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.

     

Adenoviral vectors expressing siRNAs for discovery and validation of gene function

RNA interference is a powerful tool for studying gene function and for drug target discovery in diverse organisms and cell types. In mammalian systems, small interfering RNAs (siRNAs), or DNA plasmids expressing these siRNAs, have been used to down-modulate gene expression. However, inefficient transfection protocols, in particular, for primary cell types, have hampered the use of these tools in disease-relevant cellular assays. To be able to use this technology for genome-wide function screening, a more robust transduction protocol, resulting in a longer duration of the knock-down effect, is required. Here, we describe the validation of adenoviral vectors that express hairpin RNAs that are further processed to siRNAs. Infection of cell lines, or primary human cells, with these viruses leads to an efficient, sequence-specific, and prolonged reduction of the corresponding target mRNA, resulting in a reduction of the encoded protein level in the cell. For knock-down of one of the targets, GalphaS, we have measured inhibition of ligand-dependent, G-protein-coupled signaling. It is expected that this technology will prove to be of great value in target validation and target discovery efforts.     

Erratum zu: Durchimpfung von Kindern und Jugendlichen in Deutschland: Aktuelle Daten aus KiGGS Welle 2 und Trends aus der KiGGS-Studie

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Ein Erratum zu dieser Publikation wurde veröffentlicht: https://doi.org/10.1007/s00103-019-02901-5     

An inter-centre quality assurance network for IMRT verification: results of the ESTRO QUASIMODO project.

BACKGROUND AND PURPOSE: IMRT necessitates extension of existing inter-centre quality assurance programs due to its increased complexity. We assessed the feasibility of an inter-centre verification method for different IMRT techniques. MATERIALS AND METHODS: Eight European radiotherapy institutions of the QUASIMODO network, have designed an IMRT plan for a horseshoe-shaped PTV surrounding a cylindrical OAR in a simplified pelvic phantom. All centres applied common plan objectives but used their own equipment for planning and delivery. They verified the delivery of this plan according to a common protocol with radiographic film and ionisation chamber measurements. The irradiated films, the results of the ionisation chamber measurements and the computed dose distributions were sent to one analysis centre that compared the measured and computed dose distributions with the gamma method and composite dose-area histograms. RESULTS: 4% (relative to the prescribed dose) and 3mm (distance-to-agreement) were decided feasible gamma criteria. The composite dose-area histograms showed a maximum local deviation of 3.5% in the mean dose of the PTV and 5% in the OAR. Systematic differences could be identified, and in some cases explained. CONCLUSIONS: This multi-centre dosimetric verification study demonstrated both the feasibility of a multi-centre quality assurance network to evaluate any IMRT planning and delivery system combination, as well as the validity of the methodology involved.     

TAL1 cooperates with PI3K/AKT pathway activation in T-cell acute lymphoblastic leukemia

TAL1 is ectopically expressed in about 30% of T-cell acute lymphoblastic leukemia (T-ALL) due to chromosomal rearrangements leading to the STIL-TAL1 fusion genes or due to non-coding mutations leading to a de novo enhancer driving TAL1 expression. Analysis of sequence data from T-ALL cases demonstrates a significant association between TAL1 expression and activating mutations of the PI3K-AKT pathway. We investigated the oncogenic function of TAL1 and the possible cooperation with PI3K-AKT pathway activation using isogenic pro-T-cell cultures ex vivo and in vivo leukemia models. We found that TAL1 on its own suppressed T-cell growth, in part by affecting apoptosis genes, while the combination with AKT pathway activation reduced apoptosis and was strongly driving cell proliferation ex vivo and leukemia development in vivo. As a consequence, we found that TAL1+AKT^E17K transformed cells are more sensitive to PI3K-AKT pathway inhibition compared to AKT^E17K transformed cells, related to the negative effect of TAL1 in the absence of activated PI3K-AKT signaling. We also found that both TAL1 and PI3K-AKT signaling increased the DNA-repair signature in T cells resulting in synergy between PARP and PI3K-AKT pathway inhibition. In conclusion, we have developed a novel mouse model for TAL1+AKT^E17K driven T-ALL development and have identified a vulnerability of these leukemia cells to PI3K-AKT and PARP inhibitors.     

A conceptual framework addressing the complex labour market dynamics of the work-to-retirement process

The way in which retirement is conceptualized and measured is likely to influence the research findings. The previous literature has addressed a wide range of elements related to the complex work-to-retirement process, such as early, late and partial retirement, statutory retirement, work disability and unemployment paths to retirement, or different types of bridge employment. However, conceptual clarity in terms of connections between the different elements is called for. We introduce a conceptual framework of the work-to-retirement process to guide its future measurement. Together with information on the statutory retirement age, the main elements of the framework are based on employment and pension receipt, acknowledging that these may overlap. The framework is flexible to the user, providing the possibility to add various specifications—e.g. of types of employment, types of pension receipt, unemployment, and being outside the labour force—depending on the study context and aims. The framework highlights the complexity of the work-to-retirement process, bringing forth its multifaceted, multiphased and multidirectional features. Accounting for such complexity in later-life labour market dynamics helps to elaborate what is actually addressed when investigating “retirement”. Our conceptual framework can be utilized to enhance well-defined, precise and comparable measurement of the work-to-retirement process in studies.     

Artificial Sweeteners in Breast Milk: A Clinical Investigation with a Kinetic Perspective

Artificial sweeteners (ASs) are calorie-free chemical substances used instead of sugar to sweeten foods and drinks. Pregnant women with obesity or diabetes are often recommended to substitute sugary products with ASs to prevent an increase in body weight. However, some recent controversy surrounding ASs relates to concerns about the risk of obesity caused by a variety of metabolic changes, both in the mother and the offspring. This study addressed these concerns and investigated the biodistribution of ASs in plasma and breast milk of lactating women to clarify whether ASs can transfer from mother to offspring through breast milk. We recruited 49 lactating women who were provided with a beverage containing four different ASs (acesulfame-potassium, saccharin, cyclamate, and sucralose). Blood and breast milk samples were collected before and up to six hours after consumption. The women were categorized: BMI < 25 (n = 20), BMI > 27 (n = 21) and type 1 diabetes (n = 8). We found that all four ASs were present in maternal plasma and breast milk. The time-to-peak was 30–120 min in plasma and 240–300 min in breast milk. Area under the curve (AUC) ratios in breast milk were 88.9% for acesulfame-potassium, 38.9% for saccharin, and 1.9% for cyclamate. We observed no differences in ASs distributions between the groups.