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 significance of past mania or hypomania in the course and outcome of major depression

Patients with primary major depression (N = 372) were followed for 2 years to determine the prognostic importance of past manic or hypomanic episodes. While bipolar I and bipolar II patients were more likely to relapse and bipolar I patients were more likely to attempt suicide, these patients resembled nonbipolar depressed patients in likelihood of recovery and psychosocial impairment in various areas. Compared to nonbipolar patients, those with bipolar I depression were much more likely to develop mania, while bipolar II patients were more likely to develop hypomania. Cycling during the index episode predicted a relatively low likelihood of recovery for bipolar I patients but had no apparent prognostic significance for patients with bipolar II illness.     

Computer-assisted three-dimensional reconstruction of the hippocampal region based on serial sections

A large series of rabbit hippocampal Neo-Timm stained sections were manually aligned, digitized, and by a modified median filtration noise reduced and reconstructed into a three-dimensional object. From the presented simulated grey tone cuts of this object, the reader may assemble a rabbit hippocampal model, that spatially illustrates its anatomy.     

Digital subtraction radiography for assessment of simulated root resorption cavities. Performance of conventional and reverse contrast modes

Abstract A previous study of the sensitivity and accuracy of a standardized radiographic technique for the disclosure of root cavities in a cadaver material indicated that it was not possible to perceive small artificial “resorption” cavities. Using the same material, the aim of the present study was to evaluate whether the use of subtraction radiography would improve the detection of root cavities. In an autopsy material of five mandibular blocks each containing two premolars, small, medium, and large cavities were drilled in the cervical, middle, and apical thirds of the proximal and oral root surfaces. Each jaw block was radiographed before (B) and after (A) cavity preparation with three different exposure times resulting in light, medium, and dark film densities. The radiographs were digitized. Digital subtraction was performed between the A- and B images of varying densities by a computer program developed for dental subtraction radiography. Conventional and reverse contrast modes of the subtraction image were assessed independently by four observers. The results showed small inter- and intraobserver differences in diagnostic accuracy for assessment of total number of root cavities. Original film density did not influence the diagnostic performance in the resulting subtraction image. Contrast mode in the subtraction image influenced diagnostic performance as the majority of observers did best with the reverse contrast mode (p<0.05). Some of the small root cavities were disclosed by the subtraction technique, but overall accuracy was not increased compared to conventional radiography.     

Regenerative growth is impacted by TCDD: gene expression analysis reveals extracellular matrix modulation.

Adult zebrafish can completely regenerate their caudal fin following amputation. This complex process is initiated by the formation of an epithelial wound cap over the amputation site by 12 h post amputation (hpa). Once the cap is formed, mesenchymal cells proliferate and migrate from sites distal to the wound plane and accumulate under the epithelial cap forming the blastemal structure within 48 hpa. Blastemal cells proliferate and differentiate, replacing the amputated tissues, which are populated with angiogenic vessels and innervating nerves during the regenerative outgrowth phase which is completed around 14 days post amputation (dpa). Regenerative outgrowth does not occur in TCDD-exposed zebrafish. To identify the molecular pathways that are perturbed by TCDD exposure, male zebrafish were ip injected with 50 ng/g TCDD or vehicle and caudal fins were amputated. Regenerating fin tissue was collected at 1, 3, and 5 dpa for mRNA abundance analysis. Microarray analysis and quantitative real time PCR revealed that wound healing and regeneration alone altered the expression of nearly 900 genes by at least two-fold between 1 and 5 dpa. TCDD altered the abundance of 370 genes at least two-fold. Among these, several known aryl hydrocarbon responsive genes were identified in addition to several genes involved in extracellular matrix composition and metabolism. The profile of misexpressed genes is suggestive of impaired cellular differentiation and extracellular matrix composition potentially regulated by Sox9b.     

Alternative growth opportunities for contraceptive social marketing programs.

As social marketing programs mature and exhaust their initial "natural" markets, they must seek growth from alternative sources. The author explores both conceptually and empirically four approaches to growth that vary in the degree to which they concentrate on current products/services and/or current customers. The growth experiences of three contraceptive social marketing programs are reported and lessons from those experiences are derived. The author concludes by discussing the broader issue of what circumstances should justify growth of a social marketing program beyond its initial mandate.     

Suppression of serum antibody responses by pertussis toxin after respiratory tract colonization by Bordetella pertussis and identification of an immunodominant lipoprotein

Pertussis toxin (PT), a virulence factor secreted by Bordetella pertussis, contributes to respiratory tract infection and disease caused by this pathogen. By comparing a wild-type (WT) B. pertussis strain to a mutant strain with an in-frame deletion of the ptx genes encoding PT (DeltaPT), we recently found that the lack of PT confers a significant defect in respiratory tract colonization in mice after intranasal inoculation. In this study, we analyzed serum antibody responses in mice infected with the WT or DeltaPT strain and found that infection with the DeltaPT strain elicited greater responses to several B. pertussis antigens than did infection with the WT, despite the lower colonization level achieved by the DeltaPT strain. The same enhanced antibody response was observed after infection with a strain expressing an enzymatically inactive PT; but this response was not observed after infection with B. pertussis mutant strains lacking filamentous hemagglutinin or adenylate cyclase toxin, nor when purified PT was administered with the DeltaPT inoculum, indicating a specific role for PT activity in this immunosuppressive effect. In particular, there were consistent strong serum antibody responses to one or more low-molecular-weight antigens after infection with the DeltaPT strain. These antigens were Bvg independent, membrane localized, and also expressed by the closely related pathogens Bordetella parapertussis and Bordetella bronchiseptica. Two-dimensional gel electrophoresis and mass spectrometry were used to identify one of the immunodominant low-molecular-weight antigens as a protein with significant sequence homology to peptidoglycan-associated lipoprotein in several other gram-negative bacterial species. However, a serum antibody response to this protein alone did not protect mice against respiratory tract infection by B. pertussis.     

Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling

Achromatopsia is an autosomal recessive disease of the retina, characterized clinically by an inability to distinguish colors, impaired visual acuity, nystagmus and photophobia. A genome-wide search for linkage was performed using an inbred Jewish kindred from Iran. To facilitate the genome-wide search, we utilized a DNA pooling strategy which takes advantage of the likelihood that the disease in this inbred kindred is inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as the PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pool was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest LOD score observed was 5.4 (theta = 0). When four additional small unrelated families were genotyped, the combined peak LOD score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30 cM interval which spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. A candidate gene for achromatopsia was excluded from this disease interval by radiation hybrid mapping. Linkage of achromatopsia to chromosome 2 is an essential first step in the identification of the disease-causing gene.      

Cerebrospinal fluid tau and beta-amyloid(1-42) in dementia disorders

The reliability of cerebrospinal fluid (CSF)-tau and CSF-beta-amyloid assays for diagnosis of Alzheimer's disease and other dementing disorders such as frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and Creutzfeldt-Jakob disease (CJD) is reviewed. CSF assessment of the two proteins is useful in early diagnosis of AD and to differentiate it from FTD and DLB. Extremely high CSF-tau levels can discriminate CJD from AD.