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1.
BMJ Open ; 12(Suppl 1):A16, 2022.
Article in English | ProQuest Central | ID: covidwho-1871566

ABSTRACT

BackgroundTRIM is an evaluation of the triage models used by emergency ambulance services caring for patients with suspected COVID-19 during the pandemic’s first wave in 2020. We aimed to understand experiences and concerns of staff about implementation of triage protocols.MethodResearch paramedics interviewed stakeholders from four ambulance services (call handlers, clinical advisors, paramedics, managers) and ED clinical staff from receiving hospitals. Interviews (n=23) were conducted remotely using MS Teams, recorded, and transcribed in full. Analysis generated themes from implicit and explicit ideas within participants’ accounts (Braun and Clarke 2021), conducted by researchers and PPI partners working together.ResultsWe identified the following themes:Constantly changing guidelines – at some points, updated several times a day.The ambulance service as part of the wider healthcare system - changes elsewhere in the system left ambulance services as the default.Peaks and troughs of demand - fluctuating greatly over time, and varying across the staff groups.A stretched system - resources were overextended by staff sickness and isolation, longer job times, and increased handover delays at ED.Emotional load of responding to the pandemic - including call centre staff. Doing the best they can in the face of uncertainty - a rapidly evolving situation unlike any which ambulance services had faced before.ConclusionImplementing triage protocols in response to the COVID-19 pandemic was complex and had to be actively managed by a range of frontline staff, dealing with external pressures and a heavy emotional load.Conflict of interestNone.FundingUKRI-DHSC Covid-19 Rapid Response Funding.

2.
Annals of Nutrition and Metabolism ; 77(6):372-373, 2021.
Article in English | Web of Science | ID: covidwho-1866023
4.
ACS Infect Dis ; 8(3): 596-611, 2022 03 11.
Article in English | MEDLINE | ID: covidwho-1706607

ABSTRACT

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.


Subject(s)
COVID-19 , SARS Virus , Animals , Protease Inhibitors , SARS-CoV-2 , Ubiquitin/metabolism
5.
Cell Rep Methods ; 2(2): 100173, 2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1670392

ABSTRACT

SARS-CoV-2 variants of concern (VOCs) that increase transmission or disease severity or reduce diagnostic or vaccine efficacy continue to emerge across the world. Current methods available to rapidly detect these can be resource intensive and thus sub-optimal for large-scale deployment needed during a pandemic response. Here, we describe a CRISPR-based assay that detects mutations in spike gene CRISPR PAM motif or seed regions to identify a pan-specific VOC single-nucleotide polymorphism (SNP)) ((D614G) and Alpha- and Delta-specific (S982A and D950N) SNPs. This assay exhibits good diagnostic sensitivity and strain specificity with nasal swabs and is designed for use in laboratory and point-of-care settings. This should enable rapid, high-throughput VOC identification required for surveillance and characterization efforts to inform clinical and public health decisions. Furthermore, the assay can be adapted to target similar SNPs associated with emerging SARS-CoV-2 VOCs, or other rapidly evolving viruses.

6.
Emerg Microbes Infect ; 11(1): 629-638, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1665837

ABSTRACT

Mounting evidence indicates that SARS-CoV-2 can infect multiple systemic tissues, but few studies have evaluated SARS-CoV-2 RNA dynamics in multiple specimen types due to their reduced accessibility and diminished performance of RT-qPCR with non-respiratory specimens. Here, we employed an ultrasensitive CRISPR-RT-PCR assay to analyze longitudinal mucosal (nasal, buccal, pharyngeal, and rectal), plasma, and breath samples from SARS-CoV-2-infected non-human primates (NHPs) to detect dynamic changes in SARS-CoV-2 RNA level and distribution among these specimens. We observed that CRISPR-RT-PCR results consistently detected SARS-CoV-2 RNA in all sample types at most time points post-infection, and that SARS-CoV-2 infection dose and administration route did not markedly affect the CRISPR-RT-PCR signal detected in most specimen types. However, consistent RT-qPCR positive results were restricted to nasal, pharyngeal, and rectal swab samples, and tended to decrease earlier than CRISPR-RT-PCR results, reflecting lower assay sensitivity. SARS-CoV-2 RNA was detectable in both pulmonary and extrapulmonary specimens from early to late infection by CRISPR-RT-PCR, albeit with different abundance and kinetics, with SARS-CoV-2 RNA increases detected in plasma and rectal samples trailing those detected in upper respiratory tract samples. CRISPR-RT-PCR assays for SARS-CoV-2 RNA in non-respiratory specimens may thus permit direct diagnosis of suspected COVID-19 cases missed by RT-PCR, while tracking SARS-CoV-2 RNA in minimally invasive alternate specimens may better evaluate the progression and resolution of SARS-CoV-2 infections.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Humans , Primates , RNA, Viral/analysis , Sensitivity and Specificity , Serologic Tests
7.
Hepatology ; 74(SUPPL 1):317A, 2021.
Article in English | EMBASE | ID: covidwho-1508765

