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1.
Res Sq ; 2020 Jul 22.
Article in English | MEDLINE | ID: covidwho-1431218

ABSTRACT

The COVID-19 pandemic has affected more than 10 million people worldwide with mortality exceeding half a million patients. Risk factors associated with severe disease and mortality include advanced age, hypertension, diabetes, and obesity.1 Clear mechanistic understanding of how these comorbidities converge to enable severe infection is lacking. Notably each of these risk factors pathologically disrupts the lipidome and this disruption may be a unifying feature of severe COVID-19.1-7 Here we provide the first in depth interrogation of lipidomic changes, including structural-lipids as well as the eicosanoids and docosanoids lipid mediators (LMs), that mark COVID-19 disease severity. Our data reveal that progression from moderate to severe disease is marked by a loss of specific immune regulatory LMs and increased pro-inflammatory species. Given the important immune regulatory role of LMs, these data provide mechanistic insight into the immune balance in COVID-19 and potential targets for therapy with currently approved pharmaceuticals.8.

2.
Med Pr ; 72(3): 321-325, 2021 Jun 30.
Article in Polish | MEDLINE | ID: covidwho-1413233

ABSTRACT

In 2019, COVID-19, the disease caused by the SARS-CoV-2 virus, evolved into a pandemic which is still going on. The basic clinical symptoms of the SARS-CoV-2 infection are: fever, dry cough, fatigue, muscle pain, respiratory problems, and the loss of smell or taste. Other symptoms, including those related to hearing and balance organs (hearing loss, tinnitus, dizziness), are reported less frequently by patients. They are especially rarely reported as the first symptoms of this infection. In order to answer the question of whether SARS-CoV-2 can cause hearing and balance damage, the authors reviewed the literature sources from 2019-2020 included in EMBASE and PubMed, entering the following words: "hearing loss," "COVID-19," "coronavirus," "sensorineural hearing loss," "vertigo," and "dizziness." Ultimately, 9 studies on the possible relationship between hearing impairment and SARS-CoV-2, and 4 studies on the possible relationship between damage to the balance and SARS-CoV-2, were qualified for the study. The results of the analysis suggest a possible relationship between COVID-19 and hearing loss, with no evidence of a similar relationship between this virus and the balance system. The possible existence of such a relationship should be especially remembered by hospital emergency room doctors, otolaryngologists and audiologists, especially as regards the possibility of a sudden sensironeural hearing loss as the first symptom of COVID-19. This also applies to doctors of other specialties. The authors indicate the need for further, intensive and multifaceted research on this issue. Med Pr. 2021;72(3):321-5.


Subject(s)
COVID-19/complications , Hearing Disorders/etiology , Hearing , Postural Balance , Vestibular Diseases/etiology , Adult , COVID-19/epidemiology , COVID-19/physiopathology , Female , Hearing Loss/etiology , Humans , Male , Middle Aged , Tinnitus/etiology , Vertigo/etiology , Young Adult
3.
Int J Environ Res Public Health ; 18(11)2021 May 28.
Article in English | MEDLINE | ID: covidwho-1256509

ABSTRACT

(1) Background: A balanced life is related to good health in young people, one of the groups most affected by confinement and social distancing measures during the COVID-19 pandemic. This study aims to explore the occupational balance of young adults during home confinement and its association with different sociodemographic factors. (2) Methods: A cross-sectional study was designed, and an online survey was disseminated to collect sociodemographic and occupational balance data, using the Occupational Balance Questionnaire (OBQ). The statistical analysis was performed using the SPSS statistical software package version 24.0. (3) Results: 965 young adults between 18 and 30 years old participated in the study. A predictive model showed that the main predictors of a lower occupational balance were a negative self-perception (ß= 0.377; p = <0.0001), student status (ß = 0.521; p = 0.001), not receiving enough information (ß = 0.951; p = 0.001) and long periods of quarantine (ß = 0.036; p = 0.007). (4) Conclusions: Considering people's occupational health and related factors could lessen many of the psychosocial consequences of isolation and contribute to the well-being of young people.


