Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Morphological profiling of environmental chemicals enables efficient and untargeted exploration of combination effects

Environmental chemicals are commonly studied one at a time, and there is a need to advance our understanding of the effect of exposure to their combinations. Here we apply high-content microscopy imaging of cells stained with multiplexed dyes (Cell Painting) to profile the effects of Cetyltrimethylammonium bromide (CTAB), Bisphenol A (BPA), and Dibutyltin dilaurate (DBTDL) exposure on four human cell lines; both individually and in all combinations. We show that morphological features can be used with multivariate data analysis to discern between exposures from individual compounds, concentrations, and combinations. CTAB and DBTDL induced concentration-dependent mor-phological changes across the four cell lines, and BPA exacerbated morphological effects when combined with CTAB and DBTDL. Combined exposure to CTAB and BPA induced changes in the ER, Golgi apparatus, nucleoli and cy-toplasmic RNA in one of the cell lines. Different responses between cell lines indicate that multiple cell types are needed when assessing combination effects. The rapid and relatively low-cost experiments combined with high infor-mation content make Cell Painting an attractive methodology for future studies of combination effects. All data in the study is made publicly available on Figshare.De 2 sista författarna delar sistaförfattarskapet</p

Evaluation of thermal and electrical conductivity of carbon-based PLA nanocomposites for 3D printing

PLA nanocomposites for fused-deposition modeling (FDM) technique are considered. Thermal and electrical conductivity of carbon-based PLA nanocomposites are investigated looking at the different morphological characteristic of the carbon nanoparticles. In particular commercial multi-walled carbon nanotubes (CNTs) and graphene nanoplates (GNPs) are considered as filler in order to realize filament for 3D printed devices for electrical and thermal application. In this paper a filler concentration up to 12% in weight is investigated. Transient Plane Source (TPS) measurements of thermal conductivity show that better heat conduction is obtained through the incorporation in the PLA matrix of carbonaceous nanostructures with predominantly two-dimensional shape (GNPs). DC electrical measurements show that the nanocomposite filled with the predominant mono-dimensional carbon nanoparticle (i.e. CNT) exhibits lower electrical percolation threshold, whereas a greater post percolation electrical conductivity is established with the two-dimensional filler (i.e. GNP). Such characteristics are to be considered in order to make robust and cost effective 3D printed device, by preferring 1D filler or 2D filler for electrical or thermal application respectively. Moreover, multiphase nanocomposites obtained with an optimized combination of CNT and GNP nanoparticles could be exploited to realize devices for joint electrical and thermal application

A phenomics approach for antiviral drug discovery

Background: The emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the discovery of antiviral drugs, the majority tend to focus on the effects of such drugs on a given virus, its constituent proteins, or enzymatic activity, often neglecting the consequences on host cells. This may lead to partial assessment of the efficacy of the tested anti-viral compounds, as potential toxicity impacting the overall physiology of host cells may mask the effects of both viral infection and drug candidates. Here we present a method able to assess the general health of host cells based on morphological profiling, for untargeted phenotypic drug screening against viral infections. Results: We combine Cell Painting with antibody-based detection of viral infection in a single assay. We designed an image analysis pipeline for segmentation and classification of virus-infected and non-infected cells, followed by extraction of morphological properties. We show that this methodology can successfully capture virus-induced phenotypic signatures of MRC-5 human lung fibroblasts infected with human coronavirus 229E (CoV-229E). Moreover, we demonstrate that our method can be used in phenotypic drug screening using a panel of nine host- and virus-targeting antivirals. Treatment with effective antiviral compounds reversed the morphological profile of the host cells towards a non-infected state. Conclusions: The phenomics approach presented here, which makes use of a modified Cell Painting protocol by incorporating an anti-virus antibody stain, can be used for the unbiased morphological profiling of virus infection on host cells. The method can identify antiviral reference compounds, as well as novel antivirals, demonstrating its suitability to be implemented as a strategy for antiviral drug repurposing and drug discovery

Evaluating the utility of brightfield image data for mechanism of action prediction

Fluorescence staining techniques, such as Cell Painting, together with fluorescence microscopy have proven invaluable for visualizing and quantifying the effects that drugs and other perturbations have on cultured cells. However, fluorescence microscopy is expensive, time-consuming, labor-intensive, and the stains applied can be cytotoxic, interfering with the activity under study. The simplest form of microscopy, brightfield microscopy, lacks these downsides, but the images produced have low contrast and the cellular compartments are difficult to discern. Nevertheless, by harnessing deep learning, these brightfield images may still be sufficient for various predictive purposes. In this study, we compared the predictive performance of models trained on fluorescence images to those trained on brightfield images for predicting the mechanism of action (MoA) of different drugs. We also extracted CellProfiler features from the fluorescence images and used them to benchmark the performance. Overall, we found comparable and largely correlated predictive performance for the two imaging modalities. This is promising for future studies of MoAs in time-lapse experiments for which using fluorescence images is problematic. Explorations based on explainable AI techniques also provided valuable insights regarding compounds that were better predicted by one modality over the other.De två första författarna delar förstaförfattarskapetDe två sista författarna delar sistaförfattarskapet</p

