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.

     

Transplantation of central nervous tissue

Studies of post-lesional reorganization of central nervous connections have shown that central nerve fibers respond to nearby denervation by sprouting and formation of new terminals. The connections in the central nervous system (CNS) are accordingly much more plastic than was thought for a long time. This has revived the interest in transplantation of central nervous tissue. In this study we present some historical data on CNS transplantation supplemented by recent results obtained in our laboratory. Pieces of hippocampal tissue from embryonic or early postnatal rats were transplanted to different parts of the brain of littermates or adult rats. About two-thirds of the transplants were recovered after survival times ranging from 4 d to 2 years, and their cytological organization and intrinsic connections were monitored by cell and fiber stains and histochemical methods (AChE staining and Timm sulphide silver method). Comparison with both a normal and a lesioned control material revealed that in most transplants the tissue had developed as it does when left in situ in the donor brain, but deprived of its major afferent connections. In several instances we found evidence of a major exchange of connections between the transplants and host brains. The conditions needed for this to occur appeared to involve growth stimulation of host brain fibers by transection (host to transplant) and denervation of host neuropil (transplant to host). In cases where these conditions are met, the use of transplants may have future implications in attempts to repair lesions in the central nervous systems.     

Socioeconomic position and variations in coping strategies in musculoskeletal pain: a cross-sectional study of 1,287 40- and 50-year-old men and women.

OBJECTIVE: To examine the association between socioeconomic position and coping strategies in musculoskeletal pain. DESIGN AND SUBJECTS: Cross-sectional study of a random sample of 40- and 50-year-old Danes, participation rate 69%, n=7,125. The study included 1,287 persons who reported functional limitations due to musculoskeletal pain. METHODS: Data was collected by postal questionnaires and scales were developed on problem-solving coping and avoidant coping, based on a range of preliminary studies. Multivariate logistic regression analyses was used to study the correlation with socioeconomic position, measured by occupational social class. RESULTS: Among women, there was no correlation between social class and avoidant coping, but a significant decrease in the use of problem-solving coping by decreasing social class, adjusted odds ratio (OR) = 2.64 (95% confidence interval (CI) 1.31-5.32) in social class V vs social classes I + II. Among men, there was no correlation between social class and problem-solving coping, but a significant increase in the use of avoidant coping with decreasing social class, adjusted OR = 3.31 (95% CI 1.75-6.25) in V vs I + II. CONCLUSION: It is important for clinicians who advise and support patients in their response to musculoskeletal pain to be aware of socioeconomic differences in coping strategies. Gender differences in the association between socioeconomic factors and coping should be further investigated.     

Light microscopic morphometric analysis of castration effects in the different lobes of the rat prostate

The morphologic effects of androgen deprivation in the different lobes of the rat prostate were examined by light microscopic morphometry. The prostates of Wistar male rats (260-340 g) were fixed in situ by glutaraldehyde perfusion in castrated animals 1 week after gonadectomy and in intact animals. The ventral (VP), dorsal (DP), and lateral (LP) lobes as well as the coagulating gland (CG) were dissected out, weighed, and processed for light microscopy. Using stereologic methods the following parameters were estimated for each lobe: volume fraction of connective tissue, epithelium and glandular lumina, average epithelial height, average epithelial cell volume, and total number of epithelial cells. Castration leads to a 58-76% reduction of the wet weight of all prostatic lobes. The decrease of glandular tissue is greater in VP than in LP, DP, and CG. In VP and LP, there is a 39-45% reduction of the epithelial height, and this effect is less pronounced in DP and CG. For all lobes, the shrinkage of average epithelial cell volume is in the same range (25-30%). Moreover, in VP and LP, there is a 70% reduction of the total number of cells, whereas the reduction is less in DP and CG. It thus seems that the reduction of prostatic epithelial tissue mass upon castration is due to a reduction of the number of cells as well as a reduction of the volume of individual cells. VP and LP appear to be more androgen-dependent than DP and CG.     