Subject(s)
COVID-19 , Pandemics , Adolescent , Adult , Cross-Sectional Studies , Humans , Physical Distancing , SARS-CoV-2 , Young Adult
4.
Cardiovasc Drugs Ther ; 36(4): 705-712, 2022 08.
Article in English | MEDLINE | ID: covidwho-1227866

ABSTRACT

PURPOSE: The clinical course of COVID-19 may be complicated by acute respiratory distress syndrome (ARDS) and thromboembolic events, which are associated with high risk of mortality. Although previous studies reported a lower rate of death in patients treated with heparin, the potential benefit of chronic oral anticoagulation therapy (OAT) remains unknown. We aimed to investigate the association between OAT with the risk of ARDS and mortality in hospitalized patients with COVID-19. METHODS: This is a multicenter retrospective Italian study including consecutive patients hospitalized for COVID-19 from March 1 to April 22, 2020, at six Italian hospitals. Patients were divided into two groups according to the chronic assumption of oral anticoagulants. RESULTS: Overall, 427 patients were included; 87 patients (19%) were in the OAT group. Of them, 54 patients (13%) were on treatment with non-vitamin k oral anticoagulants (NOACs) and 33 (8%) with vitamin-K antagonists (VKAs). OAT patients were older and had a higher rate of hypertension, diabetes, and coronary artery disease compared to No-OAT group. The rate of ARDS at admission (26% vs 28%, P=0.834), or developed during the hospitalization (9% vs 10%, P=0.915), was similar between study groups; in-hospital mortality (22% vs 26%, P=0.395) was also comparable. After balancing for potential confounders by using the propensity score matching technique, no differences were found in term of clinical outcome between OAT and No-OAT patients CONCLUSION: Oral anticoagulation therapy, either NOACs or VKAs, did not influence the risk of ARDS or death in patients hospitalized with COVID-19.


Subject(s)
Atrial Fibrillation , COVID-19 , Respiratory Distress Syndrome , Administration, Oral , Anticoagulants , Atrial Fibrillation/drug therapy , Fibrinolytic Agents/therapeutic use , Humans , Retrospective Studies , Vitamin K
5.
Medicina (Kaunas) ; 57(5)2021 May 13.
Article in English | MEDLINE | ID: covidwho-1227043

ABSTRACT

The objective of this article was to conduct a systematic review of the literature to contrast the existing evidence regarding the relationship between periodontal disease (PD) and diabetes mellitus (DM) with the possibly increased risk of SARS-CoV-2 infection, as well as to establish a hypothesis that explains the ways in which this interaction could take place. A literature search up from 1 January 2020 to 21 March 2021 was conducted in three electronic databases, namely, PubMed, Web of Science, and Scopus, in order to identify studies on periodontal disease alone or in conjunction with diabetes mellitus, reporting any relation with SARS-CoV-2 infection as a primary outcome. Only articles published in the English language were included. Due to the lack of studies, we decided to collect all the theoretical and clinical evidence suggesting a possible biological pathway evidencing the relationship among PD, DM, and SARS-CoV-2 infection. From a total of 29 articles, 12 were included for final review studies (five reviews, two hypotheses, one Special Issue, one perspective, one commentary, one case-control study, and one case report). In addition, this systematic review article hypothesizes the correlation between PD and type 2 diabetes mellitus (T2DM) by expression of angiotensin-converting enzyme 2 (ACE2) in periodontal tissue and the risk of SARS-CoV-2 infection. T2DM is a metabolic disorder characterized by high blood glucose levels resulting from altered insulin secretion or action. Likewise, periodontitis and T2DM are inflammatory disorders with a bidirectional association, and both diseases have a similar immunomodulatory cascade and cytokine profile. ACE2 is a crucial component of the renin-angiotensin system (RAS) and the key factor of entry in the cells by the new SARS-CoV-2. ACE2 is widely distributed in the lung and kidneys, and interestingly has a great distribution in the oral cavity, principally in the tongue and periodontal tissue. ACE2 in periodontal tissue plays a crucial role between health and disease. Moreover, the ACE2/Ang-(1-7)/MasR axis is downregulated in the dysbiotic and inflammatory periodontal environment. Nevertheless, the balance of ACE2 activity is modified in the context of concurrent diabetes, increasing the expression of ACE2 by the uncontrolled glycemia chronic in T2DM. Therefore, the uncontrolled hyperglycemia possibly increases the risk of developing periodontitis and triggering overexpression of ACE2 in periodontal tissue of T2DM patients, with these events potentially being essential to SARS-CoV-2 infection and the development of mild-to-severe form of COVID-19. In this sense, we would like to point out that the need for randomized controlled trials is imperative to support this association.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Periodontal Diseases , Case-Control Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Humans , Periodontal Diseases/complications , Periodontal Diseases/epidemiology , Renin-Angiotensin System , SARS-CoV-2
6.
Appl Psychol Health Well Being ; 13(4): 781-797, 2021 11.
Article in English | MEDLINE | ID: covidwho-1210310

