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.

     

Clinical versus ultrasonographic evaluation of scrotal disorders

Clinical and ultrasonographic examinations of scrotal disorders were compared in 166 patients in order to determine their ability to distinguish between those diseases requiring surgery and those requiring clinical follow-up only. Ultrasound examinations were efficient in discriminating between normal and pathological findings. Extra-testicular lesions were readily differentiated from testicular ones. Although both clinical and ultrasonographic examinations had high sensitivity (90%) in detecting testicular cancer, the number of false positive findings was smaller after ultrasound examination. This gave a predictive value of a positive test of 53% after ultrasound examination but only 33% after clinical examination. Ultrasound examination may, therefore, reduce the number of surgical explorations in the scrotum and should be performed in patients with suspected testicular pathology based on history and palpatory findings.     

Clinical safety of enamel matrix derivative (EMDOGAIN®) in the treatment of periodontal defects

Abstract The aim of the present clinical trial was to test tolerability during 2 treatments with EMDOGAIN® in a large number of patients. An open, controlled study design in 10 Swedish specialist clinics was chosen, with a test group of 107 patients treated with EMDOGAIN® in connection with periodontal surgery at 2 surgical test sites per patient. The procedures were performed 2 to 6 weeks apart on one-rooted teeth with at least 4 mm deep intraosseous lesions. A control group of 33 patients underwent flap surgery without EMDOGAIN® at I comparable site. In total 214 test and 33 control surgeries were performed. Serum samples were obtained from test patients for analysis of total and specific antibody levels. 10 of the patients had samples taken before and after the first surgery. 56 other samples were taken after one treatment with EMDOGAIN®, and 63 after 2 treatments. None of the samples, not even from allergy-prone patients after 2 treatments, indicated deviations from established baseline ranges. This indicates that the immunogenic potential of EMDOGAIN® is extremely low when applied in conjunction with periodontal surgery. Comparison between the test and control groups demonstrated the same type and frequency of post-surgical experiences, i.e., reactions caused by the surgical procedure itself. Clinical probing and radiographic evaluation was performed at baseline and 8 months postsurgery. About half of the patients (44 test and 21 control) were also evaluated after 3 years. There was a significant difference between the test and control results at 8 months post surgery. and this difference had increased further at the 3 year follow-up. The 2.5–3 mm increase in attachment and bone level after treatment with EMDOGAIN® was of the same magnitude as seen in the studies with split-mouth design aiming for lest of effectiveness of EMDOGAIN®.     

Comparison of blood glucose and insulin responses in non-insulin dependent diabetic patients. Studies with spaghetti and potato taken alone and as part of a mixed meal

Recently, we demonstrated that spaghetti caused significantly lower glycaemic response than rice and potato in insulin-dependent diabetic (IDDM) subjects and that this difference was also present when spaghetti and potato were taken as part of a mixed meal. We have now compared the blood glucose and insulin responses to 50 g of carbohydrate in the form of white bread, potato and white spaghetti in 6 non-insulin-dependent diabetic (NIDDM) patients. The blood glucose response after white spaghetti observed over a 3-h period was only 60 +/- 10 per cent (P less than 0.02) of that seen in response to potato (395 +/- 116 mmol/l x 180 min vs 641 +/- 108 mmol/l x 180 min) and 47 +/- 9 per cent (P less than 0.01) of that seen in response to white bread (395 +/- 116 mmol/l x 180 min vs 805 +/- 93 mmol/l x 180 min). Insulin responses showed an identical pattern reflecting the glycaemic responses. To see if the difference in the glucose responses in NIDDM patients is preserved if these carbohydrate-rich foods are taken as part of a mixed meal we looked at the blood glucose and insulin responses to 50 g of carbohydrate in the form of potato and white spaghetti when ingested together with bolognese sauce (167 g) in 7 NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of atrial natriuretic peptide on human isolated resistance arteries.

1. The action of (1-28) alpha-human atrial natriuretic peptide (ANP) was studied on human isolated resistance arteries. 2. Renal, skeletal muscle, omental and subcutaneous resistance arteries were taken from tissue removed at surgery and isometric tension responses were measured with a myograph. 3. ANP (10(-9)-10(-6) M) relaxed precontracted segments of renal and skeletal muscle arteries in a concentration-dependent manner. ANP failed to relax isolated omental or subcutaneous arteries. 4. The effect of ANP on human isolated resistance arteries varies depending on the site of origin of the artery.     

