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.

     

Candida albicans septicemia in a premature infant successfully treated with oral fluconazole.

A premature male infant, birth-weight 1460 g, was treated successfully for a Candida albicans septicemia with orally administered fluconazole for 20 days. Dosage was 5 mg/kg/day. No side effects were seen. Fluconazole may present a major progress in treatment of invasive C. albicans infections in neonatology.     

Effect of simethicone on lactulose-induced H2 production and gastrointestinal symptoms.

The results of studies of the effect of simethicone on abdominal gas-related symptoms have been contradictory. In a randomized, double-blind cross-over study, 10 healthy volunteers were given 30 g lactulose and 600 mg simethicone or placebo. End-expiratory breath samples were collected and analyzed for H2 and gastrointestinal symptoms registered. There were no differences in biochemical parameters or symptom score between simethicone and placebo. In contrast to previous studies, we used a sufficiently large dose of lactulose to produce gastrointestinal symptoms, a higher dose of simethicone and placebo tablets containing the same additives as the simethicone tablets. There was no demonstrable effect of simethicone on symptoms or intestinal gas production caused by carbohydrate malabsorption.     

The seroepidemiology of human T-lymphotropic viruses: types I and II in Europe: a prospective study of pregnant women

BACKGROUND: Up to 20 million persons are infected with the human retroviruses human T-lymphotropic virus (HTLV)-I and HTLV-II globally. Most data on the seroprevalence of HTLV-I and HTLV-II in Europe are from studies of low-risk blood donors or high-risk injection drug users (IDUs). Little is known about the general population. METHODS: A prospective anonymous study of HTLV-I and HTLV-II seroprevalence among 234,078 pregnant women in Belgium, France, Germany, Italy, Portugal, Spain, and the United Kingdom was conducted. Maternal antibody status was determined by standard methods using sera obtained for routine antenatal infection screens or eluted from infant heel prick dried blood spots obtained for routine neonatal metabolic screens. RESULTS: Anti-HTLV-I/II antibodies were detected and confirmed in 96 pregnant women (4.4 per 10,000, 95% confidence interval [CI]: 3.5-5.2). Of these, 73 were anti-HTLV-I, 17 were anti-HTLV-II, and 6 were specifically anti-HTLV but untyped. The seroprevalence ranged from 0.7 per 10,000 in Germany to 11.5 per 10,000 in France. CONCLUSIONS: Pregnant women better reflect the general population than blood donors or IDUs. The seroprevalence of HTLV-I and HTLV-II in Western Europe is 6-fold higher among pregnant women (4.4 per 10,000) than among blood donors (0.07 per 10,000). These data provide a robust baseline against which changes in HTLV-I and HTLV-II seroprevalence in Europe can be measured.     

Posttraumatic stress disorder in primary care with special reference to personality disorder comorbidity

BACKGROUND: Posttraumatic stress disorder (PTSD) is a common and disabling disturbance in primary care. Few studies have been carried out in primary care samples and none have taken into consideration the association between PTSD and personality disorder. AIM: To describe prevalence and risk factors of PTSD and its comorbidity with personality disorder. SETTING: General practice centre in Valencia (Spain). METHOD: Patients who had experienced at least one traumatic event in their lives were selected from a random sample attending a primary healthcare centre in Valencia and blindly assessed by trained professionals. Patients suffering from PTSD were compared with those who were not. PTSD and personality disorder diagnoses were established using CIDI and SCID-II interviews respectively. Sex, age at the time of experiencing trauma, frequency, multiplicity and type of trauma, dissociative symptoms, personality disorder and severity of PTSD were subjected to multivariate analysis to estimate the probability of developing PTSD and its duration. RESULTS: Life prevalence rate was 14% and current prevalence 9%. Dissociative symptoms and personality disorder were significantly associated with PTSD. Cluster analysis based on age, frequency and type of trauma revealed the existence of one subgroup composed mainly of women who had experienced frequent body-contact trauma at an early age, developed severe PTSD and suffer from a variety of personality disorders, particularly paranoid personality disorder. Time to the complete disappearance of symptoms was only explained by the initial severity of PTSD. CONCLUSION: PTSD is a frequent disorder in general practice and it is often associated with personality disorder. Women who experienced high frequency body-contact traumatic events at an early age often suffer from personality disorder and present a particularly severe form of PTSD deserving referral to specialised care.     

