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1.
J Proteome Res ; 19(4): 1351-1360, 2020 04 03.
Article in English | MEDLINE | ID: covidwho-688546

ABSTRACT

As the infection of 2019-nCoV coronavirus is quickly developing into a global pneumonia epidemic, the careful analysis of its transmission and cellular mechanisms is sorely needed. In this Communication, we first analyzed two recent studies that concluded that snakes are the intermediate hosts of 2019-nCoV and that the 2019-nCoV spike protein insertions share a unique similarity to HIV-1. However, the reimplementation of the analyses, built on larger scale data sets using state-of-the-art bioinformatics methods and databases, presents clear evidence that rebuts these conclusions. Next, using metagenomic samples from Manis javanica, we assembled a draft genome of the 2019-nCoV-like coronavirus, which shows 73% coverage and 91% sequence identity to the 2019-nCoV genome. In particular, the alignments of the spike surface glycoprotein receptor binding domain revealed four times more variations in the bat coronavirus RaTG13 than in the Manis coronavirus compared with 2019-nCoV, suggesting the pangolin as a missing link in the transmission of 2019-nCoV from bats to human.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Genome, Viral/genetics , Host-Pathogen Interactions , Models, Molecular , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Animals , Betacoronavirus/classification , Eutheria/virology , HIV-1/genetics , Humans , Metagenome , Pandemics , Protein Structure, Tertiary , Sequence Alignment , Sequence Analysis, Protein , Snakes/virology
2.
Int J Oncol ; 57(2): 533-539, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-667782

ABSTRACT

Severe acute respiratory syndrome (SARS) coronavirus­2 (SARS­CoV2) is the cause of a new disease (COVID­19) which has evolved into a pandemic during the first half of 2020. Older age, male sex and certain underlying diseases, including cancer, appear to significantly increase the risk for severe COVID­19. SARS­CoV­2 infection of host cells is facilitated by the angiotensin­converting enzyme 2 (ACE­2), and by transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL). With the exception of ACE­2, a systematic analysis of these two other SARS­CoV2 infection mediators in malignancies is lacking. Here, we analysed genetic alteration, RNA expression, and DNA methylation of TMPRSS2 and CTSL across a wide spectrum of tumors and controls. TMPRSS2 was overexpressed in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma and uterine carcinosarcoma, with PRAD and READ exhibiting the highest expression of all cancers. CTSL was upregulated in lymphoid neoplasm diffuse large B­cell lymphoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lower grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, and thymoma. Hypo­methylation of both genes was evident in most cases where they have been highly upregulated. We have expanded on our observations by including data relating to mutations and copy number alterations at pan­cancer level. The novel hypotheses that are stemming out of these data need to be further investigated and validated in large clinical studies.


Subject(s)
Betacoronavirus/pathogenicity , Biomarkers, Tumor/genetics , Cathepsin L/genetics , Coronavirus Infections/virology , Neoplasms/genetics , Opportunistic Infections/virology , Pneumonia, Viral/virology , Serine Endopeptidases/genetics , Virus Internalization , Coronavirus Infections/enzymology , Coronavirus Infections/immunology , DNA Methylation , Databases, Genetic , Female , Host-Pathogen Interactions , Humans , Immunocompromised Host , Male , Neoplasms/enzymology , Neoplasms/immunology , Opportunistic Infections/enzymology , Opportunistic Infections/immunology , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/immunology , Risk Factors
5.
J Virol ; 94(15)2020 07 16.
Article in English | MEDLINE | ID: covidwho-661225

