Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Tacrolimus Combined with Two Different Dosages of Sirolimus in Kidney Transplantation: Results of a Multicenter Study

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus-MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC-SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC-SRL0.5 mg) and 327 patients 1 g MMF (TAC-MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy-proven acute rejection was lower in the TAC-SRL2 mg group (15.7%) compared with the TAC-SRL0.5 mg (25.2%, p = 0.003) and the TAC-MMF groups (22.3%, p = 0.036). Six-month graft survival was 91.0% (TAC-SRL2 mg), 92.6% (TAC-SRL0.5 mg) and 92.4% (TAC-MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty-four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC-SRL2 mg, TAC-SRL0.5 mg and TAC-MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC-SRL2 mg group (24.0%) compared with 19.4% (TAC-SRL0.5 mg) and 11.0% (TAC-MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.     

Estimation of average flow in ungated 3D phase contrast angiograms

Three dimensional (3D) phase contrast angiograms contain velocity data, which is discarded after the reconstruction of the projections. In extension to earlier work on velocity quantification with ungated 2D phase data, this paper shows that a useful estimate of the average velocity and flow rate can be extracted from ungated 3D phase contrast angiograms. Simulations and experiments in a phantom and in vivo were performed. For pulsatile flow and strong spin saturation, an over-estimation of the flow rate at the net in-flow end of the imaging volume and underestimation at the net out-flow end was observed. Imaging at lower RF tip angles yielded flow rates close to the correct value within the entire imaging volume. In contrast to ungated 2D experiments, the flow rates determined by repeated 3D experiments showed no variation.     

Dentition planning with image-based occlusion analysis

Purpose To develop an easy-to-use, dentition planning method which is based on three-dimensional (3D) computer planning technology to replace conventional plaster-cast occlusion planning techniques. Methods The optimal dental occlusion is defined according to the condition of centric occlusion, i.e. after bringing occlusal surfaces of mandibular and opposing maxillary arches into identical 3D position. This identical position of occlusal surfaces represents the common reference frame for the 3D manipulation of all graphical elements. The planning procedure involves the following steps: (1) the optimal occlusal surface is approximated as triangle and localized both on the maxilla and mandible; (2) the original volumetric model is resampled according to the occlusal orientations; (3) the program reads in the models of ideal upper and lower dental arches from files, reshapes those to the patient anatomy and visualizes the local alignment on separate panels for mesiodistal and faciolingual inclinations. The final goal of the proposed method is to combine the requirements of functional and aesthetic designs and create an input for orthodontics, implantology and maxillofacial surgery. Results In the present study the optimal dental occlusion is created by image resampling after bringing the occlusal surfaces of mandibular and opposing maxillary arches into identical 3D position. This identical position of occlusal surfaces represents the common reference frame for manipulation of all graphical elements. Conclusions The proposed graphical environment was able to fit the elements of the ideal dentition curve to patient computed tomography under predefined centric occlusion. Rotation and scaling transformations of teeth were possible in the reformatted volumetric views about any of the axes of the teeth’s own reference space.     

Malignant tumours after renal transplantation.

The incidence of malignant tumours in 570 patients with kidney transplants was examined. It was found to be 20-30 times higher than in the average (normal) population. In accordance with the literature, mainly skin cancers were observed, but at variance with these data, the number of lymphoreticular malignancies was small. On the basis of their study, the authors emphasize the oncogenetic effect of immunosuppression. By comparing the conventional (AZA+PRED) and Cyclosporine (CYA+PRED) treatments, they point out that this risk should be taken into consideration even in Cyclosporine therapy which has otherwise a much more favourable effect.     

Biexponential diffusion tensor analysis of human brain diffusion data.

Several studies have shown that in tissues over an extended range of b-factors, the signal decay deviates significantly from the basic monoexponential model. The true nature of this departure has to date not been identified. For the current study, line scan diffusion images of brain suitable for biexponential diffusion tensor analysis were acquired in normal subjects on a clinical MR system. For each of six noncollinear directions, 32 images with b-factors ranging from 5 to 5000 s/mm2 were collected. Biexponential fits yielded parameter maps for a fast and a slow diffusion component. A subset of the diffusion data, consisting of the images obtained at the conventional range of b-factors between 5 and 972 s/mm2, was used for monoexponential diffusion tensor analysis. Fractional anisotropy (FA) of the fast-diffusion component and the monoexponential fit exhibited no significant difference. FA of the slow-diffusion biexponential component was significantly higher, particularly in areas of lower fiber density. The principal diffusion directions for the two biexponential components and the monoexponential solution were largely the same and in agreement with known fiber tracts. The second and third diffusion eigenvector directions also appeared to be aligned, but they exhibited significant deviations in localized areas.     

Invited. Brain edema development after MRI-guided focused ultrasound treatment

The aim of this study was to investigate a potential technique for image-guided minimally invasive neurosurgical interventions. Focused ultrasound (FUS) delivers thermal energy without an invasive probe, penetrating the dura mater, entering through the cerebrospinal fluid (CSF) space, or harming intervening brain tissue. We applied continuous on-line monitoring by MRI to demonstrate the effect of the thermal intervention on the brain tissue. For this, seven rabbits had a part of their skull removed to create access for the FUS beam into the brain through an acoustic window of 11 mm in diameter. Dura was left intact and skin was sutured. One week later, the rabbits were sonicated for 3 seconds with 21 W acoustic power, and the FUS focus was visualized with a temperature-sensitive T1-weighted MRI pulse sequence. The tissue reaction was documented over 7 days with T2-weighted images of the brain. The initial area of the central low signal intensity in the axial plane was .4 ± .3 mm², and for the bright hyperintensity surrounding the lesion, it was 2.3 ± .6 mm² (n = 7). In the coronal plane, the corresponding values were .4 ± .1 mm² and 3.4 ± .9 mm² (n = 5). The developing brain edema culminated 48 hours later and thereafter diminished during the next 5 days. Histology revealed a central necrosis in the white matter surrounded by edematous tissue with inflammatory cells. In summary, the image-guided thermal ablation technique described here produced a relatively small lesion in the white matter at the targeted location. This was accomplished without opening the dura or the need for a stereotactical device. MRI allowed on-line monitoring of the lesion setting and the deposition of thermal energy and demonstrated the tissue damage after the thermal injury.     

Post-ischemic administration of diazoxide attenuates long-term microglial activation in the rat brain after permanent carotid artery occlusion

Diazoxide is a putative mitochondrial, ATP-sensitive potassium channel opener that has been implicated in neuroprotection in cerebral ischemia. Administered as pretreatment, diazoxide can attenuate ischemia-related neuronal injury, but little is known about the potential neuroprotective properties of the drug when it is given after the onset of an ischemic insult. In a previous study, we applied diazoxide after imposing chronic cerebral hypoperfusion by means of permanent, bilateral occlusion of the common carotid arteries (2VO) in rats. We observed that ischemia-induced learning impairment assessed in the Morris water maze, and microglial activation visualized by immunocytochemistry, were prevented by diazoxide as determined at 13 weeks after 2VO. However, dimethyl sulfoxide, the organic solvent of diazoxide also prevented memory deficits, without any effect on microglial activity. Therefore, we have repeated our experiments with the use of an inorganic solvent, aqueous NaOH solution in order to clarify the effect of diazoxide independent of dimethyl sulfoxide. The present results demonstrated that diazoxide alone did not improve learning performance, but it prevented microglial activation in the hippocampus 13 weeks after the onset of 2VO. These data provide evidence that post-treatment with diazoxide is not effective in impeding a long-term memory deficiency, but it can attenuate ischemia-induced microglial activation, independently of the solvent used.