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Am J Bioeth ; 21(12): W1-W4, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1541440
Am J Bioeth ; 21(12): 20-22, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1541439
Am J Bioeth ; 21(12): 28-31, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1541438
J Addict Dis ; 39(4): 433-435, 2021.
Article in English | MEDLINE | ID: covidwho-1541403
J Biomol Struct Dyn ; : 1-18, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1541375


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19 disease has been exponentially increasing throughout the world. The mortality rate is increasing gradually as effective treatment is unavailable to date. In silico based screening for novel testable hypotheses on SARS-CoV-2 Mpro protein to discover the potential lead drug candidate is an emerging area along with the discovery of a vaccine. Administration of NO-releasing agents, NO inducers or the NO gas itself may be useful as therapeutics in the treatment of SARS-CoV-2. In the present study, a 3D structure of SARS-CoV-2 Mpro protein was used for the rational setting of inhibitors to the binding pocket of enzyme which proposed that phenyl furoxan derivative gets efficiently dock in the target pocket. Molecular docking and molecular dynamics simulations helped to investigate possible effective inhibitor candidates bound to SARS-CoV-2 Mpro substrate binding pocket. Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed energetic contributions of active site residues of Mpro in binding with most stable proposed NO donor heterocyclic vasodilator inhibitor molecules. Furthermore, principal component analysis (PCA) showed that the NO donor heterocyclic inhibitor molecules 14, 16, 18 and 19 was strongly bound to catalytic core of SARS-CoV-2 Mpro protein, limiting its movement to form stable complex as like control. Thus, overall in silico investigations revealed that 5-oxopiperazine-2-carboxylic acid coupled furoxan derivatives was found to be key pharmacophore in drug design for the treatment of SARS-CoV-2, a global pandemic disease with a dual mechanism of action as NO donor and a worthwhile ligand to act as SARS-CoV-2 Mpro protein inhibitor.Communicated by Ramaswamy H. Sarma.

Gastroenterology ; 161(6): 1758-1763, 2021 12.
Article in English | MEDLINE | ID: covidwho-1541265
Clin Sci (Lond) ; 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1541262


Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA).  Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCA)  and some efficacy in severe SARS-CoV-2 infection.  However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids.  We assessed how the anti-GMCSFRα approach might impact surfactant turnover in the airway.  Female C57Bl/6J mice received a mouse-GMCSFRα blocking antibody (CAM-3003) twice per week for up to 24 weeks. A parallel, comparator cohort of the mouse PAP model, GMCSFRß knock-out (KO), was maintained up to 16 weeks.  We assessed lung tissue histopathology alongside lung phosphatidylcholine (PC) metabolism using stable isotope lipidomics.  GMCSFRß KO mice reproduced the histopathological and biochemical features of PAP, accumulating surfactant PC in both broncho-alveolar lavage fluid (BALF) and lavaged lung tissue.  The incorporation pattern of methyl-D9-choline showed impaired catabolism and not enhanced synthesis.  In contrast, chronic supra-pharmacological CAM-3003 exposure (100mg/kg) over 24 weeks did not elicit a histopathological PAP phenotype despite some changes in lung PC catabolism.  Lack of significant impairment of AM catabolic function supports clinical observations that therapeutic antibodies to this pathway have not been associated with PAP in clinical trials.

Phys Chem Chem Phys ; 23(27): 14873-14888, 2021 Jul 14.
Article in English | MEDLINE | ID: covidwho-1541260


The COVID-19 disease caused by the virus SARS-CoV-2, first detected in December 2019, is still emerging through virus mutations. Although almost under control in some countries due to effective vaccines that are mitigating the worldwide pandemic, the urgency to develop additional vaccines and therapeutic treatments is imperative. In this work, the natural polyphenols corilagin and 1,3,6-tri-O-galloy-ß-d-glucose (TGG) are investigated to determine the structural basis of inhibitor interactions as potential candidates to inhibit SARS-CoV-2 viral entry into target cells. First, the therapeutic potential of the ligands are assessed on the ACE2/wild-type RBD. We first use molecular docking followed by molecular dynamics, to take into account the conformational flexibility that plays a significant role in ligand binding and that cannot be captured using only docking, and then analyze more precisely the affinity of these ligands using MMPBSA binding free energy. We show that both ligands bind to the ACE2/wild-type RBD interface with good affinities which might prevent the ACE2/RBD association. Second, we confirm the potency of these ligands to block the ACE2/RBD association using a combination of surface plasmon resonance and biochemical inhibition assays. These experiments confirm that TGG and, to a lesser extent, corilagin, inhibit the binding of RBD to ACE2. Both experiments and simulations show that the ligands interact preferentially with RBD, while weak binding is observed with ACE2, hence, avoiding potential physiological side-effects induced by the inhibition of ACE2. In addition to the wild-type RBD, we also study numerically three RBD mutations (E484K, N501Y and E484K/N501Y) found in the main SARS-CoV-2 variants of concerns. We find that corilagin could be as effective for RBD/E484K but less effective for the RBD/N501Y and RBD/E484K-N501Y mutants, while TGG strongly binds at relevant locations to all three mutants, demonstrating the significant interest of these molecules as potential inhibitors for variants of SARS-CoV-2.

Antiviral Agents/chemistry , Gallic Acid/analogs & derivatives , Glucose/analogs & derivatives , Glucosides/chemistry , Hydrolyzable Tannins/chemistry , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , Gallic Acid/chemistry , Glucose/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Protein Binding/drug effects , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
Nat Methods ; 18(8): 857, 2021 08.
Article in English | MEDLINE | ID: covidwho-1541246
Cell Discov ; 7(1): 60, 2021 Aug 04.
Article in English | MEDLINE | ID: covidwho-1541177


Severe coronavirus disease 2019 (COVID-19) is often indicated by lymphopenia and increased myelopoiesis; however, the underlying mechanism is still unclear, especially the alteration of hematopoiesis. It is important to explore to what extent and how hematopoietic stem cells contribute to the impairment of peripheral lymphoid and myeloid compartments in COVID-19 patients. In this study, we used single-cell RNA sequencing to assess bone marrow mononuclear cells from COVID-19 patients with peripheral blood mononuclear cells as control. The results showed that the hematopoietic stem cells in these patients were mainly in the G1 phase and prone to apoptosis, with immune activation and anti-viral responses. Importantly, a significant accumulation of immature myeloid progenitors and a dramatic reduction of lymphoid progenitors in severe cases were identified, along with the up-regulation of transcription factors (such as SPI1, LMO4, ETS2, FLI1, and GATA2) that are important for the hematopoietic stem cell or multipotent progenitor to differentiate into downstream progenitors. Our results indicate a dysregulated hematopoiesis in patients with severe COVID-19.

Infect Control Hosp Epidemiol ; : 1-4, 2021 Sep 21.
Article in English | MEDLINE | ID: covidwho-1541101


Healthcare workers (HCWs) experience barriers to severe acute respiratory coronavirus virus 2 (SARS-CoV-2) testing specific to their perceptions of access, and employment factors. A survey was sent to all employees at one Boston hospital to examine their perceived barriers to testing. HCWs who reported difficulty paying their bills were less likely to receive a SARS-CoV-2 test.

Infect Control Hosp Epidemiol ; 42(10): 1245-1250, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1541100

COVID-19 , Pandemics , Humans , SARS-CoV-2
Lancet HIV ; 8(11): e661-e662, 2021 11.
Article in English | MEDLINE | ID: covidwho-1541052
Lancet HIV ; 8(11): e701-e710, 2021 11.
Article in English | MEDLINE | ID: covidwho-1541051


BACKGROUND: Factors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV. METHODS: We did a retrospective cohort study using data from the PISCIS cohort of people with HIV in Catalonia (Spain) between March 1 and Dec 15, 2020. We linked PISCIS data with integrated health-care, clinical, and surveillance registries through the Public Data Analysis for Health Research and Innovation Program of Catalonia (PADRIS) to obtain data on SARS-CoV-2 diagnosis, chronic comorbidities, as well as clinical and mortality outcomes. Participants were aged at least 16 years in care at 16 hospitals in Catalonia. Factors associated with SARS-CoV-2 diagnoses and severe outcomes were assessed using univariable and multivariable Cox regression models. We estimated the effect of immunosuppression on severe outcomes (hospital admission for >24 h with dyspnoea, tachypnoea, hypoxaemia, asphyxia, or hyperventilation; or death) using Kaplan-Meier survival analysis. FINDINGS: We linked 20 847 (72·8%) of 28 666 participants in the PISCIS cohort with PADRIS data; 13 142 people had HIV. 749 (5·7%) people with HIV were diagnosed with SARS-CoV-2: their median age was 43·5 years (IQR 37·0-52·7), 131 (17·5%) were female, and 618 (82·5%) were male. 103 people with HIV (13·8%) were hospitalised, seven (0·9%) admitted to intensive care, and 13 (1·7%) died. SARS-CoV-2 diagnosis was more common among migrants (adjusted hazard ratio 1·55, 95% CI 1·31-1·83), men who have sex with men (1·42, 1·09-1·86), and those with four or more chronic comorbidities (1·46, 1·09-1·97). Age at least 75 years (5·2, 1·8-15·3), non-Spanish origin (2·1, 1·3-3·4), and neuropsychiatric (1·69, 1·07-2·69), autoimmune disease (1·92, 1·14-3·23), respiratory disease (1·84, 1·09-3·09), and metabolic disease (2·59, 1·59-4·23) chronic comorbidities were associated with increased risk of severe outcomes. A Kaplan-Meier estimator showed differences in the risk of severe outcomes according to CD4 cell count in patients with detectable HIV RNA (p=0·039) but no differences were observed in patients with undetectable HIV RNA (p=0·15). INTERPRETATION: People living with HIV with detectable HIV viraemia, chronic comorbidities, and some subpopulations could be at increased risk of severe outcomes from COVID-19. These groups should be prioritised in clinical management and SARS-CoV-2 vaccination programmes. FUNDING: Fundació "la Caixa". TRANSLATIONS: For the Catalan, Spanish and Russian translations of the Summary see Supplementary Materials section.

Lancet HIV ; 8(11): e690-e700, 2021 11.
Article in English | MEDLINE | ID: covidwho-1541050


BACKGROUND: Evidence of whether people living with HIV are at elevated risk of adverse COVID-19 outcomes is inconclusive. We aimed to investigate this association using the population-based National COVID Cohort Collaborative (N3C) data in the USA. METHODS: We included all adult (aged ≥18 years) COVID-19 cases with any health-care encounter from 54 clinical sites in the USA, with data being deposited into the N3C. The outcomes were COVID-19 disease severity, hospitalisation, and mortality. Encounters in the same health-care system beginning on or after January 1, 2018, were also included to provide information about pre-existing health conditions (eg, comorbidities). Logistic regression models were employed to estimate the association of HIV infection and HIV markers (CD4 cell count, viral load) with hospitalisation, mortality, and clinical severity of COVID-19 (multinomial). The models were initially adjusted for demographic characteristics, then subsequently adjusted for smoking, obesity, and a broad range of comorbidities. Interaction terms were added to assess moderation effects by demographic characteristics. FINDINGS: In the harmonised N3C data release set from Jan 1, 2020, to May 8, 2021, there were 1 436 622 adult COVID-19 cases, of these, 13 170 individuals had HIV infection. A total of 26 130 COVID-19 related deaths occurred, with 445 among people with HIV. After adjusting for all the covariates, people with HIV had higher odds of COVID-19 death (adjusted odds ratio 1·29, 95% CI 1·16-1·44) and hospitalisation (1·20, 1·15-1·26), but lower odds of mild or moderate COVID-19 (0·61, 0·59-0·64) than people without HIV. Interaction terms revealed that the elevated odds were higher among older age groups, male, Black, African American, Hispanic, or Latinx adults. A lower CD4 cell count (<200 cells per µL) was associated with all the adverse COVID-19 outcomes, while viral suppression was only associated with reduced hospitalisation. INTERPRETATION: Given the COVID-19 pandemic's exacerbating effects on health inequities, public health and clinical communities must strengthen services and support to prevent aggravated COVID-19 outcomes among people with HIV, particularly for those with pronounced immunodeficiency. FUNDING: National Center for Advancing Translational Sciences, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

Z Evid Fortbild Qual Gesundhwes ; 2021 Aug 30.
Article in German | MEDLINE | ID: covidwho-1541028


BACKGROUND: The process of enrolling participants is an important component and often a time-consuming step in scientific research projects. Due to different financial, organisational and ethical framework conditions, the enrolment of participants is often a challenge. In this article, we report our experiences of enrolling patients in clinical trials made in the project "Psycho-oncological care of cancer patients with a migration background - a mixed methods study" (POM). METHODS: Participants were recruited through outpatient haemato-oncology practices. Patients and relatives were primarily made aware of the project by the treating physicians and recruited to participate in qualitative interviews. RESULTS: Nine patients and relatives were interviewed nationwide in individual qualitative interviews. In addition to the COVID-19 pandemic, there were other patient enrolment challenges. In many cases, participation was refused. The reasons included: "not interested", the use of the terms "psycho-oncology" or "person with a migration background", family denying permission to participate, no face-to-face interview due to the COVID-19 pandemic as well as too much emotional distress and deterioration of health after prior consent. DISCUSSION: Enrolling study participants from vulnerable groups for a sensitive topic such as psycho-oncology entails multiple challenges. In order to achieve successful study inclusion, regular telephone and written exchanges with the respective practice staff proved to be helpful, allowing an overview of challenges to be gained and study inclusion to be evaluated and adjusted in a timely manner. CONCLUSION: In research projects with vulnerable groups and on sensitive topics, both a target-group-specific, sensitive approach in plain language (layman's terms) and regular consultations with the persons responsible for study inclusion in care facilities should take place in order to adapt the existing procedure during the study inclusion process, if necessary.

Vaccine ; 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1541010


Previous research has demonstrated a 'seductive allure' of technical or reductive language such that bad (e.g., circular) explanations are judged better when irrelevant technical terms are included. We aimed to explore if such an effect was observable in relation to a covid-19 vaccinations and if this subsequently affected behavioural intentions to take up a covid-19 vaccine. Using a between subjects design we presented participants (N = 996) with one of four possible types of vignette that explained how covid-19 vaccination and herd immunity works. The explanations varied along two factors: (1) Quality, explanations were either good or bad (i.e., tautological); (2) Language, explanations either contained unnecessary technical language or did not. We measured participants' evaluation of the explanations and intentions to vaccinate. We demonstrate a 'seductive allure' effect of technical language on bad vaccine explanations. However, an opposite 'repellent disdain' effect occurred for good explanations which were rated worse when they contained technical language. Moreover, we show that evaluations of explanations influence intentions to vaccinate. We suggest that misinformation that includes technical language could be more detrimental to vaccination rates. Importantly, however, clear explanatory public health information that omits technical language will be more effective in increasing intentions to vaccinate.