Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.

Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.

Hypercalcemia as a Biomarker of Poor Prognosis in Frail Elderly Patients with COVID-19.

The objective of this cohort study was to determine whether hypercalcemia in early COVID-19 was associated with 3-month mortality in frail elderly patients. Circulating calcium and albumin concentrations at hospital admission and 3-month mortality were assessed in geriatric patients hospitalized for COVID-19 with normal-to-high calcium concentrations. Hypercalcemia was defined as corrected calcium >2.5mmol/L. Covariables were age, sex, functional abilities, malignancies, hypertension, cardiomyopathy, number of acute health issues, use antibiotics and respiratory treatments. In total, 94 participants (mean±SD 88.0±5.5years; 47.9% women; 22.3% hypercalcemia; 0% hypocalcemia) were included. Sixty-five participants who survived at 3months exhibited less often hypercalcemia at baseline than the others (13.9% versus 41.4%, P=0.003). Hypercalcemia was associated with 3-month mortality (fully-adjusted HR=3.03, P=0.009) with specificity=0.86 and sensitivity=0.41. Those with hypercalcemia had shorter survival time than those with normocalcemia (log-rank P=0.002). In conclusion, hypercalcemia was associated with poorer survival in hospitalized frail elderly COVID-19 patients.

Measuring liveweight changes in lactating dairy ewes with an automated walk-over-weighing system.

Monitoring liveweight (LW) is an important part of sound management practices at the individual and flock level (e.g., controlling for nutritional status based on body condition, reproduction, and health-related issues), but it is time consuming and stressful. To our knowledge, no literature has reported on the evaluation of automated weighing systems in dairy sheep as an alternative to conventional static scales. The objective of this research was to evaluate the practical feasibility of using an automated walk-over-weighing (WoW) prototype to measure daily LW changes in dairy ewes without human intervention. We used adult Lacaune dairy ewes in 2 complementary trials conducted indoors. Trial 1 aimed at evaluating the repeatability, precision, and accuracy of LW measures recorded using WoW scales compared with a static scale (the gold standard). Forty-two adult ewes (LW ± standard deviation = 71.3 ± 10.4 kg) were randomly drafted from the main flock and used in a 1-day session. The trial included 3 passages. In each passage, ewes were weighed first on a static scale; once a static position was achieved and LW recorded, they continued the circuit and immediately traversed the WoW scale for an automated LW record. Trial 2 aimed to demonstrate the feasibility of using the WoW device under real-world conditions in a dairy sheep-farming system. The WoW scale was installed in the exit race of the milking parlor and evaluated over 7 wk with adult ewes in mid lactation (n = 93; LW 78.5 ± 8.1 kg). Once the ewes were acclimated to the WoW system, 1 group of ewes (n = 48) continued to receive the same feeding regimen (controls), and the other group (n = 45) underwent a nutritional challenge [challenged; 2 wk of undernutrition and then back to control regimen (refeeding) for 1 wk]. We evaluated the ability of the WoW to detect small changes in LW. We collected LW data (2 weighings per ewe per day) from the WoW after each of the 2 milking sessions (morning and evening). We also obtained LW values by weighing the ewes using a static scale once a week. The automated WoW system showed substantial agreement with the gold standard when assessed using Lin's concordance correlation coefficient and Bland and Altman's method, largely due to high repeatability. The WoW system was adequate for detecting small daily variations in LW during undernutrition and refeeding periods. Misbehaviors resulted in spurious WoW values in trial 2, requiring us to use filtration methods to exclude outlier weights and allow meaningful assessment of small LW changes. The WoW system evaluated here is an alternative to the static scales conventionally used on dairy sheep farms. If sound filtration of raw data is applied, WoW could contribute to the close (daily) monitoring of individual LW without operator intervention (i.e., voluntary weighing) and taking animal welfare into account (i.e., no stress related to the weighing session on static scales).

Intubation decision criteria in adult epiglottitis.

OBJECTIVES: To identify contributive criteria in decision-making for intubation in acute epiglottitis, based on clinical and endoscopic data in adult patients, and to study clinical and biological characteristics and management. MATERIALS AND METHODS: Diagnosis was established by flexible endoscopy showing epiglottic edema in association with general signs of sepsis in 28 patients consulting into two French hospitals between 2005 and 2016. Retrospective univariate and multivariate analysis between patients managed by intubation (Group I) or surveillance (Group S) was performed on clinical and endoscopic data. RESULTS: Ten patients were intubated (36%). On univariate analysis, 4 variables were suggestively associated with intubation. On multivariate analysis, associations remained suggestive for dyspnea (OR=50.6; 95% CI=[2.7; 940.1]) and supraglottic edema extension (OR=42.2; 95% CI=[2.2; 799.5]). The area under the curve identifying intubated patients on these 2 criteria was 90.8%, testifying to high discrimination. CONCLUSION: Intubation must always be considered in epiglottitis. Dyspnea and supraglottic extension of the edema seem to be the two main criteria to be considered in airway control decision-making.