ABSTRACT

As health systems rapidly respond to COVID-19, it is unclear how these changes influence the experiences and well-being of female healthcare providers (FHCPs), including the potential for FHCPs to develop compassion fatigue and secondary traumatic stress. We conducted qualitative interviews (n = 15) with FHCPs at three locations (Washington, California, and New York). Interviews explored FHCP's perspectives on how care delivery changed, processes of information delivery and decision-making, gender inclusion, and approaches to managing stress and well-being. An inductive coding process was used to generate themes. FHCPs described significant changes to the way they delivered care, and their work environments, during the COVID-19 pandemic. Five themes emerged that characterized the experiences of FHCPs during COVID-19, including conflicting feelings while providing care, managing information and decisions, balancing roles, coping and well-being, and considerations for moving forward. FHCPs experienced many impacts to their professional and personal lives during COVID-19 that further complicated their ability to manage stress and well-being. The themes identified through this work offer important lessons about how to support the well-being of FHCPs and signify the widespread potential for compassion fatigue among FHCPs as a result of COVID-19.


Subject(s)
COVID-19 , Pandemics , Female , Health Personnel , Humans , Qualitative Research , SARS-CoV-2 , Tsunamis
7.
J Med Virol ; 93(3): 1265-1275, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196456

ABSTRACT

Being a pandemic and having a high global case fatality rate directed us to assess the evidence strength of hydroxychloroquine efficacy in treating coronavirus disease-2019 (COVID-19) arising from clinical trials and to update the practice with the most reliable clinical evidence. A comprehensive search was started in June up to 18 July, 2020 in many databases, including PubMed, Embase, and others. Of 432 studies found, only six studies fulfilled the inclusion criteria, which includes: clinical trials, age more than 12 years with nonsevere COVID-19, polymerase chain reaction-confirmed COVID-19, hydroxychloroquine is the intervention beyond the usual care. Data extraction and bias risk assessment were done by two independent authors. Both fixed-effect and random-effect models were utilized for pooling data using risk difference as a summary measure. The primary outcomes are clinical and radiological COVID-19 progression, severe acute respiratory syndrome coronavirus-2 clearance in the pharyngeal swab, and mortality. The secondary outcomes are the adverse effects of hydroxychloroquine. Among 609 COVID-19 confirmed patients obtained from pooling six studies, 294 patients received hydroxychloroquine and 315 patients served as a control. Hydroxychloroquine significantly prevents early radiological progression relative to control with risk difference and 95% confidence interval of -0.2 (-0.36 to -0.03). On the other hand, hydroxychloroquine did not prevent clinical COVID-19 progression, reduce 5-day mortality, or enhance viral clearance on days 5, 6, and 7. Moreover, many adverse effects were reported with hydroxychloroquine therapy. Failure of hydroxychloroquine to show viral clearance or clinical benefits with additional adverse effects outweigh its protective effect from radiological progression in nonsevere COVID-19 patients. Benefit-risk balance should determine the hydroxychloroquine use in COVID-19.


