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.

     

Altered modulation of prefrontal and subcortical brain activity in newly diagnosed schizophrenia and schizophreniform disorder. A regional cerebral blood flow study.

To measure prefrontal and subcortical activity during a cognitive task, we examined 19 newly diagnosed schizophrenics and patients with schizophreniform psychosis. Seven healthy volunteers served as controls. The patients were drug naive or had received neuroleptics for a few days only. Cerebral blood flow distribution was depicted by single photon emission computed tomography at rest and during activation with the Wisconsin Card Sorting Test. A significant relative activation deficit in the left inferior-prefrontal region was revealed during the Wisconsin Card Sorting Test in the patient group. Furthermore, the patients had impaired striatal suppression on the left side during the cognitive task. The test performance was significantly impaired in the patients. The inability to reduce striatal activity may be due to a lack of corticostriatal feedback during prefrontal activation.     

Nephrotic syndrome in a mother and her infant: relationship with cytomegalovirus infection

This case report describes infantile nephrotic syndrome (NS) in a baby girl with a clinically severe cytomegalovirus (CMV) infection. Culture of the baby's urine was positive for CMV and IgM anti-CMV antibodies were detected. After an unsuccessful course of corticosteroids, gancyclovir treatment was started and a remission of cutaneous, pulmonary, and renal symptoms was achieved. As the mother also developed NS at the end of pregnancy, a common etiology could be postulated, although there were no signs of recent CMV infection in the mother, only anti-CMV IgG. The relationship between CMV infection and glomerular disease is still unclear: NS may represent another manifestation of CMV disease.     

Pharmacokinetics of terodiline and a major metabolite in dogs with a correlation to a pharmacodynamic effect

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N-tert-butyl-1-methyl-3,3-diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half-life 3 hr, the systemic clearance 40 ml/min..kg, the volume of distribution (V beta) about 7 l/kg and the unbound fraction in serum 0.14. p-Hydroxyterodiline and p-hydroxy-m-methoxyterodiline were quantitated and constituted 15-40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p-hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 micrograms/l following intravenous injection of terodiline or p-hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 micrograms/l. The potency ratios of terodiline/p-hydroxyterodiline was 0.9 +/- 0.2 (based on total concentrations) and 3.2 +/- 0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p-hydroxyterodiline constitutes 10-20% of the terodiline steady-state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.     

Influence of spinal immobilization on consolidation of posterolateral lumbosacral fusion. A roentgen stereophotogrammetric and radiographic analysis.

To determine the influence of the duration of postoperative lumbar immobilization with the aid of a rigid lumbar orthosis on the consolidation of posterolateral lumbosacral fusions, 22 patients with no previous osseous spinal surgery and with fusion without osteosynthesis due to spondylolysis-olisthesis Grade 1 to 2 or intervertebral disc or facet joint disorder were examined by roentgen stereophotogrammetric analysis in supine and erect positions and by conventional radiography for 1 year after surgery. In Series 1, patients (n = 11) were instructed to keep the trunk straight with the aid of a molded, rigid lumbar orthosis for 5 months after surgery; and in Series 2 (n = 11), the same instructions were given, but for 3 months. In Series 1, osseous fusion was seen on radiographs in eight patients. In these patients, the intervertebral translations between the fused vertebrae began to decrease 3-6 months after surgery, and within 1 year, the fusions became rigid, as defined by roentgen stereophotogrammetric analysis, or intervertebral translations of mostly less than 1 mm persisted. In three patients with poor fusion still seen on radiographs 1 year after surgery, no rigid fusion was obtained and intervertebral translations of up to 10 mm persisted. In Series 2, a similar roentgen stereophotogrammetric analysis pattern was noted in two patients with osseous fusion and in seven with poor fusion seen on radiographs. The fusion was radiographically doubtful in two patients. In these patients, the intervertebral translations decreased, but translations of 1.5 mm persisted 1 year after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

How reproducible is cutaneous electrogastrography? An in-depth evidence-based study1

