Predictive factors of clinical assays on hydroxychloroquine for COVID-19 mortality during the first year of the pandemic: A meta-synthesis

Background: The COVID-19 pandemic led to a violent debate about the efficacy of a repurposed drug hydroxychloroquine (HCQ) and a new broad-spectrum antiviral (remdesivir) and about randomized controlled trials (RCTs) and observational studies. To understand conflicting results in the literature, we performed a metasynthesis to determine whether intrinsic qualitative criteria within studies may predict apparent efficacy or ineffectiveness of HCQ and remdesivir. Methodology: Predictive criteria were identified through critical review of studies assessing HCQ and remdesivir for COVID-19 mortality from March to November 2020. Multiple correspondence analysis, comparative metaanalysis, and predictive value were used to explore and identify criteria associated with study outcomes. Results: Among the 61 included studies, potential conflict of interest, detailed therapeutic protocol, toxic treatment (overdose or use in contraindicated patients), known centers and doctors, and private data computing company were the most predictive criteria of the direction of effect of the studies. All 18 observational studies evaluating HCQ and reporting detailed therapeutic protocol without conflict of interest were Pro. Potential conflict of interest was a perfect predictor for remdesivir efficacy. RCTs were associated with HCQ inefficacy and potential conflict of interest. The most predictive criteria were validated and allowed perfect classification of 10 additional studies.Conclusion: In therapeutic trials on COVID-19, the major biases predicting the conclusions are not methodology nor data analysis, but conflict of interest and absence of medical expertise. The thorough search for declared or undeclared and direct or indirect conflict of interest, and medical expertise should be included in the quality criteria for the evaluation of future therapeutic studies in COVID-19 and beyond. A new checklist evaluating not only methodology but also conflict of interest and medical expertise is proposed

Double di ffential fragmentation cross sections measurements of 95 MeV/u 12C on thin targets for hadrontherapy

During therapeutic treatment with heavy ions like carbon, the beam undergoes nuclear fragmentation and secondary light charged particles, in particular protons and alpha particles, are produced. To estimate the dose deposited into the tumors and the surrounding healthy tissues, an accurate prediction on the fluences of these secondary fragments is necessary. Nowadays, a very limited set of double di ffential carbon fragmentation cross sections are being measured in the energy range used in hadrontherapy (40 to 400 MeV/u). Therefore, new measurements are performed to determine the double di ffential cross section of carbon on di erent thin targets. This work describes the experimental results of an experiment performed on May 2011 at GANIL. The double di ffential cross sections and the angular distributions of secondary fragments produced in the 12C fragmentation at 95 MeV/u on thin targets (C, CH2, Al, Al2O3, Ti and PMMA) have been measured. The experimental setup will be precisely described, the systematic error study will be explained and all the experimental data will be presented.Comment: Submitted to PR

In vivo imaging of pyrrole-imidazole polyamides with positron emission tomography

The biodistribution profiles in mice of two pyrrole-imidazole polyamides were determined by PET. Pyrrole-imidazole polyamides are a class of small molecules that can be programmed to bind a broad repertoire of DNA sequences, disrupt transcription factor-DNA interfaces, and modulate gene expression pathways in cell culture experiments. The 18F-radiolabeled polyamides were prepared by oxime ligation between 4-[18F]-fluorobenzaldehyde and a hydroxylamine moiety at the polyamide C terminus. Small animal PET imaging of radiolabeled polyamides administered to mice revealed distinct differences in the biodistribution of a 5-ring β-linked polyamide versus an 8-ring hairpin, which exhibited better overall bioavailability. In vivo imaging of pyrrole-imidazole polyamides by PET is a minimum first step toward the translation of polyamide-based gene regulation from cell culture to small animal studies

Comparison of two analysis methods for nuclear reaction measurements of 12C +12C interactions at 95 MeV/u for hadrontherapy

During therapeutic treatment with heavier ions like carbon, the beam undergoes nuclear fragmentation and secondary light charged particles, in particular protons and alpha particles, are produced. To estimate the dose deposited into the tumors and the surrounding healthy tissues, the accuracy must be higher than ($\pm$3% and$\pm$1 mm). Therefore, measurements are performed to determine the double differential cross section for different reactions. In this paper, the analysis of data from 12C +12C reactions at 95 MeV/u are presented. The emitted particles are detected with \DeltaEthin-\DeltaEthick-E telescopes made of a stack of two silicon detectors and a CsI crystal. Two different methods are used to identify the particles. One is based on graphical cuts onto the \DeltaE-E maps, the second is based on the so-called KaliVeda method using a functional description of \DeltaE versus E. The results of the two methods will be presented in this paper as well as the comparison between both

