PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol

BACKGROUND: A "physiologically based pharmacokinetic" (PBPK) approach uses a realistic model of the animal to describe the pharmacokinetics. Previous PBPKs have been designed for specific solutes, required specification of a large number of parameters and have not been designed for general use. METHODS: This new PBPK program (PKQuest) includes a "Standardhuman" and "Standardrat" data set so that the user input is minimized. It has a simple user interface, graphical output and many new features: 1) An option that uses the measured plasma concentrations to solve for the time course of the gastrointestinal, intramuscular, intraperotineal or skin absorption and systemic availability of a drug – for a general non-linear system. 2) Capillary permeability limitation defined in terms of the permeability-surface area products. 4) Saturable plasma and tissue protein binding. 5) A lung model that includes perfusion-ventilation mismatch. 6) A general optimization routine using either a global (simulated annealing) or local (Powell) minimization applicable to all model parameters. RESULTS: PKQuest was applied to measurements of human propranolol pharmacokinetics and intestinal absorption. A meal has two effects: 1) increases portal blood flow by 50%; and 2) decreases liver metabolism by 20%. There is a significant delay in the oval propranolol absorption in fasting subjects that is absent in fed subjects. The oral absorption of the long acting form of propranolol continues for a period of more than 24 hours. CONCLUSIONS: PKQuest provides a new general purpose, easy to use, freely distributed and physiologically rigorous PBPK software routine

Planck intermediate results: LI. Features in the cosmic microwave background temperature power spectrum and shifts in cosmological parameters

The six parameters of the standard ΛCDM model have best-fit values derived from the Planck temperature power spectrum that are shifted somewhat from the best-fit values derived from WMAP data. These shifts are driven by features in the Planck temperature power spectrum at angular scales that had never before been measured to cosmic-variance level precision. We have investigated these shifts to determine whether they are within the range of expectation and to understand their origin in the data. Taking our parameter set to be the optical depth of the reionized intergalactic medium, the baryon density ω b , the matter density ω m , the angular size of the sound horizon the spectral index of the primordial power spectrum, n s , and A s e -2τ (where A s is the amplitude of the primordial power spectrum), we have examined the change in best-fit values between a WMAP-like large angular-scale data set (with multipole moment 800, or splitting at a different multipole, yields similar results. We examined the 800 power spectrum data and find that the features there that drive these shifts are a set of oscillations across a broad range of angular scales. Although they partly appear similar to the effects of enhanced gravitational lensing, the shifts in ΛCDM parameters that arise in response to these features correspond to model spectrum changes that are predominantly due to non-lensing effects; the only exception is, which, at fixed A s e -2τ , affects the > 800 temperature power spectrum solely through the associated change in A s and the impact of that on the lensing potential power spectrum. We also ask, "what is it about the power spectrum at < 800 that leads to somewhat different best-fit parameters than come from the full range?" We find that if we discard the data at < 30, where there is a roughly 2σ downward fluctuation in power relative to the model that best fits the full range, the < 800 best-fit parameters shift significantly towards the < 2500 best-fit parameters. In contrast, including < 30, this previously noted "low-deficit" drives n s up and impacts parameters correlated with n s , such as ω m and H 0 . As expected, the < 30 data have a much greater impact on the < 800 best fit than on the < 2500 best fit. So although the shifts are not very significant, we find that they can be understood through the combined effects of an oscillatory-like set of high-residuals and the deficit in low-power, excursions consistent with sample variance that happen to map onto changes in cosmological parameters. Finally, we examine agreement between PlanckTT data and two other CMB data sets, namely the Planck lensing reconstruction and the TT power spectrum measured by the South Pole Telescope, again finding a lack of convincing evidence of any significant deviations in parameters, suggesting that current CMB data sets give an internally consistent picture of the ΛCDM model

Planck intermediate results: XLVI. Reduction of large-scale systematic effects in HFI polarization maps and estimation of the reionization optical depth

© 2016 ESO. This paper describes the identification, modelling, and removal of previously unexplained systematic effects in the polarization data of the Planck High Frequency Instrument (HFI) on large angular scales, including new mapmaking and calibration procedures, new and more complete end-to-end simulations, and a set of robust internal consistency checks on the resulting maps. These maps, at 100, 143, 217, and 353 GHz, are early versions of those that will be released in final form later in 2016. The improvements allow us to determine the cosmic reionization optical depth τ using, for the first time, the low-multipole EE data from HFI, reducing significantly the central value and uncertainty, and hence the upper limit. Two different likelihood procedures are used to constrain τ from two estimators of the CMB E-and B-mode angular power spectra at 100 and 143 GHz, after debiasing the spectra from a small remaining systematic contamination. These all give fully consistent results. A further consistency test is performed using cross-correlations derived from the Low Frequency Instrument maps of the Planck 2015 data release and the new HFI data. For this purpose, end-to-end analyses of systematic effects from the two instruments are used to demonstrate the near independence of their dominant systematic error residuals. The tightest result comes from the HFI-based τ posterior distribution using the maximum likelihood power spectrum estimator from EE data only, giving a value 0.055 ± 0.009. In a companion paper these results are discussed in the context of the best-fit PlanckΛCDM cosmological model and recent models of reionization