ABSTRACT

The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in a pandemic. Here, we used X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptors allows the definition of residues important for binding. From the 20 amino acids in ACE2 that contact S, up to 7 can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or acquisition of N-glycosylation sites located near the S interface. Of note, pigs and dogs, which are not infected or are not effectively infected and have only a few changes in the binding site, exhibit relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with that from bat coronavirus strain RaTG13 (Bat-CoV-RaTG13) and pangolin coronavirus (Pangolin-CoV) strain hCoV-19/pangolin/Guangdong/1/2019 revealed that the latter contains only one substitution, whereas Bat-CoV-RaTG13 exhibits five. However, ACE2 of pangolin exhibits seven changes relative to human ACE2, and a similar number of substitutions is present in ACE2 of bats, raccoon dogs, and civets, suggesting that SARS-CoV-2 may not be especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-CoV-2.IMPORTANCE SARS-CoV-2 is threatening people worldwide, and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear, and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes, indicating that the species barrier might be low. Exceptions are dogs and especially pigs, which revealed relatively low ACE2 expression levels in the respiratory tract. Monitoring of animals is necessary to prevent the generation of a new coronavirus reservoir. Finally, our analysis also showed that SARS-CoV-2 may not be specifically adapted to any of its putative intermediate hosts.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment , Animals , Animals, Domestic , Betacoronavirus/metabolism , Chiroptera/virology , Coronavirus Infections/metabolism , Dogs , Glycosylation , Host-Pathogen Interactions , Humans , Models, Animal , Pandemics , Pets , Pneumonia, Viral/metabolism , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Raccoons/virology , Sequence Alignment , Sequence Analysis, Protein , Swine , Viverridae/virology
6.
Cardiovasc Diabetol ; 19(1): 114, 2020 07 20.
Article in English | MEDLINE | ID: covidwho-656673

ABSTRACT

In the pandemic "Corona Virus Disease 2019" (COVID-19) people with diabetes have a high risk to require ICU admission. The management of diabetes in Intensive Care Unit is always challenging, however, when diabetes is present in COVID-19 the situation seems even more complicated. An optimal glycemic control, avoiding acute hyperglycemia, hypoglycemia and glycemic variability may significantly improve the outcome. In this case, intravenous insulin infusion with continuous glucose monitoring should be the choice. No evidence suggests stopping angiotensin-converting-enzyme inhibitors, angiotensin-renin-blockers or statins, even it has been suggested that they may increase the expression of Angiotensin-Converting-Enzyme-2 (ACE2) receptor, which is used by "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to penetrate into the cells. A real issue is the usefulness of several biomarkers, which have been suggested to be measured during the COVID-19. N-Terminal-pro-Brain Natriuretic-Peptide, D-dimer and hs-Troponin are often increased in diabetes. Their meaning in the case of diabetes and COVID-19 should be therefore very carefully evaluated. Even though we understand that in such a critical situation some of these requests are not so easy to implement, we believe that the best possible action to prevent a worse outcome is essential in any medical act.


Subject(s)
Betacoronavirus/pathogenicity , Blood Glucose/drug effects , Coronavirus Infections/therapy , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Intensive Care Units , Pneumonia, Viral/therapy , Antihypertensive Agents/therapeutic use , Biomarkers/blood , Blood Glucose/metabolism , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Coronavirus Infections/virology , Diabetes Mellitus/blood , Diabetes Mellitus/diagnosis , Diabetes Mellitus/mortality , Dyslipidemias/drug therapy , Dyslipidemias/mortality , Host-Pathogen Interactions , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypertension/drug therapy , Hypertension/mortality , Hypoglycemic Agents/adverse effects , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Risk Assessment , Risk Factors , Treatment Outcome
7.
J Thromb Haemost ; 18(7): 1648-1652, 2020 07.
Article in English | MEDLINE | ID: covidwho-644872

ABSTRACT

We present a putative link between maternal COVID-19 infection in the peripartum period and rapid maternal deterioration with early organ dysfunction and coagulopathy. The current pandemic with SARS-CoV-2 has already resulted in high numbers of critically ill patients and deaths in the non-pregnant population, mainly due to respiratory failure. During viral outbreaks, pregnancy poses a uniquely increased risk to women due to changes to immune function, alongside physiological adaptive alterations, such as increased oxygen consumption and edema of the respiratory tract. The laboratory derangements may be reminiscent of HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, and thus knowledge of the COVID-19 relationship is paramount for appropriate diagnosis and management. In addition to routine measurements of D-dimers, prothrombin time, and platelet count in all patients presenting with COVID-19 as per International Society on Thrombosis and Haemostasis (ISTH) guidance, monitoring of activated partial thromboplastin time (APTT) and fibrinogen levels should be considered in pregnancy, as highlighted in this report. These investigations in SARS-CoV-2-positive pregnant women are vital, as their derangement may signal a more severe COVID-19 infection, and may warrant pre-emptive admission and consideration of delivery to achieve maternal stabilization.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/virology , Disseminated Intravascular Coagulation/virology , Pneumonia, Viral/virology , Pregnancy Complications, Hematologic/virology , Pregnancy Complications, Infectious/virology , Adult , Blood Coagulation Tests , Clinical Laboratory Techniques , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/therapy , Female , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pregnancy , Pregnancy Complications, Hematologic/blood , Pregnancy Complications, Hematologic/diagnosis , Pregnancy Complications, Hematologic/therapy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/therapy , Pregnancy Trimester, Third/blood , Treatment Outcome , Young Adult
11.
Immunol Rev ; 296(1): 205-219, 2020 07.
Article in English | MEDLINE | ID: covidwho-641222

