Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Attosecond pump-probe methods for measurement of molecular hole dynamics

The generation of few-cycle pulses at near-infrared wavelengths is now a robust technology, as is their application to the efficient production of high-order harmonics in the extreme ultraviolet region with temporal confinement to hundreds of attoseconds. Recent years have seen considerable efforts directed to the study of electron dynamics in complex molecules in real time, with relevance to processes such as photosynthesis and radiation damage of proteins and DNA. This work describes the development of new and unique sources suited for the study of such dynamics, together with novel instrumentation and experimental methodology. This includes a pair of synchronised attosecond pulses at different photon energies in the VUV and XUV regions, which we have generated via high harmonic generation from a few-cycle NIR source and characterised with attosecond streaking. We have also explored the possibilities of sub-cycle control of these attosecond pulses by adding a second harmonic field to the high- harmonic generation process, and simultaneously characterised this second harmonic field with a novel characterisation technique known as ARIES, capable of waveform sampling at arbitrary optical wavelengths. In parallel, we have developed a few-cycle short-wavelength IR source for a UK user facility, to take advantage of the favourable wavelength scaling of the maximum photon energy achievable via high-harmonic generation. Using a commercial optical parametric amplifier and a hollow-core fibre compression system, we have generated sub-2-cycle pulses at 1750 nm, characterised via third-harmonic autocorrelation and a novel implementation of the dispersion scan technique. We have commissioned a beamline for attosecond pump-probe studies in the gas phase, including a purpose-built dual spectrometer with capabilities for simultaneous measurement of mass spectra of ions and velocity-map imaging of electrons. We have performed initial VUV-NIR pump-probe experiments on a small organic molecule, namely isopropanol, and identified a time- dependent signature as an IR-induced coupling. Finally, we have considered perspectives for future studies in attosecond pump-probe experiments with the demonstration of a two-VUV-photon process in helium performed with a moderate energy, high repetition rate attosecond source.Open Acces

Nonclassicality in phase-number uncertainty relations

We show that there are nonclassical states with lesser joint fluctuations of phase and number than any classical state. This is rather paradoxical since one would expect classical coherent states to be always of minimum uncertainty. The same result is obtained when we replace phase by a phase-dependent field quadrature. Number and phase uncertainties are assessed using variance and Holevo relation