Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5-6~g/24~h with preceding loading doses (administered as 30~min infusion) of 0.15-2~g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration-time profile did not drop at any time below four times the S/I breakpoint (= 2~mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33~g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5~g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5~g meropenem over 30~min immediately followed by continuous infusion

Jack of All Trades, Master of All: A Positive Association between Habitat Niche Breadth and Foraging Performance in Pit-Building Antlion Larvae

Species utilizing a wide range of resources are intuitively expected to be less efficient in exploiting each resource type compared to species which have developed an optimal phenotype for utilizing only one or a few resources. We report here the results of an empirical study whose aim was to test for a negative association between habitat niche breadth and foraging performance. As a model system to address this question, we used two highly abundant species of pit-building antlions varying in their habitat niche breadth: the habitat generalist Myrmeleon hyalinus, which inhabits a variety of soil types but occurs mainly in sandy soils, and the habitat specialist Cueta lineosa, which is restricted to light soils such as loess. Both species were able to discriminate between the two soils, with each showing a distinct and higher preference to the soil type providing higher prey capture success and characterizing its primary habitat-of-origin. As expected, only small differences in the foraging performances of the habitat generalist were evident between the two soils, while the performance of the habitat specialist was markedly reduced in the alternative sandy soil. Remarkably, in both soil types, the habitat generalist constructed pits and responded to prey faster than the habitat specialist, at least under the temperature range of this study. Furthermore, prey capture success of the habitat generalist was higher than that of the habitat specialist irrespective of the soil type or prey ant species encountered, implying a positive association between habitat niche-breadth and foraging performance. Alternatively, C. lineosa specialization to light soils does not necessarily confer upon its superiority in utilizing such habitats. We thus suggest that habitat specialization in C. lineosa is either an evolutionary dead-end, or, more likely, that this species' superiority in light soils can only be evident when considering additional niche axes

On the genesis of Post constraint in modern electromagnetism

The genesis of the Post constraint is premised on two attributes of modern electromagnetism: (i) its microscopic nature, and (ii) the status of e and b as the primitive electromagnetic fields. This constraint can therefore not arise in EH--electromagnetism, wherein the primitive electromagnetic fields are the macroscopic fields E and H

NLRP3 inflammasome assembly in neutrophils is supported by PAD4 and promotes NETosis under sterile conditions

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Muenzer, P., Negro, R., Fukui, S., di Meglio, L., Aymonnier, K., Chu, L., Cherpokova, D., Gutch, S., Sorvillo, N., Shi, L., Magupalli, V. G., Weber, A. N. R., Scharf, R. E., Waterman, C. M., Wu, H., & Wagner, D. D. NLRP3 inflammasome assembly in neutrophils is supported by PAD4 and promotes NETosis under sterile conditions. Frontiers in Immunology, 12, (2021): 683803, https://doi.org/10.3389/fimmu.2021.683803.Neutrophil extracellular trap formation (NETosis) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly are associated with a similar spectrum of human disorders. While NETosis is known to be regulated by peptidylarginine deiminase 4 (PAD4), the role of the NLRP3 inflammasome in NETosis was not addressed. Here, we establish that under sterile conditions the cannonical NLRP3 inflammasome participates in NETosis. We show apoptosis-associated speck-like protein containing a CARD (ASC) speck assembly and caspase-1 cleavage in stimulated mouse neutrophils without LPS priming. PAD4 was needed for optimal NLRP3 inflammasome assembly by regulating NLRP3 and ASC protein levels post-transcriptionally. Genetic ablation of NLRP3 signaling resulted in impaired NET formation, because NLRP3 supported both nuclear envelope and plasma membrane rupture. Pharmacological inhibition of NLRP3 in either mouse or human neutrophils also diminished NETosis. Finally, NLRP3 deficiency resulted in a lower density of NETs in thrombi produced by a stenosis-induced mouse model of deep vein thrombosis. Altogether, our results indicate a PAD4-dependent formation of the NLRP3 inflammasome in neutrophils and implicate NLRP3 in NETosis under noninfectious conditions in vitro and in vivo.This work was supported by a grant from National Heart, Lung, and Blood Institute of the National Institutes of Health (grant R35 HL135765) and a Steven Berzin family support to DDW, an Individual Erwin Deutsch fellowship by the German, Austrian and Swiss Society of Thrombosis and Hemostasis Research to RES, a Whitman fellowship (MBL) to DDW, and an Individual Marie Skłodowska-Curie Actions fellowship by the European Commission (796365 - COAGULANT) to PM. ANRW was funded by the Deutsche Forschungsgemeinschaft (TRR156/2 –246807620) and a research grant (We-4195/15-19). CMW was supported by the Division of Intramural Research, NHLBI, NIH