Planck intermediate results: LVII. Joint Planck LFI and HFI data processing

We present the NPIPE processing pipeline, which produces calibrated frequency maps in temperature and polarization from data from the Planck Low Frequency Instrument (LFI) and High Frequency Instrument (HFI) using high-performance computers. NPIPE represents a natural evolution of previous Planck analysis efforts, and combines some of the most powerful features of the separate LFI and HFI analysis pipelines. For example, following the LFI 2018 processing procedure, NPIPE uses foreground polarization priors during the calibration stage in order to break scanninginduced degeneracies. Similarly, NPIPE employs the HFI 2018 time-domain processing methodology to correct for bandpass mismatch at all frequencies. In addition, NPIPE introduces several improvements, including, but not limited to: inclusion of the 8% of data collected during repointing manoeuvres; smoothing of the LFI reference load data streams; in-flight estimation of detector polarization parameters; and construction of maximally independent detector-set split maps. For component-separation purposes, important improvements include: maps that retain the CMB Solar dipole, allowing for high-precision relative calibration in higher-level analyses; well-defined single-detector maps, allowing for robust CO extraction; and HFI temperature maps between 217 and 857 GHz that are binned into 0.09 pixels (Nside = 4096), ensuring that the full angular information in the data is represented in the maps even at the highest Planck resolutions. The net effect of these improvements is lower levels of noise and systematics in both frequency and component maps at essentially all angular scales, as well as notably improved internal consistency between the various frequency channels. Based on the NPIPE maps, we present the first estimate of the Solar dipole determined through component separation across all nine Planck frequencies. The amplitude is (3366.6 ± 2.7) µK, consistent with, albeit slightly higher than, earlier estimates. From the large-scale polarization data, we derive an updated estimate of the optical depth of reionization of τ = 0.051 ± 0.006, which appears robust with respect to data and sky cuts. There are 600 complete signal, noise and systematics simulations of the full-frequency and detector-set maps. As a Planck first, these simulations include full time-domain processing of the beam-convolved CMB anisotropies. The release of NPIPE maps and simulations is accompanied with a complete suite of raw and processed time-ordered data and the software, scripts, auxiliary data, and parameter files needed to improve further on the analysis and to run matching simulations

Planck 2015 results: XIII. Cosmological parameters

We present results based on full-mission Planck observations of temperature and polarization anisotropies of the CMB. These data are consistent with the six-parameter inflationary LCDM cosmology. From the Planck temperature and lensing data, for this cosmology we find a Hubble constant, H0= (67.8 +/- 0.9) km/s/Mpc, a matter density parameter Omega_m = 0.308 +/- 0.012 and a scalar spectral index with n_s = 0.968 +/- 0.006. (We quote 68% errors on measured parameters and 95% limits on other parameters.) Combined with Planck temperature and lensing data, Planck LFI polarization measurements lead to a reionization optical depth of tau = 0.066 +/- 0.016. Combining Planck with other astrophysical data we find N_ eff = 3.15 +/- 0.23 for the effective number of relativistic degrees of freedom and the sum of neutrino masses is constrained to < 0.23 eV. Spatial curvature is found to be |Omega_K| < 0.005. For LCDM we find a limit on the tensor-to-scalar ratio of r <0.11 consistent with the B-mode constraints from an analysis of BICEP2, Keck Array, and Planck (BKP) data. Adding the BKP data leads to a tighter constraint of r < 0.09. We find no evidence for isocurvature perturbations or cosmic defects. The equation of state of dark energy is constrained to w = -1.006 +/- 0.045. Standard big bang nucleosynthesis predictions for the Planck LCDM cosmology are in excellent agreement with observations. We investigate annihilating dark matter and deviations from standard recombination, finding no evidence for new physics. The Planck results for base LCDM are in agreement with BAO data and with the JLA SNe sample. However the amplitude of the fluctuations is found to be higher than inferred from rich cluster counts and weak gravitational lensing. Apart from these tensions, the base LCDM cosmology provides an excellent description of the Planck CMB observations and many other astrophysical data sets

Planck 2018 results. VII. Isotropy and statistics of the CMB

Analysis of the Planck 2018 data set indicates that the statistical properties of the cosmic microwave background (CMB) temperature anisotropies are in excellent agreement with previous studies using the 2013 and 2015 data releases. In particular, they are consistent with the Gaussian predictions of the $\Lambda$CDM cosmological model, yet also confirm the presence of several so-called "anomalies" on large angular scales. The novelty of the current study, however, lies in being a first attempt at a comprehensive analysis of the statistics of the polarization signal over all angular scales, using either maps of the Stokes parameters, $Q$ and $U$, or the $E$-mode signal derived from these using a new methodology (which we describe in an appendix). Although remarkable progress has been made in reducing the systematic effects that contaminated the 2015 polarization maps on large angular scales, it is still the case that residual systematics (and our ability to simulate them) can limit some tests of non-Gaussianity and isotropy. However, a detailed set of null tests applied to the maps indicates that these issues do not dominate the analysis on intermediate and large angular scales (i.e., $\ell \lesssim 400$). In this regime, no unambiguous detections of cosmological non-Gaussianity, or of anomalies corresponding to those seen in temperature, are claimed. Notably, the stacking of CMB polarization signals centred on the positions of temperature hot and cold spots exhibits excellent agreement with the $\Lambda$CDM cosmological model, and also gives a clear indication of how Planck provides state-of-the-art measurements of CMB temperature and polarization on degree scales

