Bayesian networks and imaging-derived phenotypes highlight the role of fat deposition in COVID-19 hospitalisation risk.

Objective: Obesity is a significant risk factor for adverse outcomes following coronavirus infection (COVID-19). However, BMI fails to capture differences in the body fat distribution, the critical driver of metabolic health. Conventional statistical methodologies lack functionality to investigate the causality between fat distribution and disease outcomes. Methods: We applied Bayesian network (BN) modelling to explore the mechanistic link between body fat deposition and hospitalisation risk in 459 participants with COVID-19 (395 non-hospitalised and 64 hospitalised). MRI-derived measures of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat were included. Conditional probability queries were performed to estimate the probability of hospitalisation after fixing the value of specific network variables. Results: The probability of hospitalisation was 18% higher in people living with obesity than those with normal weight, with elevated VAT being the primary determinant of obesity-related risk. Across all BMI categories, elevated VAT and liver fat (>10%) were associated with a 39% mean increase in the probability of hospitalisation. Among those with normal weight, reducing liver fat content from >10% to <5% reduced hospitalisation risk by 29%. Conclusion: Body fat distribution is a critical determinant of COVID-19 hospitalisation risk. BN modelling and probabilistic inferences assist our understanding of the mechanistic associations between imaging-derived phenotypes and COVID-19 hospitalisation risk.

THE FUTURE OF MANAGEMENT EDUCATION

To remain relevant, management education must reflect the realities that influence its subject matter, management, while at the same time addressing societal needs and expectations. Faced by powerful drivers of change, many of which are amplified by the immense turbulence caused by the COVID-19 pandemic in early 2020, an assessment of where management education stands and where it is going is timely. This book brings together management education scholars, practitioners, and stakeholders to identify trends and to critically analyse key challenges from their respective perspectives. They consider the requirements for providing relevant management education in the future and explore changes and opportunities around themes such as responsibility, sustainability, innovation, competitive strategy, and technological change. The different perspectives of the authors contribute distinct insights and form a fascinating kaleidoscope of reflections on the present and predictions and prescriptions for the future of management education. The result is a comprehensive volume that will be essential reading for scholars and administrators committed to the growth and development of management education. It also will be of keen interest to management educators as well as management learners who will shape and be shaped by the management education of the future. © Chinnapong and 2022 selection and editorial matter, Martin R. Fellenz, Sabine Hoidn, and Mairead Brady;individual chapters, the contributors.

Teaching1 Economics Students about Different Models for Dealing with Uncertainty and Risk Besides the Standard Capital Asset Pricing Model (CAPM) and the Subjective Expected Utility (SEU) Model

There has been a great deal of uncertainty (doubt) and fear about how the COVID-19 corona virus would impact the world's economies in the future. This fear of the future would explain the manner in which individuals and countries have responded to the outbreaks by buying gold and/or other "hard" assets, which decision makers have great confidence in. In times of uncertainty (doubt), holding gold is a reliable and dependable way of combatting the likely impact of un-certain events on future events. The COVID-19 virus has generated a great deal of fear regarding the economic ef-fects of the virus on the economy. Holding hard assets would allow the holder of such assets to feel safer and more secure about their ability to successfully deal with and/or wait out such events . We argue that undergraduate students would be better prepared for decision making in the real world after they graduate if the standard approach taken in microeconomic courses based on risk assessment alone was supplemented by alternative treatments that do not model decision making as taking place only under the assumption of additivity and linearity as is made in CAPM and SEU. It is important to teach students how to modify their probabilities to transform them into decision weights which (a) consider uncertainty, but (b) simplify to probabilities if the uncer-tainty should diminish substantially in the future. This is accomplished by using Tversky -Kahneman's Cumulative Prospect Theory and Keynes's Conventional Coefficient model from the A Treatise on Probability. © 2022 Better Advances Press. All rights reserved.

