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.

     

'Vanishing embryo syndrome' in IVF/ICSI

BACKGROUND: In a Danish population-based cohort study assessing the risk of cerebral palsy in children born after IVF, we made some interesting observations regarding 'vanishing co-embryos'. METHODS and RESULTS: All live-born children born in Denmark from 1 January 1995 to 31 December 2000 were included in this analysis. The children conceived by IVF/ICSI (9444) were identified through the IVF Register, the children conceived without IVF/ICSI (395 025) were identified through The Danish Medical Birth Register. Main outcome measure was the incidence of cerebral palsy. Within the IVF/ICSI children we found indications of an increased risk of cerebral palsy in those children resulting from pregnancies, where the number of embryos transferred was higher than the number of children born. CONCLUSIONS: The association between vanishing embryo syndrome and incidence of cerebral palsy following IVF requires further investigation in larger, adequately powered, studies.     

Two-Year Follow-Up of a Randomized Clinical Trial of Inpatient Multimodal Occupational Rehabilitation Vs Outpatient Acceptance and Commitment Therapy for Sick Listed Workers with Musculoskeletal or Common Mental Disorders

Journal of Occupational Rehabilitation - Purpose There is a lack of results on long-term effects of return to work interventions. We previously reported that an inpatient multimodal occupational...     

Cancer risk following appendectomy for acute appendicitis (Denmark)

Objective: Epidemiologic studies have not been able definitely to exclude that appendectomy carries a cancer risk. This study was conducted to clarify whether appendectomy is associated with a subsequent increase in cancer risk, since appendectomy is frequently an elective procedure. Methods: The present study included more than 82,000 persons who underwent appendectomy for acute appendicitis during 1977-89 according to the nation-wide Danish Hospital Discharge Register. During a follow-up interval of up to 17 years, cancer incidence was assessed by linkage to the Danish Cancer Registry and compared with the incidence in the general population of Denmark. Results: The total number of malignancies among appendectomized persons was 1.05 times higher than expected with 95 percent confidence intervals of 0.99-1.11. There was no clear significant excess of any specific cancer type. Conclusion: During a postsurgery period of nearly two decades, results of our study did not support the hypothesis that either appendectomy or acute appendicitis are likely to be associated with malignant neoplasms.     

Familial aggregation and heterogeneity of non-Hodgkin lymphoma in population-based samples.

The importance of genetic factors in the etiology of non-Hodgkin lymphoma (NHL) is suggested by case-control and cohort studies. Most previous studies have been too small to estimate accurately risks of specific categories of lymphoproliferative malignancies in relatives of NHL cases or to quantify the contribution of NHL case characteristics to familial risk. We have overcome sample size limitations and potential recall bias by using large databases from Sweden and Denmark. Diagnoses of lymphoproliferative malignancies were compared in 70,006 first-degree relatives of 26,089 NHL cases (including 7,432 with subtype information) versus 161,352 first-degree relatives of 58,960 matched controls. Relatives of NHL cases were at significantly increased risk for NHL [relative risk (RR), 1.73; 95% confidence interval (95% CI), 1.39-2.15], Hodgkin lymphoma (RR, 1.41; 95% CI, 1.0-1.97), and nonsignificantly for chronic lymphocytic leukemia (CLL; RR, 1.31; 95% CI, 0.93-1.85). No increased risk was found for multiple myeloma among case relatives. Findings with respect to siblings compared with parents and offspring or with respect to age at diagnosis of proband were inconsistent. In both populations, relatives of cases with an aggressive NHL subtype were at substantially increased risk of NHL (combined RR, 3.56; 95% CI, 1.80-7.02). We conclude that NHL has an important familial component, which is shared with Hodgkin lymphoma and CLL. We estimate that the absolute lifetime risk for a first-degree relative of an NHL case to develop NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL.     

Differentiated in vivo skin penetration of salicylic compounds in hairless rats measured by cutaneous microdialysis.

The purpose was to investigate the in vivo skin penetration of four 14C-salicylic compounds using microdialysis and to relate dermal concentrations to structural features. Furthermore, to compare two in vivo retrodialysis recovery methods for estimation of true unbound extracellular concentrations. Microdialysis probes were inserted in the dermis of hairless rats. Equimolal 14C-salicylic formulations were applied topically and dialysate sampled consecutively for 4h. True extracellular concentrations were estimated by retrodialysis by drug method (the 14C-salicylic compounds themselves) and by retrodialysis by calibrator method (3H-salicylic acid as internal standard). Probe depth was measured by ultrasound scanning. High dermal concentrations were found after application of 14C-salicylamide (low protein-binding) and the lipophilic ester 14C-butyl salicylate, which was completely hydrolysed to 14C-salicylic acid during skin diffusion. Protein binding and dissociation may explain the lower dermal concentrations of 14C-salicylic acid and 14C-diethylamine salicylate, respectively. Probe depth did not significantly influence dialysate concentrations. The two in vivo recovery correction methods did not reduce the variation in concentration-time curves. In conclusion, differentiated penetration kinetics was found ranking: 14C-salicylamide >/= 14C-butyl salicylate > 14C-salicylic acid > 14C-diethylamine salicylate. Dermal concentrations were related to structural features of the model compounds. The two correction methods performed alike; however, the calibrator method has the advantage of serving as a quality control during experiments.