Critical pressure in liquids due to dynamic choking.

The existence of a critical pressure ratio due to gas-dynamic choking is well known for an ideal gas. It is reasonable to assume that liquids whose compressibility is defined by the bulk modulus also have a critical pressure ratio. The problem discussed here is a fundamental one because it deals with the basic principles of the compressible flow of liquids. It has been shown that even though an ideal gas with a constant heat capacity ratio value has a critical pressure ratio, liquid with a constant bulk modulus value experiences a critical pressure difference. As the outlet pressure gradually decreases, the liquid reaches the local speed of sound, and further reduction of this pressure does not lead to an increase in mass flow. This phenomenon occurs in liquids without considering the change from a liquid to a gaseous phase. Behavior is confirmed analytically for different bulk modulus models, and for a constant bulk modulus value, the phenomenon is verified by numerical simulation using computational fluid dynamics. The conclusions published in this work point to striking analogies between the behavior of liquids and ideal gas. The equations governing the motion of liquids derived in this work, thus complete the fundamental description of the critical flow of fluids.

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

BACKGROUND: 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. METHODS: 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. DISCUSSION: We aim to compare two different doses of dexamethasone in patients with moderate to severe ARDS undergoing mechanical ventilation regarding efficacy and safety. TRIAL REGISTRATION: EudraCT No. 2020-005887-70. ClinicalTrials.gov NCT04663555. Registered on December 11, 2020.

Precursors of Viral Proteases as Distinct Drug Targets.

Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.

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.

Exploiting the unique features of Zika and Dengue proteases for inhibitor design.

Zika and Dengue viruses have attracted substantial attention from researchers in light of recent outbreaks of Dengue fever and increases in cases of congenital microcephaly in areas with Zika incidence. This review summarizes the current state of knowledge about Zika and Dengue proteases. These enzymes have several interesting features: 1) NS3 serine protease requires the activating co-factor NS2B, which is anchored in the membrane of the endoplasmic reticulum; 2) NS2B displays extensive conformational dynamics; 3) NS3 is a multidomain protein with proteolytic, NTPase, RNA 5' triphosphatase and helicase activity and has many protein-protein interaction partners; 4) NS3 is autoproteolytically released from its precursor. Attempts to design tight-binding and specific active-site inhibitors are complicated by the facts that the substrate pocket of the NS2B-NS3 protease is flat and the active-site ligands are charged. The ionic character of potential active-site inhibitors negatively influences their cell permeability. Possibilities to block cis-autoprocessing of the protease precursor have recently been considered. Additionally, potential allosteric sites on NS2B-NS3 proteases have been identified and allosteric compounds have been designed to impair substrate binding and/or block the NS2B-NS3 interaction. Such compounds could be specific to viral proteases, without off-target effects on host serine proteases, and could have favorable pharmacokinetic profiles. This review discusses various groups of inhibitors of these proteases according to their mechanisms of action and chemical structures.

Bilateral scapular fractures in adults.

PURPOSE: Bilateral scapular fracture is a very rare injury. Most of these fractures result from electrical shock or epileptic seizure. We treated six patients with such injuries, all of them caused by direct violence. The aim of this study was to report on the patients and to present an overview of the cases published so far. METHODS: Between January 2011 and August 2012, we treated six patients with bilateral scapular fractures (four men and two women, age range 20-78 years). Another 11 cases were found in the literature. All cases were analysed in terms of injury mechanism, fracture pattern and the manner of diagnosis. RESULTS: Our six patients increased the total number of recorded cases to 17 and the number of patients with traumatic bilateral scapular fractures from four to ten. In five of our cases, the injuries were classified as being the result of high-energy trauma. Computed tomography (CT) examination of the affected scapulae was performed in all six cases, in five in combination with 3D CT reconstruction; in one polytraumatised female patient, only axial CT scans were obtained. In all five high-energy trauma cases, bilateral fracture of the scapular body was recorded, of which one was classified as open. Four of the 11 cases found in the literature were caused by direct violence: in six patients, the fractures resulted from muscle spasms associated with epileptiform seizure or electrical shock, and one patient suffered a pathological fracture associated with amyloidosis. The most frequently recorded fracture in all 17 patients (34 fractures) was of the scapular body, i.e. 24 fractures, followed by 12 fractures of the glenoid fossa. CONCLUSION: According to data in the literature, bilateral scapular fracture is a rare injury. One reason may be that the potential incidence is often neglected. With the increasing number of patients with polytrauma, the potential for scapular fracture should always be taken into account, together with the fact that this injury may be bilateral. Of vital importance in diagnosing these injuries is CT scanning, including 3D CT reconstructions.