AIM: To check on reproducibility of parameters of the cutaneous electrogastrogram registered at a close or a distant time span. METHODS: Twenty-two volunteers recruited by an advertisement (11 females and 11 males, median age 25 years, range: 18-35) underwent three surface electrogastrography examinations of which two were taken on consecutive days and the third one was accomplished at least 2 weeks before or after the two other sessions. The examination involved a 30-min fasted recording, followed by a 90-min postprandial registration after intake of a 394-kcal mixed solid-liquid test meal. RESULTS: Parameters of the electrogastrogram pertaining to the frequency of the gastric slow waves exhibited good to moderate reproducibility, whereas fair reproducibility characterized parameters expected to describe the power of gastric slow waves. With the exception of the difference fed minus fasted power (DeltaDP), in no instance was the medium term reproducibility any worse than the short term one. Categorical data analysis revealed that the relative time share of normogastria postprandially exhibited a better reproducibility than in the fasted period. The Cohen's kappa-value of 0.459 for the DeltaDP for the medium term reproducibility placed this parameter within the range of moderate agreement between repeat examinations. Of the two two-parameter combinations considered, the alliance of the fasted and fed normogastria performed worse than any of those parameters considered alone, whereas a combination of the DeltaDP with the fed-state normogastria revealed a kappa-value amounting to 0.510 for the medium term reproducibility. CONCLUSIONS: The feasibility of some electrogastrographic parameters to convey clinically useful information may be hampered by their fair reproducibility. Recoding of parameters of the cutaneous electrogastrogram from primary continuous to secondary categorical may help achieve a better agreement between repeat examinations.     

CT scans and lipohaemarthrosis in hip fractures

Computed tomography was performed on 40 patients with recent hip trauma. Radiographs of 25 showed a fracture of the femoral neck with slight displacement; 24 of these had intra-articular fluid and 20 had a lipohaemarthrosis on the CT scan. In 15 patients, radiographs at the time of admission were normal but suspicion of fracture remained. A fracture was later verified in five patients, four of whom had lipohaemarthrosis on admission. In the remaining 10 patients no fracture could be detected; only one patient had a hip joint effusion but no free fat. Thus all 24 patients with lipohaemarthrosis had an intracapsular fracture of the hip. We suggest CT for patients with hip trauma and negative radiographs. The presence of a lipohaemarthrosis of the hip strongly suggests an intra-articular fracture of either the femoral neck or the acetabulum.     

In vitro activity of oral cephalosporin BAY v 3522 compared with other oral cephalosporins

Minimal inhibitory concentrations (MICs) of the oral cephalosporin BAY v 3522, and of cephprozyl, cefaclor, cefixime, cefuroxime, cefetamet, cefpodoxime and cefotaxime were determined against Gram-positive and Gram-negative clinical isolates with the NCCLS agar dilution procedures. BAY was the most active drug against Gram-positive organisms. MICs ranged from 0.01 mg/l against group A streptococci to 16 mg/l against S. faecium. Although mean MICs of BAY against methicillin-resistant S. aureus and S. epidermidis were between 0.9-1.8 mg/l, respectively, such strains showed typical heteroresistance in population studies. In addition, the biochemical correlate of methicillin-resistance, the PBP-2', showed similar low affinity to BAY as methicillin. beta-lactamase-producing H. influenzae and B. catarrhalis were inhibited by 2-8 and 0.25-2 mg/l, respectively, whereas non-producers were inhibited by 0.25-2 and 0.12-1 mg/l of the drug. The activity of BAY against enterobacteriaceae was rather low. Ampicillin-susceptible E. coli strains were inhibited by 2-8 and resistant strains by 8-32 mg/l. The mean MIC against cephalothin-susceptible K. pneumoniae strains was 2.8, and that against resistant strains 27.4 mg/l. MICs against beta-lactamase-producing enterobacteriaceae determined in broth dilution were 4-8 times higher than those determined in agar dilution. Bactericidal activity was measured in killing-curve experiments at 4 times the MIC. BAY killed equally well as standard control drugs.