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.

     

Dermatofibrosarcoma protuberans: a population-based cancer registry descriptive study of 66 consecutive cases diagnosed between 1982 and 2002

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare malignant tumour of the skin, with an estimated incidence of 0.8 to five cases per 1 million people per year. OBJECTIVE: To study epidemiological, immunohistochemical and clinical features, delay in diagnosis, type of treatment and outcome of DFSP from 1982 to 2002. METHODS: Using data from the population-based cancer registry, 66 patients with pathologically proved DFSP were included (fibrosarcomatous DFSP were excluded). Each patient lived in one of the four departments of Franche-Comté (overall population of 1 million people) at the time of diagnosis. The main data sources came from public and private pathology laboratories and medical records. The rules of the International Agency for Research on Cancer were applied. RESULTS: The estimated incidence of DFSP in Franche-Comté was about three new cases per 1 million people per year. Male patients were affected 1.2 times as often as female patients were. The trunk (45%) followed by the proximal extremities (38%) were the most frequent locations. DFSP occurred mainly in young adults between 20 and 39 years of age. Mean age at diagnosis was 43 years, and the mean delay in diagnosis was 10.08 years. Our 66 patients initially underwent a radical local excision. Among them, 27% experienced one or more local recurrences during 9.6 years of follow-up. There was one regional lymph node recurrence without visceral metastases. These recurrences were significantly related to the initial peripheral resection margins. We observed a local recurrence rate of 47% for margins less than 3 cm, vs. only 7% for margins ranging from 3 to 5 cm [P=0.004; OR=0.229 (95%, CI=0.103-0.510)]. The mean time to a first local recurrence was 2.65 years. Nevertheless, there was no death due to the DFSP course at the end of the follow-up, and the final outcome was favourable. CONCLUSION: Our study emphasizes the importance of wide local excision with margins of at least 3 cm in order to prevent local recurrence. However, the recent development of inhibitors of signal transduction by the PDGFB pathway should soon modify the surgical strategy, which is often too mutilating.     

Acquired Cutis Laxa in Childhood Sweet's Syndrome

Abstract:  In Sweet's syndrome, the essential features are the characteristic morphology of the lesions, their histologic appearance, the dramatic response to corticosteroids and the absence of scarring. We report an 8-month-old infant in whom Sweet's syndrome was diagnosed and who developed acquired cutis laxa in the skin lesions.     

Initially Accelerated Fractionation of the R1H Tumor of the Rat Increases Local Tumor Control and Might Reduce Impact of Overall Treatment Time

PURPOSE: To study the effect of treatment time prolongation following initial dose acceleration on the response of subcutaneously growing R1H tumor. MATERIAL AND METHODS: Continuous standard fractionation (30 fractions/40 days) was compared to initially accelerated treatment (30 fractions/21 days) followed by five to two fractions per week yielding total treatment times from 40 to 72 days. Local tumor control was assessed as endpoint. RESULTS: Radiation dose to control 50% of the tumors (TCD50%) decreased statistically significant from 83.5 Gy (95% confidence interval [CI]: 78.6 .. 88.4) for standard fractionation to 74.1 Gy (95% CI: 72.7 .. 75.5) determined for all accelerated treatment arms (p = 0.003). Prolongation of treatment time after initial acceleration from 40 to 72 days led to a small but statistically not significant increase in TCD50% from 72.0 Gy (95% CI: 71.0 .. 72.9) to 76.2 Gy (95% CI: 69.9 .. 82.4) corresponding to a repopulated dose of 0.9 Gy per week. This time factor is considerably smaller than for conventional radiation treatment as determined in previous experiments. CONCLUSION: The results indicate that initially accelerated irradiation not only improves local tumor control but also minimizes the negative effect of treatment time prolongation. This might be due to changes in tumor cell repopulation kinetics.     

Simultaneous assessment of blood flow in UVB-inflamed human skin by laser Doppler flowmetry and the 133-xenon washout technique.