Planck 2018 results. VII. Isotropy and Statistics of the CMB

Analysis of the Planck 2018 data set indicates that the statistical properties of the cosmic microwave background (CMB) temperature anisotropies are in excellent agreement with previous studies using the 2013 and 2015 data releases. In particular, they are consistent with the Gaussian predictions of the $\Lambda$CDM cosmological model, yet also confirm the presence of several so-called "anomalies" on large angular scales. The novelty of the current study, however, lies in being a first attempt at a comprehensive analysis of the statistics of the polarization signal over all angular scales, using either maps of the Stokes parameters, $Q$ and $U$, or the $E$-mode signal derived from these using a new methodology (which we describe in an appendix). Although remarkable progress has been made in reducing the systematic effects that contaminated the 2015 polarization maps on large angular scales, it is still the case that residual systematics (and our ability to simulate them) can limit some tests of non-Gaussianity and isotropy. However, a detailed set of null tests applied to the maps indicates that these issues do not dominate the analysis on intermediate and large angular scales (i.e., $\ell \lesssim 400$). In this regime, no unambiguous detections of cosmological non-Gaussianity, or of anomalies corresponding to those seen in temperature, are claimed. Notably, the stacking of CMB polarization signals centred on the positions of temperature hot and cold spots exhibits excellent agreement with the $\Lambda$CDM cosmological model, and also gives a clear indication of how Planck provides state-of-the-art measurements of CMB temperature and polarization on degree scales

Exploring Cosmic Origins with CORE: Survey requirements and mission design

Future observations of cosmic microwave background (CMB) polarisation havethe potential to answer some of the most fundamental questions of modernphysics and cosmology. In this paper, we list the requirements for a future CMBpolarisation survey addressing these scientific objectives, and discuss thedesign drivers of the CORE space mission proposed to ESA in answer to the "M5"call for a medium-sized mission. The rationale and options, and themethodologies used to assess the mission's performance, are of interest toother future CMB mission design studies. CORE is designed as a near-ultimateCMB polarisation mission which, for optimal complementarity with ground-basedobservations, will perform the observations that are known to be essential toCMB polarisation scienceand cannot be obtained by any other means than adedicated space mission

Overview of the medium and high frequency telescopes of the LiteBIRD space mission

LiteBIRD is a JAXA-led Strategic Large-Class mission designed to search for the existence of the primordial gravitational waves produced during the inflationary phase of the Universe, through the measurements of their imprint onto the polarization of the cosmic microwave background (CMB). These measurements, requiring unprecedented sensitivity, will be performed over the full sky, at large angular scales, and over 15 frequency bands from 34 GHz to 448 GHz. The LiteBIRD instruments consist of three telescopes, namely the Low-, Medium-and High-Frequency Telescope (respectively LFT, MFT and HFT). We present in this paper an overview of the design of the Medium-Frequency Telescope (89{224 GHz) and the High-Frequency Telescope (166{448 GHz), the so-called MHFT, under European responsibility, which are two cryogenic refractive telescopes cooled down to 5 K. They include a continuous rotating half-wave plate as the first optical element, two high-density polyethylene (HDPE) lenses and more than three thousand transition-edge sensor (TES) detectors cooled to 100 mK. We provide an overview of the concept design and the remaining specific challenges that we have to face in order to achieve the scientific goals of LiteBIRD

LiteBIRD satellite: JAXA's new strategic L-class mission for all-sky surveys of cosmic microwave background polarization

LiteBIRD, the Lite (Light) satellite for the study of B-mode polarization and Inflation from cosmic background Radiation Detection, is a space mission for primordial cosmology and fundamental physics. JAXA selected LiteBIRD in May 2019 as a strategic large-class (L-class) mission, with its expected launch in the late 2020s using JAXA's H3 rocket. LiteBIRD plans to map the cosmic microwave background (CMB) polarization over the full sky with unprecedented precision. Its main scientific objective is to carry out a definitive search for the signal from cosmic inflation, either making a discovery or ruling out well-motivated inflationary models. The measurements of LiteBIRD will also provide us with an insight into the quantum nature of gravity and other new physics beyond the standard models of particle physics and cosmology. To this end, LiteBIRD will perform full-sky surveys for three years at the Sun-Earth Lagrangian point L2 for 15 frequency bands between 34 and 448 GHz with three telescopes, to achieve a total sensitivity of 2.16 μK-arcmin with a typical angular resolution of 0.5° at 100 GHz. We provide an overview of the LiteBIRD project, including scientific objectives, mission requirements, top-level system requirements, operation concept, and expected scientific outcomes