Morphological parameters of breast cancers detected by mammography with and without organized screening; a comparative study]

Some pathological findings and prognostic indices recorded in breast cancer cases, detected, on one hand, by a provider-initiated mammography screening program (Group 1), and, opportunistically, in self-referred symptomatic women (Group 2) on the other, are compared. In 8877 symptom-free women, aged 50-65 years, individually invited to attend the screening offered for the residents of the III., XII. and XIII. districts of Budapest, 67 cancer cases were detected (7.5 in 1000 screenees), in accordance with the cancer detection rate of the first, "prevalence" round of organised screening programmes. In the other group of 1593 symptomatic, self-referred women of the same age, 113 cancer cases were diagnosed by mammography. As far as the pathological parameters are concerned, the number of cases with invasive cancer less than 15 mm in diameter, and those with axillary nodes present was found to be significantly higher in the screened group as compared to the self-referred one (p < 0.01). In "small" cancers (i.e. less than 15 mm in diameter), no significant difference was found in the proportion of histologic grade III tumours among the two groups. In screen-detected cancers both the morphometric prognostic index (as calculated by Baak et al.) and the Nottingham Prognostic Index (NPI) proved to be more favourable, as compared to those in the self-referred group. The p-value as determined by Mann-Whithey test was 0.000003 in the screened group, and 0.000015 in the other one. These findings provide convincing evidence in support of the public health importance of provider-initiated, organised mammography screening for breast cancer, therefore, the introduction on service basis of organised breast screening into the health care system in Hungary is strongly recommended by the authors.     

A reinforced rigid fixation device for unstable intertrochanteric fractures

A 120 degrees blade plate reinforced by a strut is introduced for the treatment of unstable intertrochanteric and proximal subtrochanteric fractures. Mechanical tests showed that the strength of this reinforced resistance device was 11,758 N. This strength is two and three times greater than that of the Gamma nail and sliding hip screw, respectively, and five times greater with the strut than without it. Three hundred fifty-eight patients older than 60 years of age were treated with this method between 1987 and 1991 (mean followup, 16 months). Six months after surgery the fracture had united in 82% of the patients who were walking without aid or using only a cane. Weightbearing began when the patient's general overall condition allowed such activity (average, 5 days; mode, 3 days). A chi squared test showed no difference regarding the results between stable and unstable fractures. Intraoperative and postoperative complication rates were 3% and 7.1%, respectively. The failure of fixation rate was 5.4%. Mechanical tests and clinical results showed that immediate weightbearing can be allowed in all types of intertrochanteric fractures. This reinforced device is effective in treating unstable intertrochanteric fractures and is especially indicated for the most unstable types (Evans' Grades 4 and 5).     

Decelerated growth and longevity in men

Severe dietary restriction delays the physical development of rodents and leads to adult animals of reduced body size but significantly increased life expectancy. We tried to find a similar relationship in human populations using demographical and statistical methods. We show for the total Spanish male population that the mean adult body height reliably reflects the regional living and nutritional conditions. This relation does not only hold for todays socioeconomic data but can also be reproduced using data on family income in the mid 19th century. We calculated the mean height of young men liable to the military service around 1860 and determined their longevity retrospectively using posterior census data. This was done separately for all the Spanish provinces. The linear regression between both parameters manifests a statistically highly significant relationship: the smaller the mean height at age 18 in a province, the higher the chance for people living there to reach high chronological ages. Migrational movements, selection, mortality due to epidemics or unreliability of the population censuses can be largely ruled out as explications for the described correlation. Furthermore, we determined the secular growth trend in Spain for the last 130 years. From 1860 to 1920 the mean height increased by 2.7 cm, from 1920 to 1987 by another 9.8 cm. Since 1950 the trend is above 2 cm per decade country-wide. From 1974 onwards it amounts to 2.89 +/- 0.17. Such high values were worldwide looked upon as isolated cases found only in geographically and socially isolated population subgroups during very limited periods.     

Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: a phase II multicenter study with 3 years' follow-Up.

PURPOSE: To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer. PATIENTS AND METHODS: Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival. RESULTS: All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%. CONCLUSION: UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.     

Multicenter phase II trial evaluating a three-weekly schedule of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer.

BACKGROUND: Irinotecan (CPT-11) and raltitrexed are active against advanced colorectal cancer (ACC), act through different mechanisms, and have only partially overlapping toxicity profiles. Phase I studies have shown that single-agent full doses of both drugs can be safely combined. The aim of this multicenter study was to assess the efficacy and toxicity of the combination in patients with 5-fluorouracil (5-FU)-refractory ACC. PATIENTS AND METHODS: Between October 1999 and December 2000, 52 patients (31 males, 21 females) with a median age of 62 years (range 39-75) were included and received CPT-11 (350 mg/m(2) as a 60-min infusion) plus raltitrexed (3 mg/m(2) as a 15-min infusion, 1 h after CPT-11), with courses repeated every 21 days. Objective response was assessed after every three courses, and treatment maintained until tumor progression or unacceptable toxicity. RESULTS: A total of 313 cycles were administered, with a median of six cycles per patient (range 1-14). Seven patients (13.5%) achieved a partial response and one a complete response (1.9%), for an overall intention-to-treat response rate of 15.4% (95% confidence interval 6.1% to 27.2%). The incidence of grade 3/4 toxicity was 23.1% for diarrhea, 21.2% for asthenia, 17.3% for neutropenia, 13.4% for emesis and 7.7% for infection. There were no treatment-related deaths. With a median follow-up of 20 months, median survival was 11.9 months and median time to progression was 4.6 months. CONCLUSIONS: CPT-11 plus raltitrexed is active in patients with 5-FU-refractory ACC, at the expense of moderate toxicity.