Nonresonant central exclusive production of charged-hadron pairs in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe central exclusive production of charged-hadron pairs in pp collisions at a centre-of-mass energy of 13\TeV is examined, based on data collected in a special high-$\beta^*$ run of the LHC. The nonresonant continuum processes are studied with the invariant mass of the centrally produced two-pion system in the resonance-free region, $m_{\pi^+\pi^-}$$\lt$ 0.7 GeV or $m_{\pi^+\pi^-}$$\gt$ 1.8 GeV. Differential cross sections as functions of the azimuthal angle between the surviving protons, squared exchanged four-momenta, and $m_{\pi^+\pi^-}$ are measured in a wide region of scattered proton transverse momenta, between 0.2 and 0.8 GeV, and for pion rapidities $\lvert y\rvert$$\lt$ 2. A rich structure of interactions related to double-pomeron exchange is observed. A parabolic minimum in the distribution of the two-proton azimuthal angle is observed for the first time. It can be interpreted as an effect of additional pomeron exchanges between the protons from the interference between the bare and the rescattered amplitudes. After model tuning, various physical quantities are determined that are related to the pomeron cross section, proton-pomeron and meson-pomeron form factors, pomeron trajectory and intercept, and coefficients of diffractive eigenstates of the proton

Proton reconstruction with the CMS-TOTEM Precision Proton Spectrometer

International audienceThe Precision Proton Spectrometer (PPS) of the CMS and TOTEM experiments collected 107.7 fb$^{-1}$ in proton-proton (pp) collisions at the LHC at 13 TeV (Run 2). This paper describes the key features of the PPS alignment and optics calibrations, the proton reconstruction procedure, as well as the detector efficiency and the performance of the PPS simulation. The reconstruction and simulation are validated using a sample of (semi)exclusive dilepton events. The performance of PPS has proven the feasibility of continuously operating a near-beam proton spectrometer at a high luminosity hadron collider

A search for new physics in central exclusive production using the missing mass technique with the CMS detector and the CMS-TOTEM precision proton spectrometer

A generic search is presented for the associated production of a Z boson or a photon with an additional unspecified massive particle X, $\mathrm{p}\mathrm{p}\to \mathrm{p}\mathrm{p} +\mathrm{Z}/\gamma+\mathrm{X}$, in proton-tagged events from proton-proton collisions at $\sqrt{s}=$ 13 TeV, recorded in 2017 with the CMS detector and the CMS-TOTEM precision proton spectrometer. The missing mass spectrum is analysed in the 600-1600 GeV range and a fit is performed to search for possible deviations from the background expectation. No significant excess in data with respect to the background predictions has been observed. Model-independent upper limits on the visible production cross section of $\mathrm{p}\mathrm{p}\to \mathrm{p}\mathrm{p} +\mathrm{Z}/\gamma+\mathrm{X}$ are set.A generic search is presented for the associated production of a Z boson or a photon with an additional unspecified massive particle X, pp $\to$ pp + Z/$\gamma$ + X, in proton-tagged events from proton-proton collisions at $\sqrt{s}$ = 13 TeV, recorded in 2017 with the CMS detector and the CMS-TOTEM precision proton spectrometer. The missing mass spectrum is analysed in the 600-1600 GeV range and a fit is performed to search for possible deviations from the background expectation. No significant excess in data with respect to the background predictions has been observed. Model-independent upper limits on the visible production cross section of pp $\to$ pp + Z/$\gamma$ + X are set

Search for high-mass exclusive diphoton production with tagged protons in proton-proton collisions at s= \sqrt{s} = 13 TeV

A search is presented for high-mass exclusive diphoton production via photon-photon fusion in proton-proton collisions at $\sqrt{s} =$ 13 TeV in events where both protons survive the interaction. The analysis utilizes data corresponding to an integrated luminosity of 103 fb$^{-1}$ collected in 2016--2018 with the central CMS detector and the CMS and TOTEM precision proton spectrometer (PPS). Events that have two photons with high transverse momenta ($p_{\mathrm{T}}^{\gamma} >$ 100 GeV), back-to-back in azimuth, and with a large diphoton invariant mass ($m_{\gamma\gamma} >$ 350 GeV) are selected. To remove the dominant inclusive diphoton backgrounds, the kinematic properties of the protons detected in PPS are required to match those of the central diphoton system. Only events having opposite-side forward protons detected with a fractional momentum loss between 0.035 and 0.15 (0.18) for the detectors on the negative (positive) side of CMS are considered. One exclusive diphoton candidate is observed for an expected background of 1.1 events. Limits at 95% confidence level are derived for the four-photon anomalous coupling parameters $|\zeta_1|$ 100 GeV), back-to-back in azimuth, and with a large diphoton invariant mass ($m_{\gamma\gamma} \gt$ 350 GeV) are selected. To remove the dominant inclusive diphoton backgrounds, the kinematic properties of the protons detected in PPS are required to match those of the central diphoton system. Only events having opposite-side forward protons detected with a fractional momentum loss between 0.035 and 0.15 (0.18) for the detectors on the negative (positive) side of CMS are considered. One exclusive diphoton candidate is observed for an expected background of 1.1 events. Limits at 95% confidence level are derived for the four-photon anomalous coupling parameters $\lvert\zeta_1\rvert \lt$ 0.073 TeV$^{-4}$ and $\lvert\zeta_2\rvert \lt$ 0.15 TeV$^{-4}$, using an effective field theory. Additionally, upper limits are placed on the production of axion-like particles with coupling strength to photons $f^{-1}$ that varies from 0.03 TeV$^{-1}$ to 1 TeV$^{-1}$ over the mass range from 500 to 2000 GeV