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.

     

Preparation and bioevaluation of 99mTc-carbonyl complex of 5-hydroxy tryptamine derivative.

Studies on the development of imaging agents for targeting neuroreceptors is an area of considerable interest owing to the limited availability of specific as well as selective radiolabeled agents. Therefore, with an aim of developing a receptor-specific agent, iminodiacetic acid (IDA) derivative of 5-hydroxy tryptamine viz., HTIDA has been synthesized. HTIDA could be radiolabeled with the synthon [(99m)Tc(CO)(3)(H(2)O)(3)](+) in >98% yield. The biodistribution studies in normal Swiss mice showed that the (99m)Tc(CO)(3)-HTIDA crosses the blood-brain barrier successfully with a brain uptake of 0.5%ID/g at 5min post injection. The other relevant observations from biodistribution studies included no significant uptake in any other organ and fast clearance from blood, lungs and liver.     

(iii) Minimal invasive techniques in the management of tibial plateau fractures

Intra-articular fractures of the proximal tibia present a wide spectrum of injury patterns with associated soft tissue injury. The last two decades have seen the techniques of management evolve from extensive open reduction and rigid internal fixation to arthroscopy-assisted minimal invasive surgery (MIS) and biologically benign internal fixation. The ultimate aim is to prevent the occurrence of late degenerative arthritis. This could be achieved in selected patients using minimal invasive surgery, which offers the advantages of better visualisation and management of intra-articular soft tissue injuries, confirmation of fracture reduction viewed from the joint surface, faster rehabilitation and fewer wound complications.     

Effects of amiodarone and desethylamiodarone on rabbit myocardial beta-adrenoceptors and serum thyroid hormones--absence of relationship to serum and myocardial drug concentrations

The antiadrenergic actions of amiodarone (Am) are well known but its effect and that of its metabolite, desethylamiodarone (DAm), on beta-receptor density (Bmax) and affinity (KD) are poorly defined. Thus, the acute and chronic effects of Am and DAm on myocardial beta-receptors in rabbits were determined relative to changes in thyroid hormones and serum and tissue drug concentrations. Bmax and KD were measured by radio-ligand binding, thyroid hormones by RIA, and drug levels by HPLC. Compared with controls, intravenous Am (20 mg/kg) reduced Bmax by 23% (p less than 0.05) and DAm (20 mg/kg) by 32% (p less than 0.05). After 3 weeks of chronic drug, the corresponding value for Am was 24% (p less than 0.05) versus 45% (p less than 0.05) for DAm. The effect of DAm was significantly greater (p less than 0.05) than that of Am, being comparable to that of Am (-44%) after 6 weeks. In the case of Am, doubling the dose (and myocardial level) led to no further decrease in Bmax. DAm also reduced Bmax more following chronic treatment than after acute administration (-45 versus -32%), a difference of borderline significance. Following 3 weeks of p.o. Am, T3 decreased 3% (NS) and reverse T3 (rT3) increased 90% (p less than 0.05); after 6 weeks, the corresponding values were 25% (p less than 0.05) and 181% (p less than 0.01). After 1 week of p.o. DAm, T3 did not change but rT3 increased by 34% (p less than 0.05); after 3 weeks the corresponding values were 21% (p less than 0.01) and 64% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Emergence of occult minority genotype 2b hepatitis C infection in an HIV-1-co-infected patient treated for genotype 5a HCV infection with 48 weeks of pegylated-interferon-alpha 2b and ribavirin.

An HIV-1/hepatitis C virus (HCV) co-infected patient with haemophilia received a 48-week course of pegylated interferon-alpha-2b and ribavirin therapy for genotype 5a HCV infection. Virological response was achieved at week 24. At the end of treatment, HCV RNA in serum was detected and identified to belong to genotype 2b, rather than genotype 5a. A sensitive method for identifying minority HCV genotypes in pre-treatment serum showed genotype 2b HCV carriage prior to treatment. Sequencing the interferon sensitivity-determining region of the HCV NS5A gene obtained from pre-, intra- and post-treatment sera revealed emergence of quasispecies bearing R-->K and M-->A/T mutations at codons 2222 and 2223, respectively. Occult presence of minority HCV subpopulations and their acquisition of mutations following therapy can result in poor treatment outcome.     

Alteration of pulse configuration affects the pain response during diode laser photocoagulation

Background and Objective: The shape of the treatment pulse of the diode laser (810 nm) can be easily altered electronically in contrast to ion laser photocoagulators. We investigated whether changes in laser pulse shape influenced the subjective pain response in patients undergoing retinal photocoagulation when only topical anesthesia was used. Study Design/Materials and Methods: Twenty consecutive patients required peripheral retinal photocoagulation for proliferative diabetic retinopathy or extensive retinal breaks. Three diode pulse waveforms including a square wave, shaped-wave, and an envelope of micropulses were compared to one another. Power was adjusted so that each waveform delivered the same total energy. The patients subjectively ranked the intensity of any pain they experienced for each group of lesions. Responses were compared to one another using an analysis of variance. Results: 40% of patients found the standard square wave pulse to be significantly more painful (P < 0.05) than the shaped pulse mode and 30% found the square wave significantly more painful (P < 0.05) than the micropulse mode. Conclusion: Modification of the laser pulse waveform may ameliorate pain induced by diode laser photocoagulation of the retinal periphery. © 1995 Wiley-Liss, Inc.     

Real-time imaging of Rab3a and Rab5a reveals differential roles in presynaptic function

We investigated the roles of two Rab-family proteins, Rab3a and Rab5a, in hippocampal synaptic transmission using real-time fluorescence imaging. During synaptic activity, Rab3a dissociated from synaptic vesicles and dispersed into neighbouring axonal regions. Dispersion required calcium-dependent exocytosis and was complete before the entire vesicle pool turned over. In contrast, even prolonged synaptic activity produced limited dispersion of Rab5a. A GTPase-deficient mutant, Rab3a (Q81L), dispersed more slowly than wild-type Rab3a, and decreased the rate of exocytosis and the size of the recycling pool of vesicles. While overexpression of Rab3a did not affect vesicle recycling, overexpression of Rab5a reduced the recycling pool size by 50%. We propose that while Rab3a preferentially associates with recycling synaptic vesicles and modulates their trafficking, Rab5a is largely excluded from recycling vesicles.