Granulocytes in bronchial lavage fluid after major vascular surgery

Increased numbers of polymorphonuclear granulocytes (PMN) in the airways, as measured by PMN content in bronchial lavage fluid (P less than 0.01), were found 3 h postoperatively in ten patients undergoing surgery for lumbar aortic aneurysms. An increase in plasma levels of the complement split product C3dg from 6 (0-19) AU/ml preoperatively to 20 (13-50) AU/ml 3 h after surgery (P less than 0.01), indicates an activation of the complement cascade. These changes were not accompanied by increased elastase activity in the bronchial lavage fluid or by major changes in pulmonary blood gas exchange or vascular resistance, indicating that massive PMN activation, analogous to that proposed in adult respiratory distress syndrome (ARDS) had not taken place. In conclusion, complement system activation and migration of PMN into the airways, as seen in connection with major vascular surgery, does not seem to contribute to ARDS-type pulmonary dysfunction.     

Comparison of HLA-DR1-restricted T cell response induced in HLA-DR1 transgenic mice deficient for murine MHC class II and HLA-DR1 transgenic mice expressing endogenous murine MHC class II molecules

Transgenic mice expressing human HLA class II molecules provide a useful model for identifying HLA-restricted CD4+ epitopes. However, the influence of endogenous murine H-2-restricted T cell responses on HLA-restricted responses is not known. In the present study, we show that HLA-DR1 transgenic mice deficient for H-2 class II expression (HLA-DR1+/+/IAbeta0/0) exhibit an equivalent expression level of the transgene HLA-DR1 and a similar diversity in the TCR repertoire, but a slightly different number of CD4+ peripheral T cells, when compared to HLA-DR1 transgenic mice in which H-2 class II molecules were retained (HLA-DR1+/+/IAbeta+/+). More importantly, a strong antigen-specific HLA-DR1-restricted response was observed in nearly all HLA-DR1+/+/IAbeta0/0 mice immunized with HBV envelope protein (HBs) or capsid protein (HBc), whereas weak HBs- or HBc-specific HLA-DR1-restricted responses were detected in half of the immunized HLA-DR1+/+/IAbeta+/+ mice. Conversely, strong HBs- or HBc-specific H-2-restricted T cell responses were detected in HLA-DR1+/+/IAbeta+/+ mice but not in HLA-DR1+/+/IAbeta0/0 mice. Our results indicate that the coexpression of endogenous H-2 class II molecules reduces the intensity of HLA-DR1-restricted antigen-specific responses in transgenic mice, by favoring murine over human MHC recognition and education. Thus, HLA-DR1+/+/IAbeta0/0 mice represent a better model for identifying and characterizing HLA-DR1-restricted epitopes relevant for human disease.     

Is MED13L-related intellectual disability a recognizable syndrome?

Introduction

MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.

Infective endocarditis due to Salmonella typhi--a case report

Endocarditis is a rare complication of typhoid fever. We report a case in which Salmonella enterica serotype typhi was isolated from a case of endocarditis. The isolate was resistant to ampicillin, chloramphenicol and ciprofloxacin but sensitive to ceftriaxone, amikacin and gentamicin.     

An investigation into the relationship between salivary cortisol,stress, anxiety and depression

This study examined the relationship between indices of self-reported emotional distress and absolute versus change in cortisol levels. Fifty-four women attending a diagnostic breast clinic completed scales measuring stress, anxiety and depression and provided five saliva samples over the course of a single day for the measurement of cortisol. No significant relationships were evident between absolute cortisol levels and the distress measures. Analysis of the change in cortisol levels revealed a non-linear interaction effect between stress and anxiety and time of day. There was a non-linear relation between time of day and cortisol levels, but the extent of the non-linearity was dependent upon levels of stress and anxiety, not depression. A relationship was apparent between indices of distress and change in cortisol levels, but not absolute levels of the hormone.     

Oral Disodium Cromoglycate Treatment of A topic Dermatitis

Fourteen adults and 10 children with active atopic dermatitis entered this double blind cross-over study of oral disodium cromoglycate (DSCG) (adults 200 mg qid, children 100 mg qid) compared with placebo. Oral DSCG and placebo were given for 6 weeks in random order. According to the investigators' assessments of eczema, significant differences between active and placebo were found after 6 weeks' treatment, DSCG being favoured (P less than 0.05). No differences were detected in the investigators' assessment of lichenization and overall disease. No significant differences between the two treatments were demonstrated in the patients' assessments. Results from food allergic patients were similar to those from non-food allergic patients. Two patients reported possible side effects of arthralgia and urticaria respectively. There were no treatment effects on serum IgE values or any other laboratory data.