Vitellogenin Underwent Subfunctionalization to Acquire Caste and Behavioral Specific Expression in the Harvester Ant Pogonomyrmex barbatus

PMCID: PMC3744404This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

Health and social exclusion in older age: evidence from Understanding Society, the UK household longitudinal study

Background Social exclusion of the elderly is a key policy focus but evidence on the processes linking health and social exclusion is hampered by the variety of ways that health is used in social exclusion research. We investigated longitudinal associations between health and social exclusion using an analytical framework that did not conflate them. Methods Data employed in this study came from 4 waves of Understanding Society, the UK Household Longitudinal Study 2009–2013. The sample comprised all adults who took part in all 4 waves, were 65 years or more in Wave 3, and had complete data on our variables of interest for each analysis. We used linear regression to model the relationship between Wave 2/3 social exclusion and Wave1–2 health transitions (N=4312) and logistic regression to model the relationship between Wave2/3 social exclusion and Wave 4 health states, conditional on Wave 3 health (N=4244). Results There was a dose–response relationship between poor health in Waves 1 and 2 and later social exclusion. Use of a car, mobile phone and the internet moderated the association between poor health and social exclusion. Given the health status in Wave 3, those who were more socially excluded had poorer outcomes on each of the three domains of health in Wave 4. Conclusions Use of the internet and technology protected older adults in poor health from social exclusion. Age-friendly hardware and software design might have public health benefits

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

A search for point sources of EeV photons

Measurements of air showers made using the hybrid technique developed with the fluorescence and surface detectors of the Pierre Auger Observatory allow a sensitive search for point sources of EeV photons anywhere in the exposed sky. A multivariate analysis reduces the background of hadronic cosmic rays. The search is sensitive to a declination band from -85{\deg} to +20{\deg}, in an energy range from 10^17.3 eV to 10^18.5 eV. No photon point source has been detected. An upper limit on the photon flux has been derived for every direction. The mean value of the energy flux limit that results from this, assuming a photon spectral index of -2, is 0.06 eV cm^-2 s^-1, and no celestial direction exceeds 0.25 eV cm^-2 s^-1. These upper limits constrain scenarios in which EeV cosmic ray protons are emitted by non-transient sources in the Galaxy.Comment: 28 pages, 10 figures, accepted for publication in The Astrophysical Journa

Reconstruction of inclined air showers detected with the Pierre Auger Observatory

We describe the method devised to reconstruct inclined cosmic-ray air showers with zenith angles greater than $60^\circ$ detected with the surface array of the Pierre Auger Observatory. The measured signals at the ground level are fitted to muon density distributions predicted with atmospheric cascade models to obtain the relative shower size as an overall normalization parameter. The method is evaluated using simulated showers to test its performance. The energy of the cosmic rays is calibrated using a sub-sample of events reconstructed with both the fluorescence and surface array techniques. The reconstruction method described here provides the basis of complementary analyses including an independent measurement of the energy spectrum of ultra-high energy cosmic rays using very inclined events collected by the Pierre Auger Observatory.Comment: 27 pages, 19 figures, accepted for publication in Journal of Cosmology and Astroparticle Physics (JCAP