ABSTRACT

Background: In patients infected with the SARS-CoV-2 (COVID-19) virus, obesity is associated with an increase in hospital admission, use of mechanical ventilation and patient mortality. Elevated liver fat, body mass index (BMI) and male sex are significant predictors of hospitalisation risk following COVID-19. BMI, however, is a poor indicator of body fat distribution. Here, we aim to characterise body composition and liver health through multiparametric magnetic resonance (mpMR) and compare participants hospitalised and not hospitalised following COVID-19. Methods: Participants with laboratory confirmed or clinically suspected SARSCoV-2 infection were recruited to the COVERSCAN study (NCT04369807) and underwent a multi-organ mpMR scan (median time from initial symptom = 177 days). Measures of liver fat (PDFF), liver fibroinflammation (cT1) and body composition (VAT, subcutaneous adipose tissue [SAT], skeletal muscle index [SMI]) were analysed. Differences between hospitalised (n=60) and non-hospitalised participants (n=354) were assessed using Wilcoxon signed-rank tests. Univariate and multivariate analysis were performed on all biomarkers to assess the risk of hospitalisation. Presented data are median values. Results: Hospitalised participants were older (50yrs vs 43yrs;p<0.01) and had significantly elevated liver fat (3.5% vs 2.4%;p<0.01) and liver cT1 (734ms vs 708ms;p<0.01). Though hospitalised participants had a significantly elevated BMI (27kg/m2 vs 25kg/m2;p=0.011), it was VAT, but not SAT or SMI, that was significantly elevated in hospitalised participants (131cm2 vs 80 cm2;p<0.01). Univariate analysis revealed male sex, advanced age and elevated BMI, VAT, liver fat and liver cT1 were all significantly predictive of hospitalisation. In multivariate analysis, only age remained significantly predictive of hospitalisation. In obese participants, VAT and liver fat, but not BMI nor cT1, remained significantly elevated in hospitalised participants (VAT: 200cm2 vs 159cm2, p=0.041;liver fat: 9.8% vs 4.6%, p=0.012). Conclusion: mpMR revealed significantly elevated visceral and ectopic liver fat in hospitalised participants following COVID-19 infection. In obese participants, BMI was not significantly different in hospitalised and non-hospitalised patients whereas visceral and liver fat remained significantly elevated. Our work highlights body fat distribution as an important consideration for COVID-19 risk profiling which is not sufficiently evaluated based on BMI alone.

10.
Nat Nanotechnol ; 16(9): 1039-1044, 2021 09.
Article in English | MEDLINE | ID: covidwho-1322483

ABSTRACT

Plasma SARS-CoV-2 RNA may represent a viable diagnostic alternative to respiratory RNA levels, which rapidly decline after infection. Quantitative PCR with reverse transcription (RT-qPCR) reference assays exhibit poor performance with plasma, probably reflecting the dilution and degradation of viral RNA released into the circulation, but these issues could be addressed by analysing viral RNA packaged into extracellular vesicles. Here we describe an assay approach in which extracellular vesicles directly captured from plasma are fused with reagent-loaded liposomes to sensitively amplify and detect a SARS-CoV-2 gene target. This approach accurately identified patients with COVID-19, including challenging cases missed by RT-qPCR. SARS-CoV-2-positive extracellular vesicles were detected at day 1 post-infection, and plateaued from day 6 to the day 28 endpoint in a non-human primate model, while signal durations for 20-60 days were observed in young children. This nanotechnology approach uses a non-infectious sample and extends virus detection windows, offering a tool to support COVID-19 diagnosis in patients without SARS-CoV-2 RNA detectable in the respiratory tract.