Subject(s)
COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Clinical Trials as Topic , Humans , Hydroxychloroquine/adverse effects
8.
Med Pr ; 72(3): 321-325, 2021 Jun 30.
Article in Polish | MEDLINE | ID: covidwho-1175785

ABSTRACT

In 2019, COVID-19, the disease caused by the SARS-CoV-2 virus, evolved into a pandemic which is still going on. The basic clinical symptoms of the SARS-CoV-2 infection are: fever, dry cough, fatigue, muscle pain, respiratory problems, and the loss of smell or taste. Other symptoms, including those related to hearing and balance organs (hearing loss, tinnitus, dizziness), are reported less frequently by patients. They are especially rarely reported as the first symptoms of this infection. In order to answer the question of whether SARS-CoV-2 can cause hearing and balance damage, the authors reviewed the literature sources from 2019-2020 included in EMBASE and PubMed, entering the following words: "hearing loss," "COVID-19," "coronavirus," "sensorineural hearing loss," "vertigo," and "dizziness." Ultimately, 9 studies on the possible relationship between hearing impairment and SARS-CoV-2, and 4 studies on the possible relationship between damage to the balance and SARS-CoV-2, were qualified for the study. The results of the analysis suggest a possible relationship between COVID-19 and hearing loss, with no evidence of a similar relationship between this virus and the balance system. The possible existence of such a relationship should be especially remembered by hospital emergency room doctors, otolaryngologists and audiologists, especially as regards the possibility of a sudden sensironeural hearing loss as the first symptom of COVID-19. This also applies to doctors of other specialties. The authors indicate the need for further, intensive and multifaceted research on this issue. Med Pr. 2021;72(3):321-5.


Subject(s)
COVID-19/complications , Hearing Disorders/etiology , Hearing , Postural Balance , Vestibular Diseases/etiology , Adult , COVID-19/epidemiology , COVID-19/physiopathology , Female , Hearing Loss/etiology , Humans , Male , Middle Aged , Tinnitus/etiology , Vertigo/etiology , Young Adult
9.
Blood Coagul Fibrinolysis ; 32(3): 167-171, 2021 Apr 01.
Article in English | MEDLINE | ID: covidwho-1171412

ABSTRACT

Coronavirus disease 2019 infection produce a prothrombotic state. This is initiated through multiple pathways and is finally aggravated by cross talks with cytokine storm and neutrophil, platelet, complement activation. All these combine towards the second week of illness to produce thrombosis in the lung capillaries surrounding the alveolus producing characteristic pulmonary dysfunction (PaO2/FiO2 > 300, normal or minimally increased lung compliance and very high d-dimer levels) and a high rate of peripheral venous thrombosis. International and many national guidelines have approached this state in different ways but all emphasized the need for management and prevention of widespread thrombosis. It is felt more aggressive and graded thrombosis prevention and management should be initiated early in the treatment. d-Dimer, neutrophil count, SaO2, fibrinogen levels should be used to control the hypercoagulability. Drugs like statins which have anti-inflammatory action as well as ability to reduce fibrinogen and other clotting factors should be used in the beginning along with antiplatelet drugs and progressively complement activation and neutrophil extracellular traps inhibitors, oral mucopolysaccharides, full-scale anticoagulation along with judicial use of fibrinolysis supporting drugs should be added. In the present review, we have evaluated the various studies and argued the rationality that the anticoagulation in this condition should be initiated early during the infection and should be increased in a graded manner depending on clinical and laboratory progression of the condition until a strong specific antiviral drug for coronavirus disease 2019 infection is available.


