Effect of dexamethasone in patients with ARDS and COVID-19 - prospective, multi-centre, open-label, parallel-group, randomised controlled trial (REMED trial): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: 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. TRIAL DESIGN: 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. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: 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 - PaO2/FiO2 100-200 mmHg;  • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: 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. INTERVENTION AND COMPARATOR: 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. MAIN OUTCOMES: 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: 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. BLINDING (MASKING): 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. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 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. TRIAL STATUS: 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. TRIAL REGISTRATION: 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. FULL PROTOCOL: 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

Engendering Unprecedented Activation of Oxygen Evolution via Rational Pinning of Ni Oxidation State in Prototypical Perovskite:Close Juxtaposition of Synthetic Approach and Theoretical Conception

Rational optimization of the OER activity of catalysts based on LaNiO3 oxide is achieved by maximizing the presence of trivalent Ni in the surface structure. DFT investigations of the LaNiO3 catalyst and surface structures related to it predict an improvement in the OER activity for these materials to levels comparable with the top of the OER volcano if the La content is minimized while the oxidation state of Ni is maintained. These theoretically predicted structures of high intrinsic OER activity can be prepared by a templated spray-freeze freeze-drying synthesis followed by a simple postsynthesis exfoliation-like treatment in acidic media. These nanocrystalline LaNiO3-related materials confirm the theoretical predictions, showing a dramatic improvement in OER activity. The exfoliated surfaces remain stable in OER catalysis, as shown by an in-operando ICP-OES study. The unprecedented OER activation of the synthesized LaNiO3-based materials is related to a close juxtaposition of the theoretical conception of ideal structural motifs and the ability to engender such motifs using a unique synthetic procedure, both principally related to stabilization and pinning of the Ni oxidation state within the local coordination environment of the perovskite structure. © 2021 American Chemical Society. All rights reserved

Dynamic changes in genomic and social structures in third millennium BCE central Europe

Europe’s prehistory oversaw dynamic and complex interactions of diverse societies, hitherto unexplored at detailed regional scales. Studying 271 human genomes dated ~4900 to 1600 BCE from the European heartland, Bohemia, we reveal unprecedented genetic changes and social processes. Major migrations preceded the arrival of “steppe” ancestry, and at ~2800 BCE, three genetically and culturally differentiated groups coexisted. Corded Ware appeared by 2900 BCE, were initially genetically diverse, did not derive all steppe ancestry from known Yamnaya, and assimilated females of diverse backgrounds. Both Corded Ware and Bell Beaker groups underwent dynamic changes, involving sharp reductions and complete replacements of Y-chromosomal diversity at ~2600 and ~2400 BCE, respectively, the latter accompanied by increased Neolithic-like ancestry. The Bronze Age saw new social organization emerge amid a ≥40% population turnover.Introduction Results - General sample overview - Bohemia before Corded Ware (pre-CW, before ~2800 BCE) - Corded Ware - Bell Beaker - EBA—Únětice culture Discussion Materials and methods - Processing sites for the newly reported individuals - Sampling - DNA extraction - DNA libraries and in-solution capture - Sequencing - Sex determination and authentication - Genotyping - Mitochondrial and Y chromosome haplogroups - Principal components analysis - Ancestry decomposition and admixture modeling - Y haplogroup frequency simulation

Dynamic changes in genomic and social structures in third millennium BCE central Europe

Europe’s prehistory oversaw dynamic and complex interactions of diverse societies, hitherto unexplored at detailed regional scales. Studying 271 human genomes dated ~4900 to 1600 BCE from the European heartland, Bohemia, we reveal unprecedented genetic changes and social processes. Major migrations preceded the arrival of “steppe” ancestry, and at ~2800 BCE, three genetically and culturally differentiated groups coexisted. Corded Ware appeared by 2900 BCE, were initially genetically diverse, did not derive all steppe ancestry from known Yamnaya, and assimilated females of diverse backgrounds. Both Corded Ware and Bell Beaker groups underwent dynamic changes, involving sharp reductions and complete replacements of Y-chromosomal diversity at ~2600 and ~2400 BCE, respectively, the latter accompanied by increased Neolithic-like ancestry. The Bronze Age saw new social organization emerge amid a ≥40% population turnover.Peer reviewe

