The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed ...COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days.
REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice.
The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic.
Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO
/FiO
100-200 mmHg; • Severe - PaO
/FiO
< 100 mmHg; 5. Admission to ICU in the last 24 hours.
Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days.
Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used.
Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index.
Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day.
This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed.
The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled.
This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021.
The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021.
The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Since December 2019, SARS-CoV-2 virus has infected millions of people worldwide. In patients with COVID-19 pneumonia in need of oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is ...currently recommended. However, the dose of 6 mg of dexamethasone is currently being reappraised and may miss important therapeutic potential or may prevent potential deleterious effects of higher doses of corticosteroids.
REMED is a prospective, open-label, randomised controlled trial testing the superiority of dexamethasone 20 mg (dexamethasone 20 mg on days 1-5, followed by dexamethasone 10 mg on days 6-10) vs 6 mg administered once daily intravenously for 10 days in adult patients with moderate or severe ARDS due to confirmed COVID-19. Three hundred participants will be enrolled and followed up for 360 days after randomization. Patients will be randomised in a 1:1 ratio into one of the two treatment arms. The following stratification factors will be applied: age, Charlson Comorbidity Index, CRP levels and trial centre. The primary endpoint is the number of ventilator-free days (VFDs) at 28 days after randomisation. The secondary endpoints are mortality from any cause at 60 days after randomisation; dynamics of the inflammatory marker, change in WHO Clinical Progression Scale at day 14; and adverse events related to corticosteroids and independence at 90 days after randomisation assessed by the Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days. The study will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic.
We aim to compare two different doses of dexamethasone in patients with moderate to severe ARDS undergoing mechanical ventilation regarding efficacy and safety.
EudraCT No. 2020-005887-70. ClinicalTrials.gov NCT04663555. Registered on December 11, 2020.
The study was carried out to evaluate the effect of several substrates on oxidative stress induced apoptosis and in K-562 cells.
Glucose at 5, 11 and 30 mM concentrations was tested, as well as 5 mM ...glutamine and 5 mM fructose. The cells were exposed to tert-butylhydroperoxide (tBH) and apoptotic cells were evaluated by flow cytometry with FITC-Annexin V and propidium iodide. The effect of glucose concentration on DNA damage was evaluated using hydrogen peroxide and electrophoretic "DNA comets" assay at 5 mM and 30 mM glucose concentrations.
The exposure of cells to tBH resulted in increased number of apoptotic cells, and this effect was prevented by administration of an antioxidant - N-Acetyl cysteine. Rising concentrations of glucose added to the toxic effect of tBH; we also observed some toxic effect of fructose and no effect of glutamine. We found higher susceptibility to hydrogen peroxide induced DNA damage with 30 mM glucose concentration.
Hyperglycemia increases the cell's susceptibility to oxidative stress and it also amplifies oxidative DNA damage. Glutamine - when used as a sole energetic substrate - showed no protective effect against oxidative stress.
Surfaces evolving through time are hard to analyze without prior knowledge of the represented deforming shape. Topological noise introduced by inaccuracies during surface capture and reconstruction ...renders the estimation of time-consistent correspondence an ill-posed problem. It has previously been shown that this problem may be mitigated by tracking the volume within the surface rather than the surface itself. Assuming that the captured phenomenon does not involve sudden appearance or disappearance of volume, it is possible to establish a bijective correspondence of volume elements, which in turn may be used for various purposes, such as extracting a canonical shape and guiding the computation of surface correspondence.
In this paper, we discuss an improved volume tracking methodology that provides better results by modifying the energy formulation and by incorporating a notion of volume element affinity, combined with an improved optimization strategy. We also discuss two metrics that, when combined, quantify the quality of the tracking results.
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•We present an improved pipeline for tracking volume within time-varying meshes.•ARAP based smoothness energy achieves results more robust to global rigid motion.•Weighting based on similarity of motion reduces tracking inconsistencies.•We outperform previous work on majority of tested datasets based on proposed metrics.
Analyzing the symmetries present in point clouds, which represent sets of 3D coordinates, is important for understanding their underlying structure and facilitating various applications. In this ...paper, we propose a novel decomposition-based method for detecting the entire symmetry group of 3D point clouds. Our approach decomposes the point cloud into simpler shapes whose symmetry groups are easier to find. The exact symmetry group of the original point cloud is then derived from the symmetries of these individual components. The method presented in this paper is a direct extension of the approach recently formulated in Bizzarri et al. (2022a) for discrete curves in plane. The method can be easily modified also for perturbed data. This work contributes to the advancement of symmetry analysis in point clouds, providing a foundation for further research and enhancing applications in computer vision, robotics, and augmented reality.
•We present a theoretical framework to assess exact point clouds symmetries via decomposition-based method.•The exact symmetry group of the 3D point cloud is derived from the symmetries of simpler components.•The method can be easily modified also for perturbed data.
The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) ...are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in
,
, and
gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.
Objectives
The aim of this study was to analyze the annual detection rate (DR) of transposition of the great arteries (TGA) and tetrology of Fallot (ToF), after the introduction of the three‐vessel ...view as a mandatory plane in 2012.
Methods
All registered TGA and ToF cases were retrospectively extracted from our registry between 2007 and 2016. We compared the DR in a 10‐year period, before 2011, with the DR of TGA and ToF after 2012.
Results
In the period before 2012, 23 of the 52 TGA cases were prenatally detected (44.2%), compared with 42 of the 51 cases (82.4%) after 2012. For ToF, the DRs increased from 28 of 64 cases (43.8%) to 42 of 62 cases (67.7%) in the aforementioned periods. The increase in DRs for both defects was statistically significant (P ≤ 0.001 and P ≤ 0.05).
Conclusions
In this nationally organized prenatal screening program with a quality monitoring system and a uniform protocol, DRs of 82.4% for TGA and 67.7% for ToF were reached after the introduction of the three‐vessel view as a mandatory item. The three‐vessel view significantly contributes to the detection of these conotruncal anomalies.
What's already known about this topic?
Prenatal detection of transposition of the great arteries and tetralogy of Fallot leads to decreased mortality and morbidity of affected neonates.
Screening for congenital heart defects has improved significantly over the past decade but has, however, not reached detection rates of 100%.
What does this study add?
Protocol changes like adding additional planes to echocardiographic evaluation lead to increased detection of transposition of the great arteries and tetralogy of Fallot.
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