The purpose of the study was to compare skin blood flow by laser Doppler flowmetry (LDF) and the 133-Xenon washout technique in UVB-inflamed human skin. Six healthy subjects participated in the study. Forearm skin blood flow was measured prior to irradiation and then 8, 24, 48 and 72 h after the exposure to twice the minimal erythema dose of UVB. Baseline blood flow as measured by the 133-Xenon washout method was 5.2 (range 3.0 to 10.4) ml/100g/min and LDF flux was 3.1 (range 2.7 to 5.7) arbitrary units. Following irradiation, maximum blood flow increase as evaluated by the 133-Xenon washout was 10.8 (95% confidence interval 3.7 to 11.3) times baseline blood flow, corresponding to an absolute blood flow of 47.5 (range 33.8 to 56.3) ml/100g/min. Maximum increase after induction of inflammation as assessed by LDF was 34.6 (95% confidence interval 24.6 to 56.5) times baseline flux. The two methods showed comparable time courses in all subjects. A significant correlation between the two methods was found, Spearman's rho = 0.54, p = 0.006. The relative LDF blood flow increase was 4.2-fold (95% confidence interval 2.7 to 5.0) greater than the increase measured by the 133-Xenon washout method. These results are at variance with previous comparative studies of the two methods. Some explanations are discussed.     

High Prevalence of Developmental Disabilities in Children Admitted to a General Pediatric Inpatient Unit

Objective: Evaluate a) the prevalence of developmental disabilities (DD) in children admitted to a general pediatrics inpatient unit, and b) the number of children admitted to the unit with previously undiagnosed developmental disability. Methods: Prevalence was evaluated through retrospective record review. Subjects: One hundred ninety children older than five months of age admitted to a general pediatric unit. Results: Of 190 children admitted, 155 (81.6%) had adequate developmental screening documented in the record. Forty-nine (25.7% of total, 31.6% of screened) had a developmental disability, 22 (12.1% of total, 14.8% of screened) had a previously unrecognized disability. Sample prevalence of DD was: cerebral palsy (6.8%), developmental delay or mental retardation (8.4%), language delay (4.6%), learning disability (8.2%), and hearing loss (1.5%). New diagnoses included: three children with probable mental retardation (MR), nine with learning disability (may include mild MR), seven with language delay, three with abnormal motor skills (fine and/or gross motor), one each of: neurofibromatosis type I, hearing loss, cerebral palsy, dysphagia. Some children had more than one new diagnosis. Conclusion: The prevalence of disabilities in a general pediatrics inpatient unit is much higher than the prevalence in the community. Because almost half of the disabilities were previously unrecognized, acute hospitalization is an excellent opportunity to conduct developmental screening.     

Human immunodeficiency virus infection in disadvantaged adolescents. Findings from the US Job Corps

OBJECTIVE--To describe the human immunodeficiency virus (HIV) epidemic among socially and educationally disadvantaged young persons in the United States. DESIGN.-We analyzed demographic and geographic findings from the screening of Job Corps students for antibody to HIV. SETTING--The Job Corps is a federal training program for disadvantaged, out-of-school youth. POPULATION SCREENED--Residential students aged 16 to 21 years who entered the Job Corps from October 1987 through February 1990. MAIN OUTCOME MEASURE--Rates of observed HIV infection in entering students, stratified by demographic and geographic features. RESULTS--Of 137,209 Job Corps students screened, 488 were HIV seropositive (3.6 per 1000), a seroprevalence rate higher than that among military applicants of the same age. Overall seroprevalence was slightly higher in male (3.7 per 1000) than in female (3.2 per 1000) Job Corps students, but among those students aged 16 and 17 years, seroprevalence was higher among females (2.3 per 1000) than among males (1.5 per 1000) (P less than .05). For students aged 16 to 21 years, seroprevalence increased with year of age: 1.8 per 1000 per year for males and 0.7 per 1000 per year for females. Among those aged 21 years, HIV prevalence was 8.9 per 1000. For black and Hispanic students from large Northeastern cities, seroprevalence increased by 4.3 per 1000 per year of age and reached 24.8 per 1000 (one of 40) in students aged 21 years. However, among students from rural areas and small towns, HIV seroprevalence was disproportionately high in the Southeast. Compared with recently described US patients with the acquired immunodeficiency syndrome, HIV-infected students who entered the Job Corps were much more likely to be female. CONCLUSIONS--These findings show that disadvantaged, out-of-school adolescents are at high risk for HIV infection. The screening results identified surprisingly high seroprevalence in the southeastern United States and demonstrated a marked shift in the HIV epidemic to young women. Controlling the HIV epidemic among teenagers must include interventions that will reach adolescents early and outside of the formal educational system.