Subject(s)
COVID-19/diagnosis , Extracellular Vesicles/metabolism , Liposomes/therapeutic use , RNA, Viral/blood , SARS-CoV-2/isolation & purification , Animals , Biosensing Techniques , COVID-19/blood , COVID-19 Nucleic Acid Testing , Chlorocebus aethiops , Disease Models, Animal , HEK293 Cells , Humans , Kinetics , Liposomes/metabolism , RNA, Viral/genetics , SARS-CoV-2/genetics , Tetraspanin 28/immunology , Tetraspanin 28/metabolism
11.
Stroke ; 52(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1234403

ABSTRACT

Background: Coronavirus 2019 (COVID19) has impacted acute stroke (AS) care with several reports globally showing drops in AS volumes during the pandemic. We studied the impact of COVID19 on AS and transient ischemic attack (TIA) care in a health system serving Southeast Michigan as we rolled out a policy aimed at limiting admissions and transfers. Methods: In this retrospective study conducted at 2 hospitals, we included consecutive patients presenting to the emergency department (ED) for whom a Stroke Alert (SA) was activated during the period 3/20 to 5/20/20 (COVID) and a similar period in 2019 (pre-COVID). We compared demographics, time metrics, and discharge outcomes. Results: 264 patients were seen pre-COVID compared to 121 during COVID (p<0.001). Patients seen during COVID had an equal proportion of males (55% vs 51%, p=0.444), were majority African American (57 vs 58%, p=0.74), but had a higher presenting NIHSS (median: 5 vs 2, p=0.01) and longer times since last-known-well to ED arrival (median: 9.4 vs 4.8 hours, p=0.03) compared to pre-COVID. Fewer patients were transferred from other centers (42 vs 27% p=0.008). SA activation on arrival (median: 9.6 vs 15 min, p=0.004) and imaging initiation from arrival (median: 26.4 vs 34.8 min, p=0.042) were faster as well as a trend toward statistical significance for time to tPA administration (median: 37.8 vs 51 min, p=0.051) compared to pre-COVID. There were higher rates of AS and TIA (69% vs 55%) and lower rates of stroke mimics (17 vs 37%, p<0.001). Patients discharged from the stroke unit had significantly higher discharge NIHSS (median: 3 vs 2, p=0.002) and were more likely to have an unfavorable discharge mRS (3-6) (56 vs 33%, p=0.004). There were no significant differences in medical, social histories, time to first pass for patient undergoing thrombectomy and stroke etiologies between the groups. In 2020, 9 patients (8%) were COVID19 positive, 2 had unfavorable mRS 3-5 while 3 died. Conclusion: There was greater than 50% reduction in stroke admissions during the COVID19 pandemic which is consistent with other reports. Although patients were managed more quickly, they tended to have more severe strokes, fewer stroke mimic diagnoses, and worse outcomes compared to patients treated in the pre-COVID period.

12.
Stroke ; 52(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1234390

ABSTRACT

Background: We propose that social distancing policies during COVID-19 may have negatively impacted the timely administration of intravenous tPA and mechanical thrombectomy (MT) in acute ischemic strokes (AIS). Methods: In this retrospective study conducted at 2 large stroke centers serving Southeast Michigan, we included consecutive patients admitted to our stroke unit from 3/20/20 to 5/20/20 (COVID) and a similar epoch in 2019 (pre-COVID). We compared demographics and time metrics. Results: 247 patients with AIS were included in the tPA analysis, 167 (68%) in 2019 vs 80 (32%) in 2020. Overall mean age was 67.2, 60% male and 49% African Americans (AA). tPA was given in 13/80 in 2019 vs 17/167 patients in 2019 (16% vs 10%, p=0.143). There was no difference in tPA rates between AA and non-AA in 2020. There was a trend toward faster tPA administration in 2020 vs 2019 (median: 37.8 vs 51 min, p=0.051), significant among AA (37.8 vs 58.8 min, p=0.029). Mild/rapidly improving strokes was less frequently a tPA exclusion in 2020 vs 2019 (0% vs 10%). Delayed presentation was significantly less frequent among non-AA in 2020 vs 2019 (54% vs 66%, p=0.045) but there was a trend toward more frequent delayed presentations in AA vs non-AA in 2020 (76 vs 54%, P=0.073). 69 patients were eligible to receive MT, 42 (61%) in 2019 and 27 (39%) in 2020. Mean age was 67.9 and 36% were AA. No differences were detected between 2019 and 2020 in MT rates or time metrics. In 2020, there was a slight trend toward lower MT rates for AA vs non-AA patients (69% vs 30%, p=0.10). Conclusion: During the COVID-19 pandemic in Detroit there was a trend toward faster tPA administration compared to the same period pre-COVID, especially among AA. There was no significant difference in MT rates or time metrics. In our AA-majority city, there was a trend towards more delayed presentations and lower MT rates among AA during COVID. The reasons for these differences are yet to be determined and warrant further research.