Subject(s)
Blood Coagulation/drug effects , COVID-19/drug therapy , COVID-19/physiopathology , Thrombophilia/drug therapy , Thrombosis/drug therapy , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , Blood Platelets/drug effects , Extracellular Traps/drug effects , Fibrinolytic Agents/therapeutic use , Glycosaminoglycans/pharmacology , Glycosaminoglycans/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Inflammation/drug therapy , Lung/drug effects , Lung/physiopathology , Lung/virology , Platelet Aggregation Inhibitors/therapeutic use
10.
Redox Biol ; 41: 101902, 2021 05.
Article in English | MEDLINE | ID: covidwho-1087240

ABSTRACT

SARS-CoV-2 (COVID-19) infection can cause a severe respiratory distress syndrome. The risk of severe manifestations and mortality characteristically increase in the elderly and in the presence of non-COVID-19 comorbidity. We and others previously demonstrated that the low molecular weight (LMW) and protein thiol/disulfide ratio declines in human plasma with age and such decline is even more rapid in the case of inflammatory and premature aging diseases, which are also associated with the most severe complications of COVID-19 infection. The same decline with age of the LMW thiol/disulfide ratio observed in plasma appears to occur in the extracellular fluids of the respiratory tract and in association with many pulmonary diseases that characteristically reduce the concentrations and adaptive stress response of the lung glutathione. Early evidence in literature suggests that the thiol to disulfide balance of critical Cys residues of the COVID-19 spike protein and the ACE-2 receptor may influence the risk of infection and the severity of the disease, with a more oxidizing environment producing the worst prognosis. With this hypothesis paper we propose that the age-dependent decline of LMW thiol/disulfide ratio of the extracellular fluids, could play a role in promoting the physical (protein-protein) interaction of CoV-2 and the host cell in the airways. Therefore, this redox-dependent interaction is expected to affect the risk of severe infection in an age-dependent manner. The hypothesis can be verified in experimental models of in vitro CoV-2 infection and at the clinical level in that LMW thiols and protein thiolation can now be investigated with standardized, reliable and versatile laboratory protocols. Presenting the verification strategy of our hypothesis, we also discuss available nutritional and ancillary pharmacological strategies to intervene on the thiol/disulfide ratio of extracellular fluids of subjects at risk of infection and COVID-19 patients.


Subject(s)
COVID-19 , Sulfhydryl Compounds , Aged , Disulfides , Humans , Oxidation-Reduction , SARS-CoV-2
11.
Trials ; 22(1): 42, 2021 Jan 11.
Article in English | MEDLINE | ID: covidwho-1021412

ABSTRACT

OBJECTIVES: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia. TRIAL DESIGN: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial. PARTICIPANTS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days. INTERVENTION AND COMPARATOR: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication. MAIN OUTCOMES: Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected. RANDOMIZATION: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacydata, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1). TRIAL STATUS: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021. TRIAL REGISTRATION: The trial was registered before trial start in trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 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)
COVID-19/drug therapy , Ecdysterone/therapeutic use , Respiratory Insufficiency/drug therapy , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/physiopathology , Disease Progression , Double-Blind Method , Extracorporeal Membrane Oxygenation/statistics & numerical data , Hospitalization , Humans , Hypoxia/physiopathology , Middle Aged , Mortality , Oxygen Inhalation Therapy/statistics & numerical data , Proto-Oncogene Proteins/metabolism , Randomized Controlled Trials as Topic , Receptors, Coronavirus/metabolism , Receptors, G-Protein-Coupled/metabolism , Renin-Angiotensin System , Respiration, Artificial/statistics & numerical data , Respiratory Insufficiency/physiopathology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Tachypnea/physiopathology , Treatment Outcome
12.
Biomed Pharmacother ; 136: 111193, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1009322

ABSTRACT

The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-ß, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.