Towards individualised and optimalised positioning of non-ventilated COVID-19 patients: Putting the affected parts of the lung(s) on top?

The outbreak of COVID-19 led to an unprecedented inflow of hospitalised patients with severe acute respiratory syndrome (SARS), requiring high-flow non-invasive oxygenation, if not invasive mechanical ventilation. While the best option in terms of non-invasive systems of oxygen delivery is still a matter of debate, it also remains unclear as to whether or not the optimal in-bed positioning of patients might also help to improve their oxygen saturation levels. On the basis of three representative cases, it is possible to propose the following hypotheses: (i) how patients are positioned has a strong influence on their oxygen saturation levels; (ii) saturation-optimalised positions are patient-specific; (iii) prone positions require ergonomic devices; and (iv) saturation-optimalised positions should aim to place the most affected part(s) of the lung(s) on top. Considered together, these hypotheses have led us to recommend that COVID-19 patients should undergo a specific assessment at admission to determine their saturation-optimalised in-bed position. However, further studies are still needed to assess the benefits of such a strategy on clinical outcomes.

Femtosecond Resolution of the Nonballistic Electron Energy Transport in Warm Dense Copper.

The ultrafast electron energy transport is investigated in laser-heated warm dense copper in a high flux regime (2.5±0.7×10^{13} W/cm^{2} absorbed). The dynamics of the electron temperature is retrieved from femtosecond time-resolved x-ray absorption near-edge spectroscopy near the Cu L3 edge. A characteristic time of ∼1 ps is observed for the increase in the average temperature in a 100 nm thick sample. Data are well reproduced by two-temperature hydrodynamic simulations, which support energy transport dominated by thermal conduction rather than ballistic electrons.

Nonlinear ionization dynamics of hot dense plasma observed in a laser-plasma amplifier.

Understanding the behaviour of matter under conditions of extreme temperature, pressure, density and electromagnetic fields has profound effects on our understanding of cosmologic objects and the formation of the universe. Lacking direct access to such objects, our interpretation of observed data mainly relies on theoretical models. However, such models, which need to encompass nuclear physics, atomic physics and plasma physics over a huge dynamic range in the dimensions of energy and time, can only provide reliable information if we can benchmark them to experiments under well-defined laboratory conditions. Due to the plethora of effects occurring in this kind of highly excited matter, characterizing isolated dynamics or obtaining direct insight remains challenging. High-density plasmas are turbulent and opaque for radiation below the plasma frequency and allow only near-surface insight into ionization processes with visible wavelengths. Here, the output of a high-harmonic seeded laser-plasma amplifier using eight-fold ionized krypton as the gain medium operating at a 32.8 nm wavelength is ptychographically imaged. A complex-valued wavefront is observed in the extreme ultraviolet (XUV) beam with high resolution. Ab initio spatio-temporal Maxwell-Bloch simulations show excellent agreement with the experimental observations, revealing overionization of krypton in the plasma channel due to nonlinear laser-plasma interactions, successfully validating this four-dimensional multiscale model. This constitutes the first experimental observation of the laser ion abundance reshaping a laser-plasma amplifier. The presented approach shows the possibility of directly modelling light-plasma interactions in extreme conditions, such as those present during the early times of the universe, with direct experimental verification.

[Recommendations of the Urolithiasis Committee of the French Urology Association for the management and the treatment of the stone formers patients during the COVID-19 pandemic crisis]. / Recommandations du Comité Lithiase de l'Association Française d'Urologie pour la prise en charge des calculs urinaires durant la crise sanitaire liée à la pandémie à COVID-19.

For the first time, faced with a crisis with an exceptional magnitude due to the COVID-19 pandemic responsible for saturation of emergency services and intensive care units, the urolithiasis committee of the French Urology Association designed the recommendations for care and treatment of stone-forming patients and their treatment during crisis.

Two-Color Soft X-Ray Lasing in a High-Density Nickel-like Krypton Plasma.

We report evidence of strong lasing on the 4p-4s transition at 62.7 nm in nickel-like krypton occurring simultaneously with the usual 4d-4p lasing at 32.8 nm. The gain dynamics of both transitions were experimentally and numerically investigated and found comparable. The two-color amplifier was seeded by the same harmonic pulse, therefore producing a short-duration coherent two-color soft x-ray laser pulse. Both transitions offer similar prospects of pulse energy and duration and could lead to the delivery of intense and ultrashort two-color coherent soft x-ray pulses with a controllable delay.

Acquired generalized lipodystrophy under immune checkpoint inhibition.

Immune checkpoint inhibitors are now the standard of care in the treatment of several types of cancer. Cutaneous immune-related adverse events (irAEs) are usually of low grade and reversible, while endocrine irAEs are generally irreversible and managed with hormone replacement therapy. We report a 47-year-old patient, treated with the anti-programmed cell death (PD)1 antibody pembrolizumab for a metastatic melanoma, who developed severe lipodystrophy after 10 months of treatment, characterized by the loss of subcutaneous fat tissue, central obesity and insulin resistance with a decreased leptin level. Histological analysis of a cutaneous biopsy revealed subcutaneous fat cell destruction associated with oedema, the presence of lipophages, and a CD3+ lymphocytic infiltrate involving the panniculus. This led to the diagnosis of anti-PD-1-induced acquired generalized lipodystrophy, after ruling out differential diagnoses (i.e. genetic and systemic autoimmune diseases). No corticosteroids were introduced considering the high risk of inducing severe metabolic complications, and pembrolizumab was discontinued as complete response of the melanoma was achieved. However, after 12 months of follow-up, lipodystrophy and its severe metabolic complications are still ongoing. What's already known about this topic? Anti-programmed cell death (PD)1 agents are now a standard of care in the treatment of several cancers, including melanoma. Endocrine and cutaneous immune-related adverse events (irAEs) are among the most frequent irAEs (14-30% and 30-40%, respectively) in patients treated with immune checkpoint inhibitors. What does this study add? Acquired generalized lipodystrophy can occur during anti-PD1 therapy and is associated with severe metabolic complications. With the increase in anti-PD1 prescription in several cancer types, clinicians must be aware of the whole range of irAEs that may occur.

Determinants of aspirin resistance in patients with type 2 diabetes.

BACKGROUND: Cardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin. METHODS: Included were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated. RESULTS: Using LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA1c), and strongly related to all markers of insulin resistance, especially waist circumference, HOMA-IR, QUICKI and leptin. There was no association between HPR and thrombopoietin or inflammatory markers (IL-6, IL-10, indoleamine 2,3-dioxygenase activity, TNF-α, C-reactive protein), whereas HPR was associated with more severe CAD. Similar results were found with TXB2. CONCLUSION: Our results reveal that 'aspirin resistance' is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA1c and not at all to inflammatory parameters. This may help to identify those T2DM patients who might benefit from alternative antiplatelet treatments such as twice-daily aspirin and thienopyridines.

Tunable High Spatio-Spectral Purity Undulator Radiation from a Transported Laser Plasma Accelerated Electron Beam.

Undulator based synchrotron light sources and Free Electron Lasers (FELs) are valuable modern probes of matter with high temporal and spatial resolution. Laser Plasma Accelerators (LPAs), delivering GeV electron beams in few centimeters, are good candidates for future compact light sources. However the barriers set by the large energy spread, divergence and shot-to-shot fluctuations require a specific transport line, to shape the electron beam phase space for achieving ultrashort undulator synchrotron radiation suitable for users and even for achieving FEL amplification. Proof-of-principle LPA based undulator emission, with strong electron focusing or transport, does not yet exhibit the full specific radiation properties. We report on the generation of undulator radiation with an LPA beam based manipulation in a dedicated transport line with versatile properties. After evidencing the specific spatio-spectral signature, we tune the resonant wavelength within 200-300 nm by modification of the electron beam energy and the undulator field. We achieve a wavelength stability of 2.6%. We demonstrate that we can control the spatio-spectral purity and spectral brightness by reducing the energy range inside the chicane. We have also observed the second harmonic emission of the undulator.

The European Society of Paediatric Oncology Ependymoma-II program Core-Plus model: Development and initial implementation of a cognitive test protocol for an international brain tumour trial.

It is increasingly accepted that survival alone is an inadequate measure of the success of childhood brain tumour treatments. Consequently, there is growing emphasis on capturing quality of survival. Ependymomas are the third most frequently occurring brain tumours in childhood and present significant clinical challenges. European Society of Paediatric Oncology Ependymoma II is a comprehensive international program aiming to evaluate outcomes under different treatment regimens and improve diagnostic accuracy. Importantly, there has been agreement to lower the age at which children with posterior fossa ependymoma undergo focal irradiation from three years to either eighteen months or one year of age. Hitherto radiotherapy in Europe had been reserved for children over three years due to concerns over adverse cognitive outcomes following irradiation of the developing brain. There is therefore a duty of care to include longitudinal cognitive follow-up and this has been agreed as an essential trial outcome. Discussions between representatives of 18 participating European countries over 10 years have yielded European consensus for an internationally accepted test battery for follow-up of childhood ependymoma survivors. The 'Core-Plus' model incorporates a two-tier approach to assessment by specifying core tests to establish a minimum dataset where resources are limited, whilst maintaining scope for comprehensive assessment where feasible. The challenges leading to the development of the Core-Plus model are presented alongside learning from the initial stages of the trial. We propose that this model could provide a solution for future international trials addressing both childhood brain tumours and other conditions associated with cognitive morbidity.

High-flux source of coherent XUV pulses for user applications.

We present experimental results obtained at a user-oriented XUV beamline implemented at the ELI Beamlines facility. The coherent XUV radiation is produced via high harmonic generation in gases in a loose focusing geometry. The beamline is designed to be driven by 1 kHz, 100 mJ, 20 fs pulses centered at a wavelength of 830 nm. Results such as XUV spectra, beam wavefront and pulse energy obtained during the beamline commissioning with a commercial 1 kHz, 5 mJ, 40 fs laser system are presented. A unique XUV spectrometer for source characterization designed to reach a very high sensitivity is described in detail, and we demonstrate a novel technique for single-shot and every-shot XUV pulse energy measurement.

Publisher Correction: Control of laser plasma accelerated electrons for light sources.

The original version of this Article contained an error in the last sentence of the first paragraph of the Introduction and incorrectly read 'A proper electron beam control is one of the main challenges towards the Graal of developing a compact alternative of X-ray free-electron lasers by coupling LWFA gigaelectron-volts per centimetre acceleration gradient with undulators in the amplification regime in equation 11, nx(n-ß) x ß: n the two times and beta the two times should be bold since they are vectorsin Eq. 12, ß should be bold as well.' The correct version is 'A proper electron beam control is one of the main challenges towards the Graal of developing a compact alternative of X-ray free-electron lasers by coupling LWFA gigaelectron-volts per centimetre acceleration gradient with undulators in the amplification regime.'This has been corrected in both the PDF and HTML versions of the Article.

Control of laser plasma accelerated electrons for light sources.

With gigaelectron-volts per centimetre energy gains and femtosecond electron beams, laser wakefield acceleration (LWFA) is a promising candidate for applications, such as ultrafast electron diffraction, multistaged colliders and radiation sources (betatron, compton, undulator, free electron laser). However, for some of these applications, the beam performance, for example, energy spread, divergence and shot-to-shot fluctuations, need a drastic improvement. Here, we show that, using a dedicated transport line, we can mitigate these initial weaknesses. We demonstrate that we can manipulate the beam longitudinal and transverse phase-space of the presently available LWFA beams. Indeed, we separately correct orbit mis-steerings and minimise dispersion thanks to specially designed variable strength quadrupoles, and select the useful energy range passing through a slit in a magnetic chicane. Therefore, this matched electron beam leads to the successful observation of undulator synchrotron radiation after an 8 m transport path. These results pave the way to applications demanding in terms of beam quality.

Detection of in vivo hepatitis B virus surface antigen mutations-A comparison of four routine screening assays.

An important requirement for a state-of-the-art hepatitis B surface antigen (HBsAg) screening assay is reliable detection of mutated HBsAg. Currently, there is a striking shortage of data regarding the detection rates of in vivo HBsAg mutations for these clinically important assays. Therefore, we compared the detection rates of four commercial HBsAg screening assays using a global cohort of 1553 patients from four continents with known HBV genotypes. These samples, which represent the broadest spectrum of known and novel HBsAg major hydrophilic region (MHR) mutations to date, were analyzed for the presence of HBsAg using the Roche Elecsys® HBsAg II Qualitative, Siemens ADVIA Centaur XP HBsAg II, Abbott Architect HBsAg Qualitative II and DiaSorin Liaison® HBsAg Qualitative assays, respectively. Of the 1553 samples, 1391 samples could be sequenced; of these, 1013 (72.8%) carried at least one of the 345 currently known amino acid substitutions (distinct HBsAg mutation) in the HBsAg MHR. All 1553 patient samples were positive for HBsAg using the Elecsys® HBsAg II Qual assay, with a sensitivity (95% confidence interval) of 99.94% (99.64%-100%), followed by the Abbott Architect 99.81% (99.44%-99.96%), Siemens ADVIA 99.81% (99.44%-99.96%) and DiaSorin Liaison® 99.36% (98.82%-99.69%) assays, respectively. Our results indicate that the Elecsys® HBsAg II Qual assay exhibits the highest sensitivity among the commercial HBsAg screening assays, and demonstrate that its capacity to detect HBV infection is not compromised by HBsAg MHR mutants.