The internal brakes on violent escalation:a typology

Most groups do less violence than they are capable of. Yet while there is now an extensive literature on the escalation of or radicalisation towards violence, particularly by ‘extremist’ groups or actors, and while processes of de-escalation or de-radicalisation have also received significant attention, processes of non- or limited escalation have largely gone below the analytical radar. This article contributes to current efforts to address this limitation in our understanding of the dynamics of political aggression by developing a descriptive typology of the ‘internal brakes’ on violent escalation: the mechanisms through which members of the groups themselves contribute to establish and maintain limits upon their own violence. We identify five underlying logics on which the internal brakes operate: strategic, moral, ego maintenance, outgroup definition, and organisational. The typology is developed and tested using three very different case studies: the transnational and UK jihadi scene from 2005 to 2016; the British extreme right during the 1990s, and the animal liberation movement in the UK from the mid-1970s until the early 2000s

Small intestinal mucosa expression of putative chaperone fls485

<p>Abstract</p> <p>Background</p> <p>Maturation of enterocytes along the small intestinal crypt-villus axis is associated with significant changes in gene expression profiles. <it>fls485 </it>coding a putative chaperone protein has been recently suggested as a gene involved in this process. The aim of the present study was to analyze <it>fls48</it>5 expression in human small intestinal mucosa.</p> <p>Methods</p> <p><it>fls485 </it>expression in purified normal or intestinal mucosa affected with celiac disease was investigated with a molecular approach including qRT-PCR, Western blotting, and expression strategies. Molecular data were corroborated with several <it>in situ </it>techniques and usage of newly synthesized mouse monoclonal antibodies.</p> <p>Results</p> <p>fls485 mRNA expression was preferentially found in enterocytes and chromaffine cells of human intestinal mucosa as well as in several cell lines including Rko, Lovo, and CaCo2 cells. Western blot analysis with our new anti-fls485 antibodies revealed at least two fls485 proteins. In a functional CaCo2 model, an increase in fls485 expression was paralleled by cellular maturation stage. Immunohistochemistry demonstrated fls485 as a cytosolic protein with a slightly increasing expression gradient along the crypt-villus axis which was impaired in celiac disease Marsh IIIa-c.</p> <p>Conclusions</p> <p>Expression and synthesis of fls485 are found in surface lining epithelia of normal human intestinal mucosa and deriving epithelial cell lines. An interdependence of enterocyte differentiation along the crypt-villus axis and fls485 chaperone activity might be possible.</p

Polyamide-Scorpion Cyclam Lexitropsins Selectively Bind AT-Rich DNA Independently of the Nature of the Coordinated Metal

Cyclam was attached to 1-, 2- and 3-pyrrole lexitropsins for the first time through a synthetically facile copper-catalyzed “click” reaction. The corresponding copper and zinc complexes were synthesized and characterized. The ligand and its complexes bound AT-rich DNA selectively over GC-rich DNA, and the thermodynamic profile of the binding was evaluated by isothermal titration calorimetry. The metal, encapsulated in a scorpion azamacrocyclic complex, did not affect the binding, which was dominated by the organic tail

Characterization of a gamma-ray tracking array: A comparison of GRETINA and Gammasphere using a 60Co source

In this paper, we provide a formalism for the characterization of tracking arrays with emphasis on the proper corrections required to extract their photopeak efficiencies and peak-to-total ratios. The methods are first applied to Gammasphere, a well characterized 4π array based on the principle of Compton suppression, and subsequently to GRETINA. The tracking efficiencies are then discussed and some guidelines as to what clustering angle to use in the tracking algorithm are presented. It was possible, using GEANT4 simulations, to scale the measured efficiencies up to the expected values for the full 4π implementation of GRETA

178Hg and asymmetric fission of neutron-deficient pre-actinides

International audienceFission at low excitation energy is an ideal playground to probe the impact of nuclear structure on nuclear dynamics. While the importance of structural effects in the nascent fragments is well established in the (trans-)actinide region, the observation of asymmetric fission in several neutron-deficient pre-actinides can be explained by various mechanisms. To deepen our insight into that puzzle, an innovative approach based on inverse kinematics and an enhanced version of the VAMOS++ heavy-ion spectrometer was implemented at the GANIL facility, Caen. Fission of Hg178 was induced by fusion of Xe124 and Fe54. The two fragments were detected in coincidence using VAMOS++ supplemented with a new SEcond Detection arm. For the first time in the pre-actinide region, access to the pre-neutron mass and total kinetic energy distributions, and the simultaneous isotopic identification of one the fission fragment, was achieved. The present work describes the experimental approach, and discusses the pre-neutron observables in the context of an extended asymmetric-fission island located southwest of Pb208. A comparison with different models is performed, demonstrating the importance of this new asymmetric-fission island for elaborating on driving effects in fission