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.

     

Primary glioblastomas and anaplastic astrocytoma in a glioma family.

A 72-year-old man presented with a short duration of symptoms relating to a right fronto-parietal glioblastoma and a family history of children with brain tumours. Analysis of the patient's family tree revealed that out of seven children, he had a living son with anaplastic astrocytoma, a daughter who had died with a glioblastoma, and a son who had died with a histologically undiagnosed intrinsic brain tumour. One niece was also thought to have died from a brain tumour. All of the other affected family members had onset in their third or fourth decades. Tissue was only available from two of the affected individuals, precluding familial genetic analysis at this stage. There is no clinical evidence to support a diagnosis of a multiple cancer or neurocutaneous syndrome in this family. In view of what is known about the genetics of familial glioma, it is interesting to note the clinical evidence of both 'primary' glioblastoma and anaplastic astrocytoma in the same kindred.     

Penetration and distribution of three lipophilic probes in vitro in human skin focusing on the hair follicle.

Fluorescent model substances of increasing lipophilicity (Oregon Green) 488, Bodipy, FL C5 and Bodipy 564/570 C5) were selected to enable the visualization in the skin using confocal laser scanning microscopy. After measuring the penetration for 18 h, the nonfixed human scalp skin was imaged from the bottom parallel to the stratum corneum and in a cross-section view perpendicular to the skin surface. The images were evaluated by calculating relative accumulation values for different penetrants. The studies indicate that the penetrated amount is highest for Bodipy FL C5 (medium lipophilicity) and lowest for Bodipy 564/570 C5 (high lipophilicity) whereas Bodipy 564/570 C5 (high lipophilicity) reveals the highest relative accumulation in parts of the hair follicle compared to Oregon Green 488 (low lipophilicity). The addition of 30% (v/v) ethanol to the donor phase of substance with a low lipophilicity increases the follicular delivery. From our results we conclude that delivery to the hair follicle can be improved by increasing the drugs lipophilicity and optimizing the composition of the donor phase. However, no conclusion can be drawn about the actual route of transport to the hair follicle.     

Acute and chronic whiplash disorders--a review.

OBJECTIVE: This review examines acute and chronic whiplash-associated disorders to facilitate assessment, treatment and rehabilitation for further research and evidence-based practices. DESIGN: A review of the literature. RESULTS AND CONCLUSION: Whiplash-associated disorders account for a large proportion of the overall impairment and disability caused by traffic injuries. Rarely can a definite injury be determined in the acute (or chronic) phase. Crash-related factors have been identified, and several trauma mechanisms possibly causing different injuries have been described. Most whiplash trauma will not cause injury, and the majority of patients (92-95%) will return to work. Litigation is not a major factor. Cognitive impairments are not the same as brain injury. Variables such as pain intensity, restricted motion, neurological symptoms and signs, together with central nervous system symptoms can be used to predict a situation with risk of remaining complaints. Influences of other factors--the same as for other chronic pain conditions--also exist. Persistent/chronic pain is not merely acute pain that persists over time; changes occur at different levels of the pain transmission system. Chronic whiplash-associated disorders are associated with problems concerning social functioning, daily anxieties and satisfaction with different aspects of life. Adequate information, advice and pain medication together with active interventions might be more effective in the acute stage. Early multidisciplinary rehabilitation focusing on cognitive-behavioural changes might be of value. To develop specific treatment and rehabilitation, it is important to identify homogenous subgroups.     

Deep Granuloma Annulare (Pseudorheumatoid Nodule) in Children: Clinicopathologic Study of 35 Cases

Deep granuloma annulare (DGA) is one of several lesions of skin and superficial soft tissues whose histologic character is a palisading granuloma with a small central focus of necrosis or necrobiosis. Unlike the other palisading necrobiotic lesions, DGA has a predilection for children in the first 5 to 6 years of life. A painless subcutaneous nodule(s) in the lower anterior tibial region or foot and the scalp, typically in the occiput, was the most common presenting feature in this study of 35 cases. Additional or recurrent lesions were reported in approximately 70% of cases with clinical follow-up. All lesions showed the presence of necrobiosis; however, one of the characteristic features was the multinodular character of the predominantly mononuclear cellular aggregates. The presence of vascular spaces at the periphery of the nodular profiles served as a clue to the diagnosis of DGA. The palisading arrangement of the mononuclear cells was evident only in those foci with central necrobiosis. A histiocytic disorder or fibrohistiocytic process was a common consideration in the differential diagnosis, especially in those cases with less apparent foci of necrosis. Palisading histiocytes with prominent eosinophilic cytoplasm and some nuclear atypism were problematic with regard to possible epithelioid sarcoma. Our study failed to identify any underlying or predisposing factors in the development of DGA. Despite the fact that DGA is a well-documented lesion in children, it occurs sufficiently infrequently that it is often not considered clinically when it presents as a subcutaneous mass or masses in a child. Its recognition by the pathologist is especially important as the occurrence of additional lesions in a high proportion of children can be anticipated without undue concern. Received June 16, 1997; accepted October 28, 1997.     

Changes in zinc level in the serum, whole blood and erythrocytes in disorders of thyroid function

The zinc level in serum and whole blood was determined in a series of 121 patients, 20 suffering from overt hyperthyroidism, 34 with manifest hypothyroidism and a control group of 67 euthyroid subjects. The zinc content per deciliter of erythrocytes was calculated from the haematocrit. The hyperthyroid group revealed a highly significantly elevated serum zinc level (p less than 0.01), but a most significantly reduced zinc content in whole blood (p less than 0.001) in comparison with the euthyroid group. On the other hand, the reverse changes were observed in the hypothyroid group, i.e. a most significantly reduced serum zinc content (p less than 0.001) and a highly significantly increased zinc content in whole blood (p less than 0.01). These results suggest that the determination of zinc levels both in serum and in whole blood may be a useful additional parameter of peripheral thyroid hormone effect.     

Tick-borne Borrelia-meningitis in children. An outbreak in the Kalmar area during the summer of 1984

Nine children, aged 5 to 11 years, with subacute or chronic meningitis were studied. Symptoms started during the summer season in all patients and in eight of the patients the disease began with a localized erythematous lesion (ECM), mostly in the face. In one patient only there was a history of an insect bite at the site of the erythema. The neurological abnormalities included aseptic meningitis, peripheral facial nerve palsy (5/9) and oculomotor nerve palsy (1/9). Most children complained of headache, fatigue, loss of appetite and had a low grade fever. High antibody titers to Borrelia spirochetes in serum and/or cerebrospinal fluid (CSF) were demonstrated by ELISA in eight of the nine patients and by indirect immunofluorescence assay (IFA) in three patients. All patients had a dramatic improvement in their general condition and became afebrile within three days of institution of i.v. penicillin G treatment (i.v. cefuroxime in one patient).     

Previously infertile couples and the newborn intensive care unit

Having a newborn child admitted to a newborn intensive care unit can be a traumatic experience for parents; however, parents who previously have been infertile face unique problems in coping with this situation. The authors discuss the difficulties parents must overcome in resolving their crises and in developing a good relationship with their child, or, in some cases, coming to terms with the child's death or ongoing disability. In addition, the authors offer suggestions for effective social work intervention.