonable, and how to interpret apparent subgroup effects in terms of whether further evaluation or action is necessary. A PSI/EFSPI Working Group has therefore been investigating a focused set of analysis approaches to assess treatment effect heterogeneity across subgroups in confirmatory clinical trials that take account of the number of subgroups explored and also investigating the ability of each method to detect such subgroup heterogeneity. This evaluation has shown that the plotting of standardised effects, bias‐adjusted bootstrapping method and SIDES method all perform more favourably than traditional approaches such as investigating all subgroup‐by‐treatment interactions individually or applying a global test of interaction. Therefore, these approaches should be considered to aid interpretation and provide context for observed results from subgroup analyses conducted for phase 3 clinical trials

Energy and time resolution for a LYSO matrix prototype of the Mu2e experiment

We have measured the performances of a LYSO crystal matrix prototype tested with electron and photon beams in the energy range 60$-$450 MeV. This study has been carried out to determine the achievable energy and time resolutions for the calorimeter of the Mu2e experiment.Comment: 2 pages, 3 figures, 13th Pisa Meeting on Advanced Detector

Structured oligo(aniline) nanofilms via ionic self-assembly

Conducting polymers have shown great potential for application in electronic devices. A major challenge in such applications is to control the supramolecular structures these materials form to optimise the functionality. In this work we probe the structure of oligo(aniline) thin films (of sub-μm thickness) drop cast on a silicon substrate using synchrotron surface diffraction. Self-assembly was induced through doping with an acid surfactant, bis(ethyl hexyl) phosphate (BEHP), resulting in the formation of well-ordered lamellae with the d-spacing ranging from 2.15 nm to 2.35 nm. The exact structural characteristics depended both on the oligomer chain length and film thickness, as well as the doping ratio. Complementary UV/Vis spectroscopy measurements confirm that such thin films retain their bulk electronic properties. Our results point to a simple and effective ionic self-assembly approach to prepare thin films with well-defined structures by tailoring parameters such as the oligomer molecular architecture, the nanofilm composition and the interfacial roughness

Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

Performance of the LHCb muon system with cosmic rays

The LHCb Muon system performance is presented using cosmic ray events collected in 2009. These events allowed to test and optimize the detector configuration before the LHC start. The space and time alignment and the measurement of chamber efficiency, time resolution and cluster size are described in detail. The results are in agreement with the expected detector performance.Comment: Submitted to JINST and accepte

The Boom of cohabitation in Colombia and in the Andean Region : social and spatial patterns

In this chapter we use census microdata to document the rise in cohabitation in Colombia and in the Andean countries of Ecuador, Bolivia, Perú and Venezuela over the last four decades. We use multilevel logistic regression models to examine the effect of individual and contextual variables on cohabitation. We show the individual and contextual effects of social stratification, ethnicity and religion on cohabitation. Cohabitation levels follow a negative gradient with education and vary according to ethnic background. The Bolivian, Ecuadorian and Peruvian censuses reveal that the two largest ethnic groups (i.e. the Quechua and Aymara) have, controlling for other characteristics, the lowest incidence of cohabitation. By contrast, Afro-American populations show the highest levels of cohabitation. The joint use of individual- and contextual-level explanatory variables is sufficient to account for the majority of Bolivia's internal diversity regarding cohabitation, but not sufficient to account for the internal diversity identified in Colombia, Peru or Ecuador. Even after controls, residence in the Andes mountain areas continues to be a factor associated with lower levels of cohabitation. This invites further investigations on how the institutionalization of marriage occurred in the Andes

Measurement of {\eta} meson production in {\gamma}{\gamma} interactions and {\Gamma}({\eta}-->{\gamma}{\gamma}) with the KLOE detector

We present a measurement of {\eta} meson production in photon-photon interactions produced by electron-positron beams colliding with \sqrt{s}=1 GeV. The measurement is done with the KLOE detector at the \phi-factory DA{\Phi}NE with an integrated luminosity of 0.24 fb^{-1}. The e^+e^- --> e^+e^-{\eta} cross section is measured without detecting the outgoing electron and positron, selecting the decays {\eta}-->{\pi}^+{\pi}^-{\pi}^0 and {\eta}-->{\pi}^0{\pi}^0{\pi}^0. The most relevant background is due to e^+e^- --> {\eta}{\gamma} when the monochromatic photon escapes detection. The cross section for this process is measured as {\sigma}(e^+e^- -->{\eta}{\gamma}) = (856 \pm 8_{stat} \pm 16_{syst}) pb. The combined result for the e^+e^- -->e^+e^-{\eta} cross section is {\sigma}(e^+e^- -->e^+e^-{\eta}) = (32.72 \pm 1.27_{stat} \pm 0.70_{syst}) pb. From this we derive the partial width {\Gamma}({\eta}-->{\gamma}{\gamma}) = (520 \pm 20_{stat} \pm 13_{syst}) eV. This is in agreement with the world average and is the most precise measurement to date.Comment: Version accepted by JHE

Precision measurement of σ(e+e−→π+π−γ)/σ(e+e−→μ+μ−γ)\sigma(e^+e^-\rightarrow\pi^+\pi^-\gamma)/\sigma(e^+e^-\rightarrow \mu^+\mu^-\gamma) and determination of the π+π−\pi^+\pi^- contribution to the muon anomaly with the KLOE detector

We have measured the ratio $\sigma(e^+e^-\rightarrow\pi^+\pi^-\gamma)/\sigma(e^+e^-\rightarrow \mu^+\mu^-\gamma)$, with the KLOE detector at DA$\Phi$NE for a total integrated luminosity of $\sim$ 240 pb$^{-1}$. From this ratio we obtain the cross section $\sigma(e^+e^-\rightarrow\pi^+\pi^-)$. From the cross section we determine the pion form factor $|F_\pi|^2$ and the two-pion contribution to the muon anomaly $a_\mu$ for $0.592<M_{\pi\pi}<0.975$ GeV, $\Delta^{\pi\pi} a_\mu$= $({\rm 385.1\pm1.1_{stat}\pm2.7_{sys+theo}})\times10^{-10}$. This result confirms the current discrepancy between the Standard Model calculation and the experimental measurement of the muon anomaly.Comment: 18 pages, 8 figures, minor text corrections, one table added, version to appear on Physics Letters

Grain rotation and lattice deformation during perovskite spray coating and annealing probed in situ by GI-WAXS

We report for the first time on grain rotation in CH3NH3PbI3 perovskite films for ∼12% efficient planar solar cells and present a new method for investigating their texture evolution during thermal annealing. Our technique is based on in situ 2D grazing incidence wide-angle X-ray scattering (GI-WAXS) and employs a 10 keV wide-focussed X-ray beam to simultaneously probe a large number of grains. The ability to track the texture dynamics from a statistically relevant number of spots diffracting from single grains during thermal annealing and in grazing incidence geometry can have applications understanding the processing dynamics of a range of new materials