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The recent and recurrent spillover of three highly pathogenic coronaviruses, SARS-CoV-1, MERS-CoV and SARS-CoV-2, into human populations has stressed the importance of pandemic preparedness. Here, we describe how, in the absence of antiviral therapeutic options against coronaviruses, early clinical investigations have focused on the prompt repurposing of approved antiviral therapies. We discuss how, despite international collaborative efforts, their outcomes so far have been disappointing as none of the early drugs tested demonstrated effective clinical efficacy. We also outline innovative strategies and tools developed to fast-track development of novel classes of antivirals. These capitalise on a deeper understanding of viral molecular pathogenesis and how coronaviruses hijack the host cellular machinery to maximise their replication and counteract host defences. Collectively, these approaches are crucial to identify and validate novel targets for therapeutic interventions and expand the repertoire of broad-spectrum antiviral agents, so that these can be promptly deployed for current and future pandemics.Copyright © ERS 2021.
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Background: Adjuvant chemotherapy has been an integral component of breast cancer care for decades. Advances in supportive care have been made, but despite this, infective complications of therapy remain a significant toxicity concern. Case Presentation: A premenopausal patient presented to the emergency department during the third wave of the Covid-19 pandemic with sepsis after a second course of adjuvant docetaxel-cyclophosphamide chemotherapy. Overnight she developed tetraplegia. An urgent MRI cervical spine revealed a pre-vertebral, vertebral, and epidural abscess. This was treated with an emergency C4-C7 posterior cervical laminectomy and decompression. Her inpatient care involved a protracted ICU admission followed by rehabilitation. She remains tetraplegic and requires continued inpatient care over a year after presentation. Restricted pandemic-related hospital visiting has compounded the impact of her illness. Conclusion: Infective complications of adjuvant breast cancer chemotherapy remain an issue despite advances in supportive care. This case highlights the devastating, life-altering impact that these complications can have as emphasized by the inclusion of the patient's perspective. Copyright © 2022.
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Drone technology is widely available and is rapidly becoming a crucial instrument in the functions of businesses and government agencies worldwide. The demand for delivery services is accelerating particularly since the Covid-19 pandemic. Both companies and customers want these services to be efficient, timely, safe, and sustainable, but these are major challenges. Last-mile delivery by lightweight short-range drones has the potential to address these challenges. However, there is a lack of consistency and transparency in assessing and reporting the sustainability of last-mile delivery services and drones. This paper presents a critical review of published assessments (specifically lifecycle assessment and circularity). The study reveals a lack of comprehensive studies, and a need to examine composite and battery manufacturing developments and provides key considerations for future study development. © 2022 Mitchell et al.
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Background. Quantifying neutralising capacity of circulating SARS-COV-2 antibodies is critical in evaluating protective humoral immune responses generated postinfection/post-vaccination. Here we describe a novel medium-throughput flow cytometry based micro-neutralisation assay to evaluate Neutralising Antibody (NAb) responses against live SARS-CoV-2 Wild Type (D641G) and Variants of Concern (VoC) in convalescent/vaccinated populations. Methods. Micro-Neutralisation assay (Micro-NT) was performed in 96-well plates using clinical isolate 2019-nCoV/Italy-INMI1, D641G (SARS-CoV-2/human/ IRL/AIIDV1446/2020) and/or VOCs Beta (SARS-CoV-2/human/IRL/AIIDV1752/ 2021) and Omicron (SARS-Cov-2/human/IRL/AIIDV2326/2021). Plasma samples (All Ireland Infectious Diseases (AIID) Cohort) were serially diluted (8 points, halflog) from 1/20 and pre-incubated with SARