Cloaking, trapping and superlensing of lamb waves with negative refraction.

We report on experimental and numerical implementations of devices based on the negative refraction of elastic guided waves, the so-called Lamb waves. Consisting in plates of varying thickness, these devices rely on the concept of complementary media, where a particular layout of negative index media can cloak an object with its anti-object or trap waves around a negative corner. The diffraction cancellation operated by negative refraction is investigated by means of laser ultrasound experiments. However, unlike original theoretical predictions, these intriguing wave phenomena remain, nevertheless, limited to the propagating component of the wave-field. To go beyond the diffraction limit, negative refraction is combined with the concept of metalens, a device converting the evanescent components of an object into propagating waves. The transport of an evanescent wave-field is then possible from an object plane to a far-field imaging plane. Twenty years after Pendry's initial proposal, this work thus paves the way towards an elastic superlens.

Picosecond ultrasonics with a free-running dual-comb laser.

We present a free-running 80-MHz dual-comb polarization-multiplexed solid-state laser which delivers 1.8 W of average power with 110-fs pulse duration per comb. With a high-sensitivity pump-probe setup, we apply this free-running dual-comb laser to picosecond ultrasonic measurements. The ultrasonic signatures in a semiconductor multi-quantum-well structure originating from the quantum wells and superlattice regions are revealed and discussed. We further demonstrate ultrasonic measurements on a thin-film metalized sample and compare these measurements to ones obtained with a pair of locked femtosecond lasers. Our data show that a free-running dual-comb laser is well-suited for picosecond ultrasonic measurements and thus it offers a significant reduction in complexity and cost for this widely adopted non-destructive testing technique.

A Randomized Trial of Otilimab in Severe COVID-19 Pneumonia (OSCAR)

BACKGROUNDIncreasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19. METHODSWe conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60. RESULTSOverall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI -0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined [≥]70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19. CONCLUSIONSAlthough not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged [≥]70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged [≥]70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684).

Prognostic and predictive biomarkers in patients with COVID-19 treated with tocilizumab in a randomised controlled trial

BackgroundRetrospective observational studies suggest that interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, lymphocytes, monocytes, neutrophils, D-dimer, and platelets are associated with disease progression, treatment outcomes, or both, in patients with COVID-19 pneumonia. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti-IL-6 receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 pneumonia. MethodsCandidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomisation) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. FindingsModelling in the placebo arm showed all candidate biomarkers except LDH and D-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modelling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction p=0.03), mechanical ventilation (predictive interaction p=0.01), and clinical status (predictive interaction p=0.02) compared with placebo. InterpretationMultiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28. RESEARCH IN CONTEXT Evidence before this studyThe efficacy and safety of the anti-interleukin-6 receptor antibody tocilizumab in the treatment of patients hospitalised with COVID-19 pneumonia was investigated in COVACTA, a double-blind, randomised, placebo-controlled trial. The primary endpoint of improved clinical status on a seven-category ordinal scale (1, discharged/ready for discharge; 7, death) at day 28 was not met in this trial. Among the secondary endpoints, no difference in mortality at day 28 was observed, but time to hospital discharge was shorter in the tocilizumab group. Subgroup analysis suggested there might be a treatment benefit in patients grouped according to their ordinal scale category at baseline. We searched PubMed on September 14, 2020, using the terms "tocilizumab AND (COVID-19 OR coronavirus) AND biomarker" with no language or date restrictions. The search retrieved 18 articles, four of which identified laboratory measures as potential biomarkers in patients who received tocilizumab for the treatment of COVID-19 pneumonia. The biomarkers reported in these studies include interleukin-6, C-reactive protein, ferritin, fibrinogen, liver transaminases, lymphocytes, platelets, and D-dimer. However, these previous studies were single-centre, retrospective, observational studies. Larger, prospective, controlled trials are needed to investigate potential prognostic and predictive biomarkers to assess the outcomes and response to treatments for COVID-19. Added value of this studyThis exploratory analysis of data from COVACTA demonstrated interleukin-6, C-reactive protein, ferritin, neutrophils (percentage and absolute count), neutrophil-to-lymphocyte ratio, lymphocytes (percentage and absolute count), monocytes (percentage), and platelets as strong prognostic biomarkers in patients hospitalised with severe COVID-19 pneumonia. More important, ferritin showed predictive value for tocilizumab treatment effects on day 28 clinical outcomes of mortality, mechanical ventilation (among the subgroup of patients not receiving mechanical ventilation at randomisation), and clinical status compared with placebo. Implications of all the available evidenceIn patients with elevated levels of ferritin at baseline, tocilizumab decreased the probability of death, mechanical ventilation, and worsening clinical status at day 28 compared with placebo, suggesting that ferritin might be useful as a predictive biomarker of efficacy outcomes for tocilizumab in patients with severe COVID-19 pneumonia.

Functional alteration of innate T cells in critically ill Covid-19 patients

Covid-19 can induce lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors in Covid-19-driven ARDS are poorly understood. Here, we dynamically analyzed the biology of innate T cells, a heterogeneous class (MAIT, {gamma}{delta}T and iNKT cells) of T lymphocytes, presenting potent anti-infective and regulatory functions. Patients presented a compartmentalized lung inflammation paralleled with a limited systemic inflammation. Circulating innate T cells of critically ill Covid-19 patients presented a profound and persistent phenotypic and functional alteration. Highly activated innate T cells were detected in airways of patients suggesting a recruitment to the inflamed site and a potential contribution in the regulation of the local inflammation. Finally, the expression of the CD69 activation marker on blood iNKT and MAIT cells at inclusion was predictive of disease severity. Thus, patients present an altered innate T cell biology that may account for the dysregulated immune response observed in Covid-19-related acute respiratory distress syndrome.

Towards real-time assessment of anisotropic plate properties using elastic guided waves.

A method to recover the elastic properties, thickness, or orientation of the principal symmetry axes of anisotropic plates is presented. This method relies on the measurements of multimode guided waves, which are launched and detected in arbitrary directions along the plate using a multi-element linear transducer array driven by a programmable electronic device. A model-based inverse problem solution is proposed to optimally recover the properties of interest. The main contribution consists in defining an objective function built from the dispersion equation, which allows accounting for higher-order modes without the need to pair each experimental data point to a specific guided mode. This avoids the numerical calculation of the dispersion curves and errors in the mode identification. Compared to standard root-finding algorithms, the computational gain of the procedure is estimated to be on the order of 200. The objective function is optimized using genetic algorithms, which allow identifying from a single out-of-symmetry axis measurement the full set of anisotropic elastic coefficients and either the plate thickness or the propagation direction. The efficiency of the method is demonstrated using data measured on materials with different symmetry classes. Excellent agreement is found between the reported estimates and reference values from the literature.

Laser beam shaping for enhanced Zero-Group Velocity Lamb modes generation.

Optimization of Lamb modes induced by laser can be achieved by adjusting the spatial source distribution to the mode wavelength (λ). The excitability of Zero-Group Velocity (ZGV) resonances in isotropic plates is investigated both theoretically and experimentally for axially symmetric sources. Optimal parameters and amplitude gains are derived analytically for spot and annular sources of either Gaussian or rectangular energy profiles. For a Gaussian spot source, the optimal radius is found to be λZGV/π. Annular sources increase the amplitude by at least a factor of 3 compared to the optimal Gaussian source. Rectangular energy profiles provide higher gain than Gaussian ones. These predictions are confirmed by semi-analytical simulation of the thermoelastic generation of Lamb waves, including the effect of material attenuation. Experimentally, Gaussian ring sources of controlled width and radius are produced with an axicon-lens system. Measured optimal geometric parameters obtained for Gaussian and annular beams are in good agreement with theoretical predictions. A ZGV resonance amplification factor of 2.1 is obtained with the Gaussian ring. Such source should facilitate the inspection of highly attenuating plates made of low ablation threshold materials like composites.

Investigation of interfacial stiffnesses of a tri-layer using Zero-Group Velocity Lamb modes.

Zero-Group Velocity (ZGV) Lamb waves are studied in a structure composed of two plates bonded by an adhesive layer. The dispersion curves are calculated for a Duralumin/epoxy/Duralumin sample, where the adhesion is modeled by a normal and a tangential spring at both interfaces. Several ZGV modes are identified and their frequency dependence on interfacial stiffnesses and on the bonding layer thickness is numerically studied. Then, experiments achieved with laser ultrasonic techniques are presented. Local resonances are measured using a superimposed source and probe. Knowing the thicknesses and elastic constants of the Duralumin and epoxy layers, the comparison between theoretical and experimental ZGV resonances leads to an evaluation of the interfacial stiffnesses. A good agreement with theoretical dispersion curves confirms the identification of the resonances and the parameter estimations. This non-contact technique is promising for the local evaluation of bonded structures.

Phase-sensitive narrowband heterodyne holography.

We report on amplitude and phase imaging of out-of-plane sinusoidal surface vibration at nanometer scales with a heterodyne holographic interferometer. The originality of the proposed method is to make use of a multiplexed local oscillator to address several optical sidebands into the temporal bandwidth of a sensor array. This process is called coherent frequency-division multiplexing. It enables simultaneous recording and pixel-to-pixel division of sideband holograms, which permits quantitative wide-field mapping of optical phase-modulation depths. Additionally, a linear frequency chirp ensures the retrieval of the local mechanical phase shift of the vibration with respect to the excitation signal. The proposed approach is validated by quantitative motion characterization of the lamellophone of a musical box, behaving as a group of harmonic oscillators, under weak sinusoidal excitation. Images of the vibration amplitude versus excitation frequency show the resonance of the nanometric flexural response of one individual cantilever, at which a phase hop is measured.