13.
J Clin Invest ; 131(7)2021 04 01.
Article in English | MEDLINE | ID: covidwho-1076050

ABSTRACT

BACKGROUNDCirculating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA may represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples.METHODSA CRISPR-augmented RT-PCR assay that sensitively detects SARS-CoV-2 RNA was employed to analyze viral RNA kinetics in longitudinal plasma samples from nonhuman primates (NHPs) after virus exposure; to evaluate the utility of blood SARS-CoV-2 RNA detection for coronavirus disease 2019 (COVID-19) diagnosis in adults cases confirmed by nasal/nasopharyngeal swab RT-PCR results; and to identify suspected COVID-19 cases in pediatric and at-risk adult populations with negative nasal swab RT-qPCR results. All blood samples were analyzed by RT-qPCR to allow direct comparisons.RESULTSCRISPR-augmented RT-PCR consistently detected SARS-CoV-2 RNA in the plasma of experimentally infected NHPs from 1 to 28 days after infection, and these increases preceded and correlated with rectal swab viral RNA increases. In a patient cohort (n = 159), this blood-based assay demonstrated 91.2% diagnostic sensitivity and 99.2% diagnostic specificity versus a comparator RT-qPCR nasal/nasopharyngeal test, whereas RT-qPCR exhibited 44.1% diagnostic sensitivity and 100% specificity for the same blood samples. This CRISPR-augmented RT-PCR assay also accurately identified patients with COVID-19 using one or more negative nasal swab RT-qPCR results.CONCLUSIONResults of this study indicate that sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results, suggesting that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict the severity of infection.TRIAL REGISTRATIONClinicalTrials.gov. NCT04358211.FUNDINGDepartment of Defense, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the National Center for Research Resources.


Subject(s)
COVID-19/blood , COVID-19/virology , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/genetics , RNA, Viral/blood , RNA, Viral/genetics , SARS-CoV-2 , Adolescent , Adult , Aged , Animals , COVID-19/diagnosis , COVID-19 Nucleic Acid Testing/methods , COVID-19 Nucleic Acid Testing/statistics & numerical data , CRISPR-Cas Systems , Child , Child, Preschool , Disease Models, Animal , Female , Humans , Infant , Longitudinal Studies , Macaca mulatta , Male , Middle Aged , Pandemics , SARS-CoV-2/genetics , Sensitivity and Specificity , Time Factors
14.
BMJ Innovations ; 2021.
Article in English | Scopus | ID: covidwho-1039884

ABSTRACT

Background: During the COVID-19 pandemic it is anticipated that there will be a shortage of mechanical ventilators available for patients in critical condition. This has sparked many discussions about rationing resources and withholding care;however, an alternative may be to implement manual ventilation in these situations instead. Manual ventilation and a safety device were assessed for efficacy of extended use, such as may be required during this pandemic. Methods: To evaluate physical output characteristics of extended manual ventilation and efficacy of a barotrauma mitigation device, 47 medical students, nurses and medics completed two 1-hour manual ventilation sessions using the SmartLung 2000 Lung Simulator and 5300 Series Mass Flow Meter with a SPUR II resuscitator bag and endotracheal tube, mimicking a healthy adult with normal lung physiology, both with and without the Sotair device. Providers were randomised to complete their initial session either with or without the Sotair device. Findings: Collected data show wide variability in tidal volume and peak pressure in unmitigated manual breaths despite prior training and independent exploration of the resuscitation equipment prior to testing. The mean (±SD) tidal volume with bag only was 563.9±128.8 mL and with the safety device 536.1±80.9 mL (p<0.0001). The mean peak inspiratory pressure with bag only was 17.2±6.3 cm H2O and with the safety device 14.9±2.4 cm H2O (p<0.0001). Interpretation: While extended manual ventilation cannot replace mechanical ventilation, it is feasible with a safety device, which may reduce barotrauma, underventilation and overventilation. These results also demonstrate that withholding care and rationing resources may not be necessary. © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

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