Ethical Issues in the Use of Animal Models for Tissue Engineering:Reflections on Legal Aspects, Moral Theory, Three Rs Strategies, and Harm-Benefit Analysis

Animal experimentation requires a solid and rational moral foundation. Objective and emphatic decision-making and protocol evaluation by researchers and ethics committees remain a difficult and sensitive matter. This article presents three perspectives that facilitate a consideration of the minimally acceptable standard for animal experiments, in particular, in tissue engineering (TE) and regenerative medicine. First, we review the boundaries provided by law and public opinion in America and Europe. Second, we review contemporary moral theory to introduce the Neo-Rawlsian contractarian theory to objectively evaluate the ethics of animal experiments. Third, we introduce the importance of available reduction, replacement, and refinement strategies, which should be accounted for in moral decision-making and protocol evaluation of animal experiments. The three perspectives are integrated into an algorithmic and graphic harm-benefit analysis tool based on the most relevant aspects of animal models in TE. We conclude with a consideration of future avenues to improve animal experiments

Quijote PNG: The information content of the halo power spectrum and bispectrum

We investigate how much can be learnt about four types of primordial non-Gaussianity (PNG) from small-scale measurements of the halo field. Using the QUIJOTE-PNG simulations, we quantify the information content accessible with measurements of the halo power spectrum monopole and quadrupole, the matter power spectrum, the halo-matter cross spectrum and the halo bispectrum monopole. This analysis is the first to include small, non-linear scales, up to $k_\mathrm{max}=0.5 \mathrm{h/Mpc}$, and to explore whether these scales can break degeneracies with cosmological and nuisance parameters making use of thousands of N-body simulations. We perform all the halo measurements in redshift space with a single sample comprised of all halos with mass $>3.2 \times 10^{13}~h^{-1}M_\odot$. For local PNG, measurements of the scale dependent bias effect from the power spectrum using sample variance cancellation provide significantly tighter constraints than measurements of the halo bispectrum. In this case measurements of the small scales add minimal additional constraining power. In contrast, the information on equilateral and orthogonal PNG is primarily accessible through the bispectrum. For these shapes, small scale measurements increase the constraining power of the halo bispectrum by up to $\times4$, though the addition of scales beyond $k\approx 0.3 \mathrm{h/Mpc}$ improves constraints largely through reducing degeneracies between PNG and the other parameters. These degeneracies are even more powerfully mitigated through combining power spectrum and bispectrum measurements. However even with combined measurements and small scale information, equilateral non-Gaussianity remains highly degenerate with $\sigma_8$ and our bias model.Comment: Updated to accepted versio

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Quijote-PNG: Optimizing the summary statistics to measure Primordial non-Gaussianity

International audienceWe apply a suite of different estimators to the Quijote-PNG halo catalogues to find the best approach to constrain Primordial non-Gaussianity (PNG) at non-linear cosmological scales, up to $k_{\rm max} = 0.5 \, h\,{\rm Mpc}^{-1}$. The set of summary statistics considered in our analysis includes the power spectrum, bispectrum, halo mass function, marked power spectrum, and marked modal bispectrum. Marked statistics are used here for the first time in the context of PNG study. We perform a Fisher analysis to estimate their cosmological information content, showing substantial improvements when marked observables are added to the analysis. Starting from these summaries, we train deep neural networks (NN) to perform likelihood-free inference of cosmological and PNG parameters. We assess the performance of different subsets of summary statistics; in the case of $f_\mathrm{NL}^\mathrm{equil}$, we find that a combination of the power spectrum and a suitable marked power spectrum outperforms the combination of power spectrum and bispectrum, the baseline statistics usually employed in PNG analysis. A minimal pipeline to analyse the statistics we identified can be implemented either with our ML algorithm or via more traditional estimators, if these are deemed more reliable

Quijote-PNG: Quasi-maximum likelihood estimation of Primordial Non-Gaussianity in the non-linear dark matter density field

Future Large Scale Structure surveys are expected to improve over current bounds on primordial non-Gaussianity (PNG), with a significant impact on our understanding of early Universe physics. The level of such improvements will however strongly depend on the extent to which late time non-linearities erase the PNG signal on small scales. In this work, we show how much primordial information remains in the bispectrum of the non-linear dark matter density field by implementing a new, simulation-based, methodology for joint estimation of PNG amplitudes ($f_{\rm NL}$) and standard $\Lambda$CDM parameters. The estimator is based on optimally compressed statistics, which, for a given input density field, combine power spectrum and modal bispectrum measurements, and numerically evaluate their covariance and their response to changes in cosmological parameters. We train and validate the estimator using a large suite of N-body simulations (QUIJOTE-PNG), including different types of PNG (local, equilateral, orthogonal). We explicitly test the estimator's unbiasedness, optimality and stability with respect to changes in the total number of input realizations. While the dark matter power spectrum itself contains negligible PNG information, as expected, including it as an ancillary statistic increases the PNG information content extracted from the bispectrum by a factor of order $2$. As a result, we prove the capability of our approach to optimally extract PNG information on non-linear scales beyond the perturbative regime, up to $k_{\rm max} = 0.5~h\,{\rm Mpc}^{-1}$, obtaining marginalized $1$-$\sigma$ bounds of $\Delta f_{\rm NL}^{\rm local} \sim 16$, $\Delta f_{\rm NL}^{\rm equil} \sim 77$ and $\Delta f_{\rm NL}^{\rm ortho} \sim 40$ on a cubic volume of $1~(\mathrm{Gpc}/h)^3$ at $z=1$. At the same time, we discuss the significant information on cosmological parameters contained on these scales

Quijote-PNG: Quasi-maximum likelihood estimation of Primordial Non-Gaussianity in the non-linear dark matter density field

Future Large Scale Structure surveys are expected to improve over current bounds on primordial non-Gaussianity (PNG), with a significant impact on our understanding of early Universe physics. The level of such improvements will however strongly depend on the extent to which late time non-linearities erase the PNG signal on small scales. In this work, we show how much primordial information remains in the bispectrum of the non-linear dark matter density field by implementing a new, simulation-based, methodology for joint estimation of PNG amplitudes ($f_{\rm NL}$) and standard $\Lambda$CDM parameters. The estimator is based on optimally compressed statistics, which, for a given input density field, combine power spectrum and modal bispectrum measurements, and numerically evaluate their covariance and their response to changes in cosmological parameters. We train and validate the estimator using a large suite of N-body simulations (QUIJOTE-PNG), including different types of PNG (local, equilateral, orthogonal). We explicitly test the estimator's unbiasedness, optimality and stability with respect to changes in the total number of input realizations. While the dark matter power spectrum itself contains negligible PNG information, as expected, including it as an ancillary statistic increases the PNG information content extracted from the bispectrum by a factor of order $2$. As a result, we prove the capability of our approach to optimally extract PNG information on non-linear scales beyond the perturbative regime, up to $k_{\rm max} = 0.5~h\,{\rm Mpc}^{-1}$, obtaining marginalized $1$-$\sigma$ bounds of $\Delta f_{\rm NL}^{\rm local} \sim 16$, $\Delta f_{\rm NL}^{\rm equil} \sim 77$ and $\Delta f_{\rm NL}^{\rm ortho} \sim 40$ on a cubic volume of $1~(\mathrm{Gpc}/h)^3$ at $z=1$. At the same time, we discuss the significant information on cosmological parameters contained on these scales.Comment: 22 pages, 12 figure