ECTOPIC FAT DEPOSITION IN THE LIVER AND PANCREAS AND THE PRESENCE OF EXCESS VISCERAL ADIPOSE TISSUE SIGNIFICANTLY INCREASE HOSPITALISATION RISK FOLLOWING COVID-19

Background and Aims: In patients with COVID-19, obesity may increase risk of hospitalisation, use of mechanical ventilation and patient mortality. High liver fat, body mass index (BMI) and male sex are significant predictors of hospitalisation risk following COVID-19. However, BMI is a poor indicator of body fat distribution. Here, we studied ectopic fat accumulation within the liver and pancreas and body composition through multiparametric magnetic resonance (mpMR) and compared participants with and without hospitalisation for COVID-19. Method: Participants with laboratory-confirmed or clinically suspected SARSCoV- 2 infection were recruited to the COVERSCAN study (NCT04369807;median time from initial symptoms = 177 days) and underwent a multi-organ mpMR scan (CoverScan®, Perspectum Ltd). Measures of liver and pancreatic fat (PDFF), liver fibroinflammation (cT1) and body composition [visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle index (SMI)] were analysed. Differences between participants hospitalised (n = 59) and not hospitalised (n = 348) for COVID-19 were assessed using Wilcoxon signedrank tests. Univariate and multivariate analyses were performed on all biomarkers to assess the hospitalisation risk. Data presented are median values. Results: Approximately 6-months after initial symptoms, participants hospitalised following COVID-19 had significantly elevated pancreatic fat (3.8 % vs 2.8 %, p < 0.01), liver fat (3.8 % vs 2.4 %, p < 0.01) and liver cT1 (735ms vs 706ms, p < 0.01) compared to those who convalesced at home. Though hospitalised participants had a significantly elevated BMI (27 kg/m2 vs 25 kg/m2, p = 0.014), it was VAT, but not SAT, that was significantly elevated (132 cm2 vs 86 cm2, p < 0.01). Univariate analysis revealed that male sex, advanced age and elevated BMI, VAT, pancreatic fat, liver fat, and liver cT1 were all significantly predictive of hospitalisation following COVID- 19. In multivariate analysis, only age remained significantly predictive of hospitalisation. In hospitalised people with obesity (³ 30 kg/m2), VAT, liver cT1 and liver fat, but not BMI nor pancreatic fat, remained significantly elevated [VAT: 220 cm2 vs 152cm2, p = 0.01 (Figure 1);liver fat: 9.9 % vs 4.2 %, p = 0.003;liver cT1: 782ms vs 742ms, p = 0.012]. Conclusion: mpMR revealed significantly elevated visceral and ectopic fat deposition within the liver and pancreas in hospitalised participants following COVID-19. In obese participants, BMI was not significantly different in hospitalised, and non-hospitalised patients, whereas visceral fat, liver fibroinflammation and liver fat were significantly elevated. Our work highlights body fat distribution an important consideration for COVID-19 risk profiling, which cannot be sufficiently evaluated based on BMI alone. (Figure Presented) Figure 1. Comparison of liver fat (left), pancreatic fat (middle) and visceral adipose tissue (right) between participants hospitalised and not hospitalised following COVID-19.

‘Every day was a learning curve’: implementing COVID-19 triage protocols in UK ambulance services – a qualitative study

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.

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses.

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.

Rapid detection of multiple SARS-CoV-2 variants of concern by PAM-targeting mutations.

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.

CRISPR-based assay reveals SARS-CoV-2 RNA dynamic changes and redistribution patterns in non-human primate model.

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.

Elevated visceral and liver fat content significantly increase risk of hospitalisation following COVID-19 infection

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.

Liposome-mediated detection of SARS-CoV-2 RNA-positive extracellular vesicles in plasma.

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.

Impact of COVID-19 on acute ischemic stroke care at henry ford Hospital's Detroit and West Bloomfield Campuses

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.

Impact of COVID-19 on thrombolysis and thrombectomy time metrics at henry ford hospital's Detroit and west bloomfield campuses

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.

Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection.

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.

Feasibility of manual ventilation replacing mechanical ventilation

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.