ABSTRACT

This article provides a review of studies evaluating the role of host (and viral) genetics (including variation in HLA genes) in the immune response to coronaviruses, as well as the clinical outcome of coronavirus-mediated disease. The initial sections focus on seasonal coronaviruses, SARS-CoV, and MERS-CoV. We then examine the state of the knowledge regarding genetic polymorphisms and SARS-CoV-2 and COVID-19. The article concludes by discussing research areas with current knowledge gaps and proposes several avenues for future scientific exploration in order to develop new insights into the immunology of SARS-CoV-2.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Disease Resistance/genetics , Genetic Predisposition to Disease , Host-Pathogen Interactions/genetics , Pneumonia, Viral/immunology , Animals , Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Coronavirus Infections/virology , Host-Pathogen Interactions/immunology , Humans , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , SARS Virus/immunology , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology
12.
Pharmacol Res Perspect ; 8(4): e00623, 2020 08.
Article in English | MEDLINE | ID: covidwho-641200

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS-CoV-2 and SARS-CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID-19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesis of COVID-19 and potential therapeutic targets, focusing on the role of the renin-angiotensin-aldosterone system.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Renin-Angiotensin System , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Evidence-Based Medicine , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Renin-Angiotensin System/drug effects
13.
Trials ; 21(1): 639, 2020 Jul 13.
Article in English | MEDLINE | ID: covidwho-641150