Subject(s)
Acute Lung Injury/virology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , SARS-CoV-2/physiology , Virus Internalization , COVID-19/pathology , Humans
13.
Alzheimers Res Ther ; 12(1): 170, 2020 12 30.
Article in English | MEDLINE | ID: covidwho-1004349

ABSTRACT

COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence of central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It is unclear how much of the ischaemic damage is mediated by direct or inflammatory effects of virus on the CNS vasculature and how much is secondary to extracranial cardiorespiratory disease. Limited data suggest that the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibres, or by haematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons. Extracranially, SARS-CoV-2 targets endothelial cells and pericytes, causing endothelial cell dysfunction, vascular leakage and immune activation, sometimes leading to disseminated intravascular coagulation. It remains to be confirmed whether endothelial cells and pericytes in the cerebral vasculature are similarly targeted. Several aspects of COVID-19 are likely to impact on cognition. Cerebral white matter is particularly vulnerable to ischaemic damage in COVID-19 and is also critically important for cognitive function. There is accumulating evidence that cerebral hypoperfusion accelerates amyloid-ß (Aß) accumulation and is linked to tau and TDP-43 pathology, and by inducing phosphorylation of α-synuclein at serine-129, ischaemia may also increase the risk of development of Lewy body disease. Current therapies for COVID-19 are understandably focused on supporting respiratory function, preventing thrombosis and reducing immune activation. Since angiotensin-converting enzyme (ACE)-2 is a receptor for SARS-CoV-2, and ACE inhibitors and angiotensin receptor blockers are predicted to increase ACE-2 expression, it was initially feared that their use might exacerbate COVID-19. Recent meta-analyses have instead suggested that these medications are protective. This is perhaps because SARS-CoV-2 entry may deplete ACE-2, tipping the balance towards angiotensin II-ACE-1-mediated classical RAS activation: exacerbating hypoperfusion and promoting inflammation. It may be relevant that APOE ε4 individuals, who seem to be at increased risk of COVID-19, also have lowest ACE-2 activity. COVID-19 is likely to leave an unexpected legacy of long-term neurological complications in a significant number of survivors. Cognitive follow-up of COVID-19 patients will be important, especially in patients who develop cerebrovascular and neurological complications during the acute illness.


Subject(s)
Brain Diseases/epidemiology , Brain Diseases/virology , COVID-19/complications , Cognition Disorders/epidemiology , Cognition Disorders/virology , Humans , SARS-CoV-2
14.
Geriatr Gerontol Int ; 20(6): 547-558, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-998919

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has casted a huge impact on global public health and the economy. In this challenging situation, older people are vulnerable to the infection and the secondary effects of the pandemic and need special attention. To evaluate the impacts of COVID-19 on older people, it is important to balance the successful pandemic control and active management of secondary consequences. These considerations are particularly salient in the Asian context, with its diversity among countries in terms of sociocultural heritage, healthcare setup and availability of resources. Thus, the Asian Working Group for Sarcopenia summarized the considerations of Asian countries focusing on responses and difficulties in each country, impacts of health inequity related to the COVID-19 pandemic and proposed recommendations for older people, which are germane to the Asian context. More innovative services should be developed to address the increasing demands for new approaches to deliver healthcare in these difficult times and to establish resilient healthcare systems for older people. Geriatr Gerontol Int 2020; 9999: n/a-n/a.


Subject(s)
Aging/ethnology , Communicable Disease Control/standards , Coronavirus Infections/epidemiology , Geriatric Assessment/methods , Pandemics/statistics & numerical data , Pneumonia, Viral/epidemiology , Sarcopenia/epidemiology , Aged , Aged, 80 and over , Aging/physiology , Asia/epidemiology , COVID-19 , Coronavirus Infections/prevention & control , Delivery of Health Care/organization & administration , Female , Humans , Male , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Practice Guidelines as Topic , Prevalence , Public Health , Risk Assessment , Sarcopenia/diagnosis
15.
Clin Nutr ; 40(5): 3462-3469, 2021 05.
Article in English | MEDLINE | ID: covidwho-967936

ABSTRACT

BACKGROUND & AIMS: Iron is an essential trace element to almost all organism, and the delicate balance between host defend system and viral proliferation plays an important role in infective conditions. While the association of the iron metabolism with the prognosis of COVID-19 remains poorly understood. We aimed to estimate the associations of systemic iron metabolism parameters with the severity and risks of adverse outcomes in COVID-19. METHODS: In this retrospective cohort study, we included 158 confirmed COVID-19 patients in Tongji Hospital, Wuhan, China (27 January to 5 April, 2020). Demographic data, comorbidities, laboratory examinations, treatments, and clinical outcomes were all collected. Multivariable Poisson regression was used to estimate the association of iron parameter levels with the severity and risks of adverse outcomes in COVID-19 patients. RESULTS: We identified 60 (38%) severe cases in 158 COVID-19 patients. The median age was 63 years (interquartile range [IQR]: 54-73) and the median length of hospital stay was 28 days (IQR: 17-40). After adjusting for age, sex, IL-6, and pre-existing comorbidities, all iron parameters were associated with the severity of COVID-19 with adjusted risk ratio of 0.42 [95% CI: 0.22-0.83], 4.38 [95% CI: 1.86-10.33], 0.19 [95% CI: 0.08-0.48], and 0.25 [95% CI: 0.10-0.58] for serum iron, ferritin, transferrin, and total iron-binding capacity, respectively. These iron indices were also related to the risk of ARDS, coagulopathy, acute cardiac injury, acute liver injury, and acute kidney injury in COVID-19 patients and high cytokine concentrations. CONCLUSIONS: Patients with low serum iron status likely suffered from severe condition and multiple-organ injury in COVID-19. The iron metabolism parameters might be risk factors and clinical biomarkers for COVID-19 prognosis.


Subject(s)
COVID-19/blood , Ferritins/metabolism , Iron/metabolism , Severity of Illness Index , Transferrin/metabolism , Aged , COVID-19/epidemiology , COVID-19/physiopathology , China/epidemiology , Cohort Studies , Cytokines , Female , Humans , Male , Middle Aged , Receptors, Transferrin/metabolism , Retrospective Studies , SARS-CoV-2
16.
Front Immunol ; 11: 572635, 2020.
Article in English | MEDLINE | ID: covidwho-895302

ABSTRACT

The effects of cytokine inhibition in the different phases of the severe coronavirus disease 2019 (COVID-19) are currently at the center of intense debate, and preliminary results from observational studies and case reports offer conflicting results thus far. The identification of the correct timing of administration of anti-cytokine therapies and other immunosuppressants in COVID-19 should take into account the intricate relationship between the viral burden, the hyperactivation of the innate immune system and the adaptive immune dysfunction. The main challenge for effective administration of anti-cytokine therapy in COVID-19 will be therefore to better define a precise "window of therapeutic opportunity." Only considering a more specific set of criteria able to integrate information on direct viral damage, the cytokine burden, and the patient's immune vulnerability, it will be possible to decide, carefully balancing both benefits and risks, the appropriateness of using immunosuppressive drugs even in patients affected primarily by an infectious disease.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokines/antagonists & inhibitors , Immunosuppressive Agents/therapeutic use , Immunotherapy/methods , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Betacoronavirus/drug effects , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/pathology , Humans , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2 , Viral Load/immunology
17.
JCO Glob Oncol ; 6: 1494-1509, 2020 10.
Article in English | MEDLINE | ID: covidwho-814636