Zn-substituted iron oxide nanoparticles from thermal decomposition and their thermally treated derivatives for magnetic solid-phase extraction

Controlled thermal decomposition of zinc and iron acetylacetonates in the presence of oleic acid and oleylamine provided surfactant-capped magnetic nanoparticles with narrow size distribution and the mean diameter of ≈15 nm. The combined study by XRD, XRF and Mössbauer spectroscopy revealed three important features of the as-prepared nanoparticles. First, the actual ratio of Zn:Fe was considerably lower in the product compared to the initial ratio of metal precursors (0.14 vs. 0.50). Second, a pure stoichiometric Zn-doped magnetite system, specifically of the composition Zn0.37Fe2.63O4, with no signatures of oxidation to maghemite was formed. Third, Zn2+ ions were distributed at both tetrahedral and octahedral sites, and the observed preference for the tetrahedral site was only twice as high as for the octahedral site. Furthermore, carbon-coated nanoparticles were achieved by pyrolysis of the surfactants at 500 °C, providing a potential sorbent of organic pollutants with room-temperature magnetization as high as 79.1 emu g−1 and very low carbon content of 5 wt%. The thermal treatment, albeit intended only for the carbonization of surfactants, did alter also the non-equilibrium cation distribution toward the equilibrium one by the relocation of a considerable fraction of the octahedrally coordinated Zn2+ to the tetrahedral sites. Preliminary experiments with magnetic solid-phase extraction of β-estradiol from aqueous solutions evidenced applicability and reusability of the carbon-coated product in the separation of steroid pollutants

Management of hypotension after general anaesthesia induction - multicenter questionnaire study

Cíl studie: Cílem naší práce bylo posouzení variability terapie hypotenze po úvodu do celkové anestezie (GAIH). Typ studie: Multicentrická dotazníková studie. Typ pracovišť: Osm anesteziologických pracovišť různé velikosti z České a Slovenské republiky. Materiál a metoda: Respondenti odpovídali na tři identifikační otázky (pracoviště, délka praxe, specializovaná způsobilost) a deset zjišťovacích otázek týkajících se managementu GAIH v online dotazníku. Byla použita jednoduchá popisná statistika hodnotící zastoupení odpovědí respondentů v absolutních a relativních četnostech. Normalizovaná entropie (H) byla použita k posouzení variability odpovědí. Výsledky: Plně vyplněný dotazník jsme získali od 172 respondentů. Největší míra variability byla pozorována u otázky č. 1.: „Za referenční hodnotu tlaku krve, se kterou porovnávám další hodnoty..., považuji…“ (H = 0,966). Nejnižší míra variability odpovědí byla zaznamenána u otázky č. 4.: „Za hypotenzi považuji pokles…“ (H = 0,070). Závěr: Výsledky práce ukazují vysokou variabilitu názorů na terapii GAIH.Objective: The aim of our study was to assess the management of hypotension after general anaesthesia induction (GAIH). Design: Multicenter questionnaire study. Setting: Eight different size anaesthesiology departments located in the Czech or Slovak Republics. Materials and methods: The respondents responded to three identification questions (workplace, length of practince) and ten GAIH management questions in our online questionnaire. Simple descriptive statistics describing the representation of the respondents' answers in absolute and relative terms were used. Normalized entropy (H) was used to assess the variability of responses. Results: A fully completed questionnaire was obtained from 172 respondents. The highest rate of variability was observed in question 1.: "As the baseline blood pressure value (BP), to which I compare other BP values, I consider..." H = 0.966. The lowest response variability rate was observed in question 4.: "As hypotension, I consider the Of BP..." H = 0.07). Conclusion: Our results indicate high variability of GAIH management among anaesthetists.Web of Science303-412511