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.

     

The relationship of scoring systems and mortality in the surgical intensive care unit

To determine the relationship between severity of illness and mortality, therapeutic intervention score (TISS) and acute physiology score (APS) were determined on admission to the Surgical Intensive Care Unit (SICU). Patients were divided into survivors and nonsurvivors and differences were compared by chi-square analysis. The 1524 patients admitted to the SICU during a 12-month period had a mean TISS of 3.03 and a mean APS of 13. The average length of stay (LOS) was 3.75 days. Of the 1524 patients, 97 (6.4%) died. The number of nonsurvivors increased with higher TISS and APS scores (P less than 0.001). There were no deaths in the TISS Category 1 patients or in the APS 0-5 group. Mortality rates dramatically increased with APS greater than 20 (P less than 0.001). There were 1286 patients with APS less than 20, and 24 (2%) of these patients died, whereas 73 (31%) of 238 patients with APS greater than 20 died. Nonsurvivors had a mean TISS of 3.6, mean APS of 27, and LOS of 4.88 days, all of which totals were higher than the survivors' totals. In this study population, risk of death was one in three if the APS was greater than 20. These data indicate that TISS and APS scores are effective means of assessing mortality risk in SICU patients.     

Bridges and barriers to recovery: Clinical observations from an opiate recovery project

Clinical issues are described in opiate addicts attempting to taper off methadone maintenance, and techniques are suggested to help this patient population. The observations were generated in an experimental “Tapering Network” project, in which opiate addicts on methadone maintenance had the opportunity to receive individual and group counseling, relapse prevention training, self-help groups, and other services. Vignettes illustrate clinical problems with intimacy and social isolation, identity as a former addict, and a “post methadone syndrome” characterized by vulnerability, dramatic swings in mood, and disordered thinking for a period of up to six months after detoxification. To counteract these barriers to recovery, a program model is suggested that uses curricula available in the emerging literature on treatment of substance abuse. These techniques can provide bridges to recovery.     

Inconsistencies in paranoid functioning, premorbid adjustment, and chronicity: question of diagnostic criteria

Despite the widely held belief that paranoid behavior is associated with good premorbid adjustment, low chronicity, and high current functioning in psychiatric inpatients, inconsistencies in the literature suggest that supportive evidence may be an artifact of the measurement model commonly used to index paranoid status. In a sample of 497 nonorganic inpatients selected from 19 treatment units, paranoid behavior, when measured by a dimensional/cumulative model, was not found to indicate higher functioning and associated relationships, but simply to reflect a narrower class of problem behavior. Only when paranoid status was defined using a traditional model based on the predominance of the defining class of behavior did paranoid subjects demonstrate better premorbid adjustment, lower chronicity, and higher levels of functioning than nonparanoid subjects. Serious problems exist in the use of information obtained from traditional predominance/class models for either theoretical or practical purposes.     

Damage mechanics and load failure of fiber-reinforced composite fixed partial dentures

OBJECTIVES: Damage mechanics has been defined as the study of the initiation (initial failure) and accumulation of damage to and including rupture (final failure). This study was designed to evaluate the effect of increasing fiber-reinforced composite (FRC) substructure within a standardized fixed partial denture (FPD) model on the failure performance, in terms of damage mechanics. METHODS: The two FRC restorative systems, Targis/Vectris (TV) (Ivoclar Vivadent) and EverStick (ES) (Stick Tech with Gradia, GC Corp.), were used to restore the molar FPD model (1.5 mm axial and 2.0 mm occlusal reduction). Templates were used to standardize substructure designs with 0, 18, 43, and 66% cross-sectional FRC volume fraction (V(FRC)) of fiber substructure. Specimens (n = 5) were homogenized at 29 points and stored for 1 week at 37 degrees C in distilled water. Specimens were luted with calcium hydroxide, then statically loaded until failure. Initial failure (IF), final failure (FF) and the mode of failure were recorded. RESULTS: The lowest mean load to initial failure was 530 N (TV 18%) and the highest was 1208 N (ES 66%). Linear regression analysis calculated the Pearson's correlation coefficient (r) for the interactions between V(FRC) and IF (ES: r = 0.7879, TV: r = 0.6184), V(FRC) and FF (ES: r = 0.912, TV: r = 0.8152), and between IF and FF (ES: r = 0.892, TV: r = 0.7237). Unreinforced specimens universally fractured instantaneously. SIGNIFICANCE: The highest loads to initial and final failure were yielded by specimens with the highest cross-sectional V(FRC).     

1 alpha,25-dihydroxyvitamin D3-induced increments in hepatocyte cytosolic calcium and lysophosphatidylinositol: inhibition by pertussis toxin and 1 beta,25-dihydroxyvitamin D3

1 alpha,25-Dihydroxyvitamin D3 rapidly increases cytosolic calcium and alters membrane phospholipid metabolism in hepatocytes. To define the causal relationship between these events, we examined the effects of 1 alpha,25-dihydroxyvitamin D3 on 32P-labeled lysophosphatidylinositol levels and cytosolic calcium as affected by pertussis toxin and 1 beta,25-dihydroxyvitamin D3, the biologically inactive analog. 32P-labeled lysophosphatidylinositol was determined by two-dimensional thin-layer chromatography. Cytosolic calcium was measured in cells loaded with quin-2AM. Within 5 min, 1 alpha,25-dihydroxyvitamin D3 increased hepatocyte cytosolic calcium by 31% (p less than 0.05) and 32P-labeled lysophosphatidylinositol by 38% (p less than 0.05). Pertussis toxin inhibited the hormone-induced rise in cytosolic calcium but not the increase in 32P-labeled lysophosphatidylinositol. Exposure to exogenous lysophosphatidylinositol for 5 min increased cytosolic calcium by 40% (p less than 0.05), an effect that was also inhibited by pertussis toxin. 1 beta,25-Dihydroxyvitamin D3 had no effect on either hepatocyte cytosolic calcium or 32P-labeled lysophosphatidylinositol but prevented the 1 alpha,25-dihydroxyvitamin D3-induced increments. The results suggest that a G protein sensitive to pertussis toxin is required for the transduction of the lysophosphatidylinositol signal but not the generation of the signal. The ability of 1 beta,25-dihydroxyvitamin D3 to inhibit the 1 alpha,25-dihydroxyvitamin D3-induced changes in phospholipids suggests that the epimer may compete with 1 alpha,25-dihydroxyvitamin D3 for an initiating receptor.