Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

The spatiotemporal evolution of cerebral microcirculatory adjustments to functional brain stimulation is the fundamental determinant of the functional specificity of hemodynamically weighted neuroimaging signals. Very little data, however, exist on the functional reactivity of capillaries, the vessels most proximal to the activated neuronal population. Here, we used two-photon laser scanning microscopy, in combination with intracranial electrophysiology and intravital video microscopy, to explore the changes in cortical hemodynamics, at the level of individual capillaries, in response to steady-state forepaw stimulation in an anesthetized rodent model. Overall, the microcirculatory response to functional stimulation was characterized by a pronounced decrease in vascular transit times (20%+/-8%), a dilatation of the capillary bed (10.9%+/-1.2%), and significant increases in red blood cell speed (33.0%+/-7.7%) and flux (19.5%+/-6.2%). Capillaries dilated more than the medium-caliber vessels, indicating a decreased heterogeneity in vessel volumes and increased blood flow-carrying capacity during neuronal activation relative to baseline. Capillary dilatation accounted for an estimated approximately 18% of the total change in the focal cerebral blood volume. In support of a capacity for focal redistribution of microvascular flow and volume, significant, though less frequent, local stimulation-induced decreases in capillary volume and erythrocyte speed and flux also occurred. The present findings provide further evidence of a strong functional reactivity of cerebral capillaries and underscore the importance of changes in the capillary geometry in the hemodynamic response to neuronal activation.

We propose an echo planar imaging (EPI) distortion correction method (DR-BUDDI), specialized for diffusion MRI, which uses data acquired twice with reversed phase encoding directions, often referred to as blip-up blip-down acquisitions. DR-BUDDI can incorporate information from an undistorted structural MRI and also use diffusion-weighted images (DWI) to guide the registration, improving the quality of the registration in the presence of large deformations and in white matter regions. DR-BUDDI does not require the transformations for correcting blip-up and blip-down images to be the exact inverse of each other. Imposing the theoretical “blip-up blip-down distortion symmetry” may not be appropriate in the presence of common clinical scanning artifacts such as motion, ghosting, Gibbs ringing, vibrations, and low signal-to-noise. The performance of DR-BUDDI is evaluated with several data sets and compared to other existing blip-up blip-down correction approaches. The proposed method is robust and generally outperforms existing approaches. The inclusion of the DWIs in the correction process proves to be very important to obtain a reliable correction of distortions in the brain stem. Methods that do not use DWIs may produce a visually appealing correction of the non-diffusion weighted b = 0 s/mm2 images, but the directionally encoded color maps computed from the tensor reveal an abnormal anatomy of the white matter pathways.

No abstract

Diffusion tensor imaging (DTI) is the most widely used method for characterizing non-invasively structural and architectural features of brain tissues. However, the assumption of a Gaussian spin displacement distribution intrinsic to DTI weakens its ability to describe intricate tissue microanatomy. Consequently, the biological interpretation of microstructural parameters, such as fractional anisotropy or mean diffusivity is often equivocal. We evaluate the clinical feasibility of assessing brain tissue microstructure with mean apparent propagator (MAP) MRI, a powerful analytical framework that efficiently measures the probability density function (PDF) of spin displacements and quantifies useful metrics of this PDF indicative of diffusion in complex microstructure (e.g., restrictions, multiple compartments). Rotation invariant and scalar parameters computed from the MAP show consistent variation across neuroanatomical brain regions and increased ability to differentiate tissues with distinct structural and architectural features compared with DTI-derived parameters. The return-to-origin probability (RTOP) appears to reflect cellularity and restrictions better than MD, while the Non-Gaussianity (NG) measures diffusion heterogeneity by comprehensively quantifying the deviation between the spin displacement PDF and its Gaussian approximation. Both RTOP and NG can be decomposed in the local anatomical frame for reference determined by the orientation of the diffusion tensor and reveal additional information complementary to DTI. The Propagator Anisotropy (PA) shows high tissue contrast even in deep brain nuclei and cortical gray matter and is more uniform in white matter than the FA, which drops significantly in regions containing crossing fibers. Orientational profiles of the propagator computed analytically from the MAP MRI series coefficients allow separation of different fiber populations in regions of crossing white matter pathways, which in turn improves our ability to perform whole brain fiber tractography. Reconstructions from subsampled data sets suggest that MAP MRI parameters can be computed from a relatively small number of DWIs acquired with high b-value and good signal-tonoise ratio in clinically achievable scan durations of less than 10 minutes. The neuroanatomical consistency across healthy subjects and reproducibility in test-retest experiments of MAP MRI microstructural parameters further substantiate the robustness and clinical feasibility of this technique. The MAP MRI metrics could potentially provide more sensitive clinical biomarkers with increased pathophysiological specificity compared to microstructural measures derived using conventional diffusion MRI techniques.

No abstract

No abstract

SUMMARYWe generated a knockout mouse for the neuronalspecific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3−/− mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total b-tubulin levels in Tubb3−/− and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins.