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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335169

ABSTRACT

Two mutations occurred in SARS-CoV-2 early during the COVID-19 pandemic that have come to define circulating virus lineages 1 first a change in the spike protein (D614G) that defines the B.1 lineage and second, a double substitution in the nucleocapsid protein (R203K, G204R) that defines the B.1.1 lineage, which has subsequently given rise to three Variants of Concern: Alpha, Gamma and Omicron. While the latter mutations appear unremarkable at the protein level, there are dramatic implications at the nucleotide level: the GGG→AAC substitution generates a new Transcription Regulatory Sequence (TRS) motif, driving SARS-CoV-2 to express a novel subgenomic mRNA (sgmRNA) encoding a truncated C-terminal portion of nucleocapsid (N.iORF3), which is an inhibitor of type I interferon production. We find that N.iORF3 also emerged independently within the Iota variant, and further show that additional TRS motifs have convergently evolved to express novel sgmRNAs;notably upstream of Spike within the nsp16 coding region of ORF1b, which is expressed during human infection. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level, reminiscent of eukaryotic evolution. Greater attention to this aspect in the assessment of emerging strains of SARS-CoV-2 is warranted.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-333026

ABSTRACT

Background: SARS-CoV2 infection causes severe, life-threatening pneumonia. Hyper-inflammation, coagulopathy and lymphopenia are associated with pathology and poor outcomes in these patients. Cell-free (cf) chromatin is prominent in COVID-19 patients, amplifies inflammation and promotes coagulopathy and immune dysfunction. We hypothesized that cf-chromatin clearance by nebulised dornase alfa may reduce inflammation and improve disease outcomes. Here, we evaluated the efficacy of nebulized dornase alfa in patients hospitalised with severe COVID-19 pneumonia. Methods: In this randomised controlled single-centre phase 2 proof-of-concept trial, we recruited adult patients admitted to hospital that exhibited stable oxygen saturation (≥94%) on supplementary oxygen and a C-reactive protein (CRP) level ≥30mg/L post dexamethasone treatment. Participants were randomized at a 3:1 ratio to receive twice-daily nebulised dornase alfa in addition to best available care (BAC) or BAC alone for seven days or until hospital discharge. A 2:1 ratio of historical controls to treated individuals (HC, 2:1) were included as the primary endpoint comparators. The primary outcome was a reduction in systemic inflammation measured by blood CRP levels over 7 days post-randomisation, or to discharge if sooner. Secondary and exploratory outcomes included time to discharge, time on oxygen, D-dimer levels, lymphocyte counts and levels of circulating cf-DNA. Results: We screened 75 patients and enrolled 39 participants out of which 30 in dornase alfa arm, and 9 in BAC group. We also matched the recruited patients in the treated group (N=30) to historical controls in the BAC group (N=60). For the the primary outcome, 30 patients in the dornase alfa were compared to 69 patients in the BAC group. Dornase alfa treatment reduced CRP by 33% compared to the BAC group at 7-days (P=0.01). The dornase alfa group least squares mean CRP was 23.23 mg/L (95% CI 17.71 to 30.46) and the BAC group 34.82 mg/L (95% CI 28.55 to 42.47). A significant difference was also observed when only randomised participants were compared. Furthermore, compared to the BAC group, the chance of live discharge was increased by 63% in the dornase alfa group (HR 1.63, 95% CI 1.01 to 2.61, P=0.03), lymphocyte counts were improved (least-square mean: 1.08 vs 0.87, P=0.02) and markers of coagulopathy such as D-dimer were diminished (least-square mean: 570.78 vs 1656.96μg/mL, P=0.004). Moreover, the dornase alfa group exhibited lower circulating cf-DNA levels that correlated with CRP changes over the course of treatment. No differences were recorded in the rates and length of stay in the ICU or the time on oxygen between the groups. Dornase alfa was well-tolerated with no serious adverse events reported. Conclusions: In this proof-of-concept study in patients with severe COVID-19 pneumonia, treatment with nebulised dornase alfa resulted in a significant reduction in inflammation, markers of immune pathology and time to discharge. The effectiveness of dornase alfa in patients with acute respiratory infection and inflammation should be investigated further in larger trials. Trial registration number: NCT04359654

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332251

ABSTRACT

For COVID-19 vaccines, high-affinity antigen-specific antibody, CD8+ T cell and memory B cell responses are essential to maximize protection against Variants of Concern (VOC). We report results in vitro, in mice and human volunteers immunized with bacterially-derived, non-living nanocells (EDVTM) packaged with bacterial plasmid expressing spike protein of SARS-CoV-2 and IFNγ stimulating adjuvant α-galactosylceramide (EDV-COVID-αGC). EDV-COVID-αGC is shown to elicit iNKT-licensed dendritic cell activation/maturation, follicular helper T cell cognate help to B cells to undergo germinal center based somatic hypermutation and production of high affinity antibodies able to neutralize Alpha, Beta, Gamma, Delta, and Omicron VOC including a memory B cell response. Type I and Type II interferon stimulation and S-specific CD8+ T cells was also achieved. EDV-COVID-αGC are lyophilized, stored and transported at room temperature.

4.
Hypertens Res ; 45(5): 834-845, 2022 05.
Article in English | MEDLINE | ID: covidwho-1768813

ABSTRACT

The impact of pre-existing hypertension on outcomes in patients with the novel corona virus (SARS-CoV-2) remains controversial. To address this, we examined the impact of pre-existing hypertension and its treatment on in-hospital mortality in patients admitted to hospital with Covid-19. Using the CAPACITY-COVID patient registry we examined the impact of pre-existing hypertension and guideline-recommended treatments for hypertension on in-hospital mortality in unadjusted and multi-variate-adjusted analyses using logistic regression. Data from 9197 hospitalised patients with Covid-19 (median age 69 [IQR 57-78] years, 60.6% male, n = 5573) was analysed. Of these, 48.3% (n = 4443) had documented pre-existing hypertension. Patients with pre-existing hypertension were older (73 vs. 62 years, p < 0.001) and had twice the occurrence of any cardiac disease (49.3 vs. 21.8%; p < 0.001) when compared to patients without hypertension. The most documented class of anti-hypertensive drugs were angiotensin receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEi) (n = 2499, 27.2%). In-hospital mortality occurred in (n = 2020, 22.0%), with more deaths occurring in those with pre-existing hypertension (26.0 vs. 18.2%, p < 0.001). Pre-existing hypertension was associated with in-hospital mortality in unadjusted analyses (OR 1.57, 95% CI 1.42,1.74), no significant association was found following multivariable adjustment for age and other hypertension-related covariates (OR 0.97, 95% CI 0.87,1.10). Use of ACEi or ARB tended to have a protective effect for in-hospital mortality in fully adjusted models (OR 0.88, 95% CI 0.78,0.99). After appropriate adjustment for confounding, pre-existing hypertension, or treatment for hypertension, does not independently confer an increased risk of in-hospital mortality patients hospitalized with Covid-19.


Subject(s)
COVID-19 , Hypertension , Aged , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/complications , Female , Hospitals , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/epidemiology , Male , Retrospective Studies , SARS-CoV-2
5.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324003

ABSTRACT

The COVID-19 pandemic and its impact on the US economy led to an unprecedented bailout in the early days of the subsequent recession. Companies lined up for a share of the funds, but many of them were in our estimation unworthy of assistance given risky use of free cashflow for share repurchases, limiting their ability to adjust to an economic downturn. Our research resulted in the creation of the Executive Actions for Self-Enrichment (EASE) score, a quarterly determination of the companies that are working toward long-term business outcomes vis a vis those working towards hollowing out their business in the pursuit of short-term market gains. Scores were determined through the combination of pricing, key financials, and executive stock sales/purchases via SEC Form 4 data. We believe that EASE is able to accurately identify the overleveraging of debt to buy back company shares while executives offload their equity at artificially-induced prices. Conversely, this data also indicates an outsized return effect for the top decile of long-term-focused businesses. Going forward, we expect that EASE will provide a clear window into how companies are being run in a way that is immediately actionable, providing the public with the means to hold companies accountable via their investment decisions and beyond.

7.
Clin Med (Lond) ; 21(6): e620-e628, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1551859

ABSTRACT

Patients and public have sought mortality risk information throughout the pandemic, but their needs may not be served by current risk prediction tools. Our mixed methods study involved: (1) systematic review of published risk tools for prognosis, (2) provision and patient testing of new mortality risk estimates for people with high-risk conditions and (3) iterative patient and public involvement and engagement with qualitative analysis. Only one of 53 (2%) previously published risk tools involved patients or the public, while 11/53 (21%) had publicly accessible portals, but all for use by clinicians and researchers.Among people with a wide range of underlying conditions, there has been sustained interest and engagement in accessible and tailored, pre- and postpandemic mortality information. Informed by patient feedback, we provide such information in 'five clicks' (https://covid19-phenomics.org/OurRiskCoV.html), as context for decision making and discussions with health professionals and family members. Further development requires curation and regular updating of NHS data and wider patient and public engagement.


Subject(s)
COVID-19 , Humans , Pandemics , Prognosis , SARS-CoV-2 , Surveys and Questionnaires
8.
EClinicalMedicine ; 41: 101152, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1474486

ABSTRACT

BACKGROUND: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. METHODS: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. FINDINGS: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. INTERPRETATION: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. FUNDING: Vicore Pharma AB and LifeArc, UK.

10.
Crit Care Explor ; 3(8): e0488, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1356719

ABSTRACT

OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-ß, interferon-γ, interleukin-1ß, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-ß, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. CONCLUSIONS: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.

17.
J Infect ; 82(6): 276-316, 2021 06.
Article in English | MEDLINE | ID: covidwho-1131509

ABSTRACT

OBJECTIVE: Our objective was to describe the characteristics of patients admitted, discharged and readmitted, due to COVID-19, to a central London acute-care hospital during the second peak, in particular in relation to corticosteroids use. METHODS: We reviewed patients admitted from the community to University College Hospital (UCH) with COVID-19 as their primary diagnosis between 1st-31st December 2020. Re-attendance and readmission data were collected for patients who re-presented within 10 days following discharge. Data were retrospectively collected. RESULTS: 196 patients were admitted from the community with a diagnosis of COVID-19 and discharged alive in December 2020. Corticosteroids were prescribed in hospital for a median of 5 days (IQR 3-8). 20 patients (10.2%) were readmitted within 10 days. 11/20 received corticosteroids in the first admission of which 10 had received 1-3 days of corticosteroids. Readmission rate in those receiving 1-3 days of corticosteroids was 25%. CONCLUSIONS: Most international guidelines have recommended providing up to 10 days of corticosteroids for severe COVID-19 but stopping on discharge. Our findings show shorter courses of corticosteroids during admission are associated with an increased risk of being readmitted and support continuing the course of corticosteroids after hospital discharge monitored in the virtual ward setting.


Subject(s)
COVID-19 , Patient Readmission , Adrenal Cortex Hormones/therapeutic use , Humans , London/epidemiology , Patient Discharge , Retrospective Studies , SARS-CoV-2 , United States
18.
Eur J Prev Cardiol ; 28(14): 1599-1609, 2021 12 20.
Article in English | MEDLINE | ID: covidwho-1091243

ABSTRACT

AIMS: Cardiovascular diseases (CVDs) increase mortality risk from coronavirus infection (COVID-19). There are also concerns that the pandemic has affected supply and demand of acute cardiovascular care. We estimated excess mortality in specific CVDs, both 'direct', through infection, and 'indirect', through changes in healthcare. METHODS AND RESULTS: We used (i) national mortality data for England and Wales to investigate trends in non-COVID-19 and CVD excess deaths; (ii) routine data from hospitals in England (n = 2), Italy (n = 1), and China (n = 5) to assess indirect pandemic effects on referral, diagnosis, and treatment services for CVD; and (iii) population-based electronic health records from 3 862 012 individuals in England to investigate pre- and post-COVID-19 mortality for people with incident and prevalent CVD. We incorporated pre-COVID-19 risk (by age, sex, and comorbidities), estimated population COVID-19 prevalence, and estimated relative risk (RR) of mortality in those with CVD and COVID-19 compared with CVD and non-infected (RR: 1.2, 1.5, 2.0, and 3.0).Mortality data suggest indirect effects on CVD will be delayed rather than contemporaneous (peak RR 1.14). CVD service activity decreased by 60-100% compared with pre-pandemic levels in eight hospitals across China, Italy, and England. In China, activity remained below pre-COVID-19 levels for 2-3 months even after easing lockdown and is still reduced in Italy and England. For total CVD (incident and prevalent), at 10% COVID-19 prevalence, we estimated direct impact of 31 205 and 62 410 excess deaths in England (RR 1.5 and 2.0, respectively), and indirect effect of 49 932 to 99 865 deaths. CONCLUSION: Supply and demand for CVD services have dramatically reduced across countries with potential for substantial, but avoidable, excess mortality during and after the pandemic.


Subject(s)
COVID-19 , Cardiovascular Diseases , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Communicable Disease Control , Humans , Pandemics , SARS-CoV-2
19.
BMJ Open ; 11(2): e043625, 2021 02 16.
Article in English | MEDLINE | ID: covidwho-1088257

ABSTRACT

INTRODUCTION: Whether ACE inhibitors (ACEi) or angiotensin II receptor blocker (ARB) therapy should be continued, initiated or ceased in patients with COVID-19 is uncertain. Given the widespread use of ACEi/ARBs worldwide, guidance on the use of these drugs is urgently needed. This prospective meta-analysis aims to pool data from randomised controlled trials (RCTs) to assess the safety and efficacy of ACEi/ARB therapy in adults infected with SARS-CoV-2. METHODS AND ANALYSIS: RCTs will be eligible if they compare patients with COVID-19 randomised to ACEi/ARB continuation or commencement versuss no ACEi/ARB therapy; study duration ≥14 days; recruitment completed between March 2020 and May 2021. The primary outcome will be all-cause mortality at ≤30 days. Secondary outcomes will include mechanical ventilation, admission to intensive care or cardiovascular events at short-term follow-up (≤30 days) and all-cause mortality at longer-term follow-up (>1 month). Prespecified subgroup analyses will assess the effect of sex; age; comorbidities; smoking status; ethnicity; country of origin on all-cause mortality. A search of ClinicalTrials.gov has been performed, which will be followed by a formal search of trial registers, preprint servers, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify RCTs that meet inclusion criteria. To date, a search of ClinicalTrials.gov identified 21 potentially eligible trials for this meta-analysis. We will request trial investigators/sponsors to contribute standardised grouped tabular outcome data. ETHICS AND DISSEMINATION: Ethics approval and informed consent will be the responsibility of the individual RCTs. Dissemination of results will occur by peer-reviewed publication. The results of our analysis can inform public health policy and clinical decision making regarding ACEi/ARB use in patients with COVID-19 on a global scale.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/drug therapy , Meta-Analysis as Topic , Humans , Prospective Studies , Randomized Controlled Trials as Topic , Renin-Angiotensin System , Research Design
20.
Eur Heart J ; 41(48): 4580-4588, 2020 12 21.
Article in English | MEDLINE | ID: covidwho-1066303

ABSTRACT

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antihypertensive Agents/pharmacology , Hypertension , Kidney Tubules/metabolism , Lung/metabolism , Renin-Angiotensin System/drug effects , Adrenergic beta-Antagonists/pharmacology , Adult , Age Factors , Aged , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , COVID-19/complications , Diuretics/pharmacology , Female , Gene Expression Profiling , Glomerular Filtration Rate , Humans , Hypertension/drug therapy , Hypertension/genetics , Kidney Tubules/physiopathology , Male , Middle Aged , Rats , Rats, Inbred SHR , SARS-CoV-2 , Sequence Analysis, RNA , Sex Factors , Transcriptome/drug effects
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