ABSTRACT

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has had a global impact, and Singapore has seen 33,000 confirmed cases. Patients with cancer, their caregivers, and health care workers (HCWs) need to balance the challenges associated with COVID-19 while ensuring that cancer care is not compromised. This study aimed to evaluate the psychological effect of COVID-19 on these groups and the prevalence of burnout among HCWs. METHODS: A cross-sectional survey of patients, caregivers, and HCWs at the National Cancer Centre Singapore was performed over 17 days during the lockdown. The Generalized Anxiety Disorder-7 and Maslach Burnout Inventory were used to assess for anxiety and burnout, respectively. Self-reported fears related to COVID-19 were collected. RESULTS: A total of 624 patients, 408 caregivers, and 421 HCWs participated in the study, with a response rate of 84%, 88%, and 92% respectively. Sixty-six percent of patients, 72.8% of caregivers, and 41.6% of HCWs reported a high level of fear from COVID-19. The top concern of patients was the wide community spread of COVID-19. Caregivers were primarily worried about patients dying alone. HCWs were most worried about the relatively mild symptoms of COVID-19. The prevalence of anxiety was 19.1%, 22.5%, and 14.0% for patients, caregivers, and HCWs, respectively. Patients who were nongraduates and married, and caregivers who were married were more anxious. The prevalence of burnout in HCWs was 43.5%, with more anxious and fearful HCWs reporting higher burnout rates. CONCLUSION: Fears and anxiety related to COVID-19 are high. Burnout among HCWs is similar to rates reported prepandemic. An individualized approach to target the specific fears of each group will be crucial to maintain the well-being of these vulnerable groups and prevent burnout of HCWs.


Subject(s)
Anxiety/epidemiology , Burnout, Professional/epidemiology , Caregivers/psychology , Coronavirus Infections/psychology , Neoplasms/psychology , Pneumonia, Viral/psychology , Adult , Aged , Anxiety/diagnosis , Anxiety/psychology , Betacoronavirus/pathogenicity , Burnout, Professional/diagnosis , Burnout, Professional/psychology , COVID-19 , Cancer Care Facilities/organization & administration , Cancer Care Facilities/standards , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Cross-Sectional Studies , Fear/psychology , Female , Health Personnel/psychology , Health Services Accessibility/organization & administration , Health Services Accessibility/standards , Humans , Infection Control/standards , Infectious Disease Transmission, Patient-to-Professional/prevention & control , Infectious Disease Transmission, Professional-to-Patient/prevention & control , Male , Medical Oncology/organization & administration , Medical Oncology/standards , Middle Aged , Neoplasms/therapy , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Prevalence , SARS-CoV-2 , Singapore/epidemiology , Workload/psychology
18.
Sci Immunol ; 5(51)2020 09 28.
Article in English | MEDLINE | ID: covidwho-808356

ABSTRACT

Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Mucosal-Associated Invariant T Cells/immunology , Pneumonia, Viral/pathology , Adult , Aged , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , COVID-19 , Coronavirus Infections/immunology , Female , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interleukin-17/metabolism , Lectins, C-Type/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Receptors, CXCR3/metabolism , SARS-CoV-2 , Young Adult
19.
Drug Saf ; 43(8): 809-821, 2020 08.
Article in English | MEDLINE | ID: covidwho-611871

ABSTRACT

INTRODUCTION AND OBJECTIVE: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile. METHODS: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. RESULTS: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95-1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments. CONCLUSIONS: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.


Subject(s)
Coronavirus Infections , Pandemics , Pneumonia, Viral , Ritonavir , Adult , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Humans , Lopinavir , Risk Assessment , SARS-CoV-2
20.
J Med Virol ; 92(7): 770-775, 2020 07.
Article in English | MEDLINE | ID: covidwho-145051

ABSTRACT

Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Hydroxychloroquine/therapeutic use , Hyperglycemia/drug therapy , Hyperglycemia/epidemiology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Angiotensin-Converting Enzyme 2 , Antibodies, Neutralizing/biosynthesis , Antibody-Dependent Cell Cytotoxicity/drug effects , Azithromycin/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Glucose/immunology , Glucose/metabolism , Glycosylation/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Hyperglycemia/complications , Hyperglycemia/metabolism , Incidence , Macrophages/drug effects , Macrophages/immunology , Macrophages/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
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