Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat

Abstract Background Sepsis is characterized by the loss of the perm-selectivity properties of the glomerular filtration barrier (GFB) with consequent albuminuria. We examined whether the pharmacokinetics–pharmacodynamics (PK/PD) of ceftriaxone (CTX), an extensively protein-bound 3rd generation cephalosporin, is altered during early sepsis and whether an increase in urinary loss of bound-CTX, due to GFB alteration, can occur in this condition. Methods A prospective, experimental, randomized study was carried out in adult male Sprague–Dawley rats. Sepsis was induced by cecal ligation and puncture (CLP). Rats were divided into two groups: Sham-operated and CLP. CTX (100 mg i.p., equivalent to 1 g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6 h after administration. CTX was measured by High Performance Liquid Chromatography (HPLC). The morphological status of the sialic components of the GFB barrier was assessed by lectin histo-chemistry. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA >90%) for 80 and 100% of Tfree > minimum inhibitory concentration (MIC) for 80 and 100% of dosing interval. Measurements and main results After CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1 × 101 CFU in sham rats vs 5 × 104–1 × 105 CFU in CLP rats). CTX plasma concentrations were higher in CLP than in sham rats at 2 and 4 h after administration (difference at 2 h was 47.3, p = 0.012; difference at 4 h was 24.94, p = 0.004), while lung penetration tended to be lower. An increased urinary elimination of protein-bound CTX occurred (553 ± 689 vs 149 ± 128 mg/L, p < 0.05; % of bound/total CTX 22 ± 6 in septic rats vs 11 ± 4 in sham rats, p < 0.01) and it was associated with loss of the GFB sialic components. According to Monte Carlo simulation a PTA > 90% for 100% of the dosing interval was reached neither for sham nor CLP rats using MIC = 1 mg/L, the clinical breakpoint for Enterobacteriacee. Conclusions Sepsis causes changes in the PK of CTX and an alteration in the sialic components of the GFB, with consequent loss of protein-bound CTX. Among factors that can affect drug pharmacokinetics during the early phases of sepsis, urinary loss of both free and albumin–bound antimicrobials should be considered

The crystal ball, the spider and other stories: a journey around the test tower of the M4 adaptive mirror

M4 is the adaptive mirror of ELT, currently at its FDR. It is composed by 6 thin shell mirror segments, controlled by 5136 voice coil actuators. Before its installation at the telescope, it will be optically calibrated on a test facility (OTT) in Italy. The calibration includes the computation of the flattening command and the segments co-phasing, i.e. the correction of the differential piston amongst them. Given the large complexity of the deformable mirror and the very tight requests on the measurement accuracy, we set-up a risk-mitigation activity based on the laboratory demonstration of some key elements within the test tower. In this paper we present the results of the experimentation. We measured at nanometer level the interferometric cavity; we investigated how the interferometer reacts in presence of spider arms dividing the test mirror into separated islands; we integrated and tested a multi wavelength sensor to measure the inter-segment absolute differential piston; we aligned and tested for stability the pupil relaying optical system to be installed on the OTT. Such activity is performed in the AO laboratory at INAF-Arcetri in Italy, in preparation of the M4 optical calibration on the OTT, scheduled to start in 2020. The M4 project is led by the Italian consortium AdOptica under an ESO contract

Design of the EnVisS instrument optical head

The EnVisS (Entire Visible Sky) instrument is one of the payloads of the European Space Agency Comet Interceptor mission. The aim of the mission is the study of a dynamically new comet, i.e. a comet that never travelled through the solar system, or an interstellar object, entering the inner solar system. As the mission three-spacecraft system passes through the comet coma, the EnVisS instrument maps the sky, as viewed from the interior of the comet tail, providing information on the dust properties and distribution. EnVisS is mounted on a spinning spacecraft and the full sky (i.e. 360°x180°) is entirely mapped thanks to a very wide field of view (180°x45°) optical design selected for the EnVisS camera. The paper presents the design of the EnVisS optical head. A fisheye optical layout has been selected because of the required wide field of view (180°x45°). This kind of layout has recently found several applications in Earth remote sensing (3MI instrument on MetOp SG) and in space exploration (SMEI instrument on Coriolis, MARCI on Mars reconnaissance orbiter). The EnVisS optical head provides a high resolved image to be coupled with a COTS detector featuring 2kx2k pixels with pitch 5.5µm. Chromatic aberration is corrected in the waveband 550-800nm, while the distortion has been controlled over the whole field of view to remain below 8% with respect to an Fθ mapping law. Since the camera will be switched on 24 hours before the comet closest encounter, the operative temperature will change during the approaching phase and crossing of the comet’s coma. In the paper, we discuss the solution adopted for reaching these challenging performances for a space-grade design, while at the same time respecting the demanding small allocated volume and mass for the optical and mechanical design. The view expressed herein can in no way be taken to reflect the official opinion of the European Space Agency

Gamma-Ray Burst observations by the high-energy charged particle detector on board the CSES-01 satellite between 2019 and 2021

In this paper we report the detection of five strong Gamma-Ray Bursts (GRBs) by the High-Energy Particle Detector (HEPD-01) mounted on board the China Seismo-Electromagnetic Satellite (CSES-01), operational since 2018 on a Sun-synchronous polar orbit at a $\sim$ 507 km altitude and 97$^\circ$ inclination. HEPD-01 was designed to detect high-energy electrons in the energy range 3 - 100 MeV, protons in the range 30 - 300 MeV, and light nuclei in the range 30 - 300 MeV/n. Nonetheless, Monte Carlo simulations have shown HEPD-01 is sensitive to gamma-ray photons in the energy range 300 keV - 50 MeV, even if with a moderate effective area above $\sim$ 5 MeV. A dedicated time correlation analysis between GRBs reported in literature and signals from a set of HEPD-01 trigger configuration masks has confirmed the anticipated detector sensitivity to high-energy photons. A comparison between the simultaneous time profiles of HEPD-01 electron fluxes and photons from GRB190114C, GRB190305A, GRB190928A, GRB200826B and GRB211211A has shown a remarkable similarity, in spite of the different energy ranges. The high-energy response, with peak sensitivity at about 2 MeV, and moderate effective area of the detector in the actual flight configuration explain why these five GRBs, characterised by a fluence above $\sim$ 3 $\times$ 10$^{-5}$ erg cm$^{-2}$ in the energy interval 300 keV - 50 MeV, have been detected.Comment: Accepted for publication in The Astrophysical Journal (ApJ

Evidence of an upper ionospheric electric field perturbation correlated with a gamma ray burst

Abstract Earth’s atmosphere, whose ionization stability plays a fundamental role for the evolution and endurance of life, is exposed to the effect of cosmic explosions producing high energy Gamma-ray-bursts. Being able to abruptly increase the atmospheric ionization, they might deplete stratospheric ozone on a global scale. During the last decades, an average of more than one Gamma-ray-burst per day were recorded. Nevertheless, measurable effects on the ionosphere were rarely observed, in any case on its bottom-side (from about 60 km up to about 350 km of altitude). Here, we report evidence of an intense top-side (about 500 km) ionospheric perturbation induced by significant sudden ionospheric disturbance, and a large variation of the ionospheric electric field at 500 km, which are both correlated with the October 9, 2022 Gamma-ray-burst (GRB221009A)