Mechanical function of intermediate filaments in arteries of different size examined using desmin deficient mice

Protein composition and mechanical function of intermediate filaments were examined in arteries of different sizes using desmin deficient mice (Des−/−) and their wild-type controls (Des+/+). Using SDS-PAGE gels and Western blots we found a gradient in desmin expression in the arterial tree; the desmin content increased from the elastic artery aorta, via the muscular mesenteric artery to the resistance-sized mesenteric microarteries ∼150 μm in diameter in Des+/+ mice. Mechanical experiments were performed on the aorta, the mesenteric artery and resistance-sized arteries using wire myographs. For aorta and mesenteric artery, no differences in passive or active circumference- stress relations were found between Des−/− and Des+/+ mice. In microarteries, both passive and active stress were lower in the Des−/− group. In conclusion, large elastic and muscular arteries contain a relatively low amount of desmin, and the desmin intermediate filaments do not seem to play a major role in the mechanical properties of these larger arterial vessels. In the microarteries, where expression of desmin is high, desmin plays a role in supporting both passive and active tension.     

Long-term neurological outcome of childhood brain tumors treated by surgery only.

PURPOSE: To evaluate the pattern of neurological late effects in patients who have received surgery only for a brain tumor in childhood and to identify possible risk factors for neurological sequelae. PATIENTS AND METHODS: The medical, histologic, and operative records were reviewed for 65 consecutive patients operated for a benign brain tumor from 1970 to 1997, and all patients were re-examined after a median length of follow-up of 10.7 years. Thirty-four patients had posterior fossa tumors, 22 patients had cerebral hemisphere tumors, and nine patients had midline tumors. RESULTS: At the time of follow-up, 20 patients (31%) had no neurological deficits, 22 patients (34%) had minor deficits that did not interfere with their daily life activities, and 23 patients (35%) had moderate or severe deficits such as severe ataxia, spastic paresis, seriously reduced vision, or epilepsy with more than two seizures per year. Fourteen of the 31 patients (45%) registered with ataxia preoperatively had recovered fully. Six of seven patients had persistence of a pre- or postoperatively developed hemiparesis. Thirteen of 23 patients had persistence of cranial nerve deficits that developed second to surgery. Fifty-five percent of the 18 patients with seizures at diagnosis were seizure-free at follow-up. At follow-up both ataxia and hemiparesis were significantly more frequent among females (P =.02 and P =.03, respectively). CONCLUSION: In patients who received operation as the only treatment for their brain tumor, there was a good chance of total or partial recovery of preoperative and postoperative neurological deficits, although only one third of the patients will have no long-term neurological deficits.     

Reduced prevalence of early preterm delivery in women with Type 1 diabetes and microalbuminuria--possible effect of early antihypertensive treatment during pregnancy.

AIMS: In normotensive women with Type 1 diabetes and microalbuminuria we previously found preterm delivery (< 34 weeks) in 23% of the pregnancies. Antihypertensive treatment was initiated in late pregnancy when preeclampsia was diagnosed and diastolic blood pressure > 90 mmHg. From April 2000 our routine was changed and early antihypertensive treatment with methyldopa was initiated if antihypertensive treatment was given prior to pregnancy, if urinary albumin excretion (UAE) was > 2 g/24 h, or blood pressure > 140/90 mmHg. The present study describes the impact of this more aggressive antiypertensive treatment in the prevalence of preterm delivery. METHODS: The old cohort (1995-1999) consisted of 26 and the new cohort (2000-2003) of 20 pregnant women with Type 1 diabetes and microalbuminuria. All were referred before gestational week 17. RESULTS: The cohorts were comparable with regard to age, diabetes duration, prepregnancy body mass index, HbA1c, blood pressure 121 (13)/71 (8) vs. 121 (14)/73 (8) mmHg [mean (sd)] and early UAE 69 (16-278) vs. 74 (30-287) mg/24 h (geometric mean and range). Antihypertensive treatment was initiated in the old cohort at 29 (20-33) weeks, n = 9, and in the new at 13 (0-34) weeks, n = 10. The prevalence of preterm delivery before 34 weeks was reduced from 23% to zero (P = 0.02), preterm delivery before 37 weeks from 62% to 40% (P = 0.15) and preeclampsia from 42% to 20% (P = 0.11). Perinatal mortality occurred in 4% vs. 0%. Birth weight was 3124 (767) g vs. 3279 (663) g. CONCLUSION: Introduction of early antihypertensive treatment with methyldopa in normotensive pregnant women with Type 1 diabetes and microalbuminuria resulted in a significant reduction in preterm delivery before gestational week 34.     

Immature ovarian teratoma: a review of 14 cases

We conducted a clinical and pathologic review of 14 patients with immature ovarian teratoma. In this series of patients, one had monodermal malignant neuroectodermal teratoma and two others had immature ovarian teratoma in association with immature presacral teratoma. Because of the small number of cases of immature ovarian teratoma and the diverse therapeutic modalities used in this study, we cannot recommend a specific treatment for patients with this tumor on the basis of our findings. The histologic grade of the tumor seemed to be a reliable indicator of prognosis. Grade 0 metastatic lesions should be considered benign and are associated with a favorable prognosis.