ABSTRACT

OBJECTIVES: Primary Objective • To evaluate the effect of ravulizumab, a long-acting complement (C5) inhibitor plus best supportive care (BSC) compared with BSC alone on the survival of patients with COVID-19. Secondary Objectives • Number of days free of mechanical ventilation at Day 29 • Duration of intensive care unit stay at Day 29 • Change from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 29 • Change from baseline in peripheral capillary oxygen saturation/ fraction of inspired oxygen (SpO2 /FiO2) at Day 29 • Duration of hospitalization at Day 29 • Survival (based on all-cause mortality) at Day 60 and Day 90 Safety • Incidence of treatment-emergent adverse events and treatment-emergent serious adverse events. PK/PD/Immunogenicity • Change in serum ravulizumab concentrations over time • Change in serum free and total C5 concentrations over time • Incidence and titer of anti-ALXN1210 antibodies Biomarkers • Change in absolute level of soluble biomarkers in blood associated with complement activation, inflammatory processes, and hypercoagulable states over time Exploratory • Incidence of progression to renal failure requiring dialysis at Day 29 • Time to clinical improvement (based on a modified 6-point ordinal scale) over 29 days • SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores at Day 29 (or discharge), Day 60, and Day 90 • EuroQol 5-dimension 5-level (EQ-5D-5L) scores at Day 29 (or discharge), Day 60, and Day 90 TRIAL DESIGN: This is a multicenter Phase 3, open-label, randomized, controlled, study. The study is being conducted in acute care hospital settings in the United States, United Kingdom, Spain, France, Germany, and Japan. PARTICIPANTS: Male or female patients at least 18 years of age, weighing ≥ 40 kg, admitted to a designated hospital facility for treatment will be screened for eligibility in this study. Key Inclusion criteria • Confirmed diagnosis of SARS-CoV-2 infection (eg, via polymerase chain reaction [PCR] and/or antibody test) presenting as severe COVID-19 requiring hospitalization • Severe pneumonia, acute lung injury, or ARDS confirmed by computed tomography (CT) or X-ray at Screening or within the 3 days prior to Screening, as part of the patient's routine clinical care • Respiratory distress requiring mechanical ventilation, which can be either invasive (requiring endotracheal intubation) or non-invasive (with continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]) Key Exclusion criteria • Patient is not expected to survive for more than 24 hours • Patient is on invasive mechanical ventilation with intubation for more than 48 hours prior to Screening • Severe pre-existing cardiac disease (ie, NYHA Class 3 or Class 4, acute coronary syndrome, or persistent ventricular tachyarrhythmias) • Patient has an unresolved Neisseria meningitidis infection Excluded medications and therapies • Current treatment with a complement inhibitor • Intravenous immunoglobulin (IVIg) within 4 weeks prior to randomization on Day 1 Excluded prior/concurrent clinical study experience • Treatment with investigational therapy in a clinical study within 30 days before randomization, or within 5 half-lives of that investigational therapy, whichever is greater • Exceptions a. Investigational therapies will be allowed if received as part of best supportive care through an expanded access protocol or emergency approval for the treatment of COVID-19. b. Investigational antiviral therapies (such as remdesivir) will be allowed even if received as part of a clinical study. INTERVENTION AND COMPARATOR: The study consists of a Screening Period of up to 3 days, a Primary Evaluation Period of 4 weeks, a final assessment at Day 29, and a Follow-up Period of 8 weeks. For patients randomized to ravulizumab plus BSC, a weight-based dose of ravulizumab (≥40 to < 60 kg/2400 mg, 60 to < 100 kg/2700 mg, ≥ 100 kg/3000 mg) will be administered on Day 1. On Day 5 and Day 10, additional doses of 600 mg (≥40 to <60 kg) or 900 mg (>60 kg) ravulizumab will be administered and on Day 15 patients will receive 900 mg ravulizumab. There is no active or placebo comparator in this open-label clinical trial. The total duration of each patient's participation is anticipated to be approximately 3 months. MAIN OUTCOMES: The primary efficacy outcome of this study is survival (based on all-cause mortality) at Day 29. RANDOMISATION: Patients will be randomized in a 2:1 ratio (ravulizumab plus BSC:BSC alone). Randomization will be stratified by intubated or not intubated on Day 1. Computer-generated randomization lists will be prepared by a third party under the direction of the sponsor. Investigators, or designees, will enrol patients and then obtain randomization codes using an interactive voice/web response system. The block size will be kept concealed so that investigators cannot select patients for a particular treatment assignment. Blinding (masking): This is an open-label study. Numbers to be randomised (sample size): Approximately 270 patients will be randomly assigned in a 2:1 ratio to ravulizumab plus BSC (n=180) or BSC alone (n=90). TRIAL STATUS: Protocol Number: ALXN1210-COV-305 Original Protocol: 09 Apr 2020 Protocol Amendment 1 (Global): 13 Apr 2020 Protocol Amendment 2 (Global): 17 Apr 2020 Protocol Amendment 3 (Global): 09 Jun 2020 Recruitment is currently ongoing. Recruitment was initiated on 11 May 2020. We expect recruitment to be completed by 30 Nov 2020. TRIAL REGISTRATION: Clinicaltrials.gov: Protocol Registry Number: NCT04369469 ; First posted; 30 Apr 2020 EU Clinical Trials Register: EudraCT Number: https://www.clinicaltrialsregister.eu/ctr-search/search?query=ALXN1210-COV-305 , Start date: 07 May 2020 FULL PROTOCOL: The full redacted protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Complement Inactivating Agents/administration & dosage , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Administration, Intravenous , Antibodies, Monoclonal, Humanized/adverse effects , Antiviral Agents/adverse effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Clinical Trials, Phase III as Topic , Complement Inactivating Agents/adverse effects , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Host-Pathogen Interactions , Humans , Male , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Time Factors , Treatment Outcome
14.
Trials ; 21(1): 635, 2020 Jul 10.
Article in English | MEDLINE | ID: covidwho-640432

ABSTRACT

OBJECTIVES: The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64. TRIAL DESIGN: Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial. PARTICIPANTS: Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate <20, mental state alert, no signs of septic shock. Cardiac risk is minimised by requiring a Tisdale score ≤ 6. Patients are recruited in the two german cities of Ulm and Tübingen in various ambulatory care settings. INTERVENTION AND COMPARATOR: Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2nd day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g. MAIN OUTCOMES: Rate of hospitalization or death at day 7 after study inclusion RANDOMISATION: All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list. BLINDING (MASKING): Patients and investigators, as well as treating physicians are blinded to the treatment- allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients. TRIAL STATUS: Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 TRIAL REGISTRATION: ClinicalTrials.gov: NCT04351516 , date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Ambulatory Care , Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Clinical Laboratory Techniques , Coronavirus Infections/drug therapy , Hydroxychloroquine/administration & dosage , Pneumonia, Viral/drug therapy , Age Factors , Aged , Aging , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , Cause of Death , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Coronavirus Infections/virology , Double-Blind Method , Drug Administration Schedule , Female , Germany , Hospitalization , Host-Pathogen Interactions , Humans , Hydroxychloroquine/adverse effects , Male , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Predictive Value of Tests , Randomized Controlled Trials as Topic , Risk Factors , Time Factors , Treatment Outcome
15.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640304
17.
Trials ; 21(1): 609, 2020 Jul 03.
Article in English | MEDLINE | ID: covidwho-630127

ABSTRACT

OBJECTIVES: To evaluate the therapeutic effects of ultra-short-wave diathermy (SWD) on COVID-19 pneumonia. The hypothesis is that SWD may minimise pneumonic inflammation and shorten the duration of the time to positive-to-negative conversion of COVID-19 nucleic acid test. TRIAL DESIGN: This is a single centre, 2-arm (1:1 ratio), evaluator blinded, parallel group design superiority randomised, controlled clinical trial. PARTICIPANTS: The inclusion criteria were: (1) Age 18-65 years, (2) COVID-19 nucleic acid test is positive, (3) Lung CT showed multiple patchy ground glass shadows or other typical manifestations of both lungs. The exclusion criteria were: (1) Patients who need ICU management, (2) Positive tests for other pathogens such as Tuberculosis, Mycoplasma, (3) Patients with respiratory failure or requiring mechanical ventilation, (4) Patients with metal implants or pacemakers, (5) Those with shock (6) Those that have bleeding tendency or active bleeding in the lungs, (7) Patients with multiple organ failure who need ICU monitoring and treatment, (8) Cancer patients and those with severe underlying diseases, (9) Pregnant or lactating women, (10) Patients with severe cognitive impairment who cannot follow the instructions to complete the treatment, (11) Those without signed informed consent and (12) Those with other contraindications to short wave. This study will be conducted in Tongji Hospital, Caidian, Wuhan, People's Republic of China. INTERVENTION AND COMPARATOR: The experimental group will be given the nationally recommended standard medical treatment + ultra-short-wave diathermy treatment. Ultra-short-wave therapy treatment will be performed through application of ultra-short-wave therapy machine electrodes on the anterior and posterior parts of the trunk for 10 minutes, twice a day for 12 consecutive days. The comparator will be the control, not receiving ultra-short-wave therapy, and will be given only the nationally recommended standard medical treatment. MAIN OUTCOMES: The primary outcome measures will be time to positive-to-negative conversion of COVID-19 nucleic acid test by pharyngeal swab, in days assessed at 7th, 14th ,21st and 28th days. The secondary outcome measures include nucleic acid test rate and recovery from symptoms, Vital signs assessment, Computed Tomography, Complete blood count, serum analysis and SIRS scale scores. Blinded evaluation will be at baseline (the day of starting ultra-short-wave diathermy) and after 28 days following the interventions. RANDOMISATION: A Randomization plan will be generated online on www.randomization.com using permuted blocks method, by a statistician who will not be part of the study. Small blocks of various sizes will be used. Patients will be randomized (1:1) between the experimental and control groups BLINDING (MASKING): This will be an evaluator blinded study. Due to the nature of the intervention, blinding of patients and healthcare workers is not possible. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 410 patients will be randomised in 1:1 ratio to two groups: experimental group (n=205) and control group (n=205). TRIAL STATUS: Protocol version 1 was approved on 02/12/2020. Recruitment for this trial began on 02/18/2020 and will be ongoing till the required sample size is reached. The analysis deadline is August 2020. TRIAL REGISTRATION: This randomised controlled trial has been prospectively registered with the Chinese Clinical Trials ( ChiCTR2000029972 ) on 17 February 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol." The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Short-Wave Therapy , Adolescent , Adult , Aged , China , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Equivalence Trials as Topic , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Short-Wave Therapy/adverse effects , Time Factors , Treatment Outcome , Young Adult
18.
Trials ; 21(1): 610, 2020 Jul 03.
Article in English | MEDLINE | ID: covidwho-629630

ABSTRACT

OBJECTIVES: As there is no treatment for COVID-19 with a proven mortality benefit at this moment in the pandemic, supportive management including mechanical ventilation is the core management in an intensive care unit (ICU). It is a challenge to provide consistent care in this situation, highly demanding and leading to potential staff shortages in ICU. We need to reduce unnecessary exposure of healthcare workers to the virus. This study aims to examine the impact of care using a non-invasive oscillating device (NIOD) for chest physiotherapy in the care of mechanically ventilated patients with COVID-19. In particular, we aim to explore if a NIOD performed by non-specialized personnel is not inferior to the standard chest physiotherapy (CPT) undertaken by physiotherapists caring for patients with COVID-19. TRIAL DESIGN: A pilot multicenter prospective crossover noninferiority randomized controlled trial. PARTICIPANTS: All mechanically ventilated patients with COVID-19 admitted to one of the two ICUs, and CPT ordered by the responsible physician. The participants will be recruited from two intensive care units in Canadian Academic Hospitals (one pediatric and one adult ICU). INTERVENTION AND COMPARATOR: We will implement NIOD and CPT alternatingly for 3 h apart over 3 h. We will apply a pragmatic design, so that other procedures including hypertonic saline nebulization, intermittent positive pressure ventilation, suctioning (e.g., oral or nasal), or changing the ventilator settings or modality (i.e., increasing positive end-expiratory pressure or changing the nasal mask to total face continuous positive airway pressure) can be provided at the direction of bedside intensivists in charge. MAIN OUTCOMES: The primary outcome measurement is the oxygenation level before and after the procedure (SpO2/FiO2 ratio). For cases with invasive ventilation (i.e., the use of an endotracheal tube to deliver positive pressure) and non-invasive ventilation, we will also document expiratory tidal volume, vital signs, and any related complications such as vomiting, hypoxemia, or unexpected extubation. We will collect the data before, 10 min after, and 30 min after the procedure. RANDOMIZATION: The order of the procedures (i.e., NIOD or CPT) will be randomly allocated using manual generated random numbers for each case. Randomization will be carried out by the independent research assistant in the study coordinating center by using opaque sealed envelopes, assigning an equal number of cases to each intervention arm. Stratification will be applied for age (> 18 years or ≤ 18 years of age) and the study sites. BLINDING (MASKING): No blinding will be performed. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): We estimate the necessary sample size as 25 for each arm (total 50 cases), with a power of 0.90 and an alpha of 0.05, with a non-inferiority design. TRIAL STATUS: The protocol version number 1 was approved on 27 March 2020. Currently, recruitment has not yet started, with the start scheduled by the mid-June 2020 and the end anticipated by December 2020. TRIAL REGISTRATION: ClinicalTrials.gov NCT04361435 . Registered on 28 April 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional File 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/therapy , Lung/virology , Physical Therapy Modalities , Pneumonia, Viral/therapy , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Critical Illness , Equivalence Trials as Topic , Host-Pathogen Interactions , Humans , Lung/physiopathology , Multicenter Studies as Topic , Pandemics , Physical Therapy Modalities/adverse effects , Physical Therapy Modalities/instrumentation , Pilot Projects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Prospective Studies , Quebec , Respiration, Artificial , Time Factors , Treatment Outcome
19.
Am J Physiol Cell Physiol ; 319(2): C244-C249, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-624886

ABSTRACT

The outbreak of COVID-19 pneumonia caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is posing a global health emergency and has led to more than 380,000 deaths worldwide. The cell entry of SARS-CoV-2 depends on two host proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). There is currently no vaccine available and also no effective drug for the treatment of COVID-19. Hydrogen sulfide (H2S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, antioxidative stress, antiviral, prosurvival, and antiaging effects. In light of the research advances on H2S signaling in biology and medicine, this review proposed H2S as a potential defense against COVID-19. It is suggested that H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development. Preclinical studies and clinical trials with slow-releasing H2S donor(s) or the activators of endogenous H2S-generating enzymes should be considered as a preventative treatment or therapy for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydrogen Sulfide/therapeutic use , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Virus Replication/drug effects , Animals , Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Hydrogen Sulfide/metabolism , Lung/drug effects , Lung/metabolism , Lung/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Serine Endopeptidases/metabolism , Signal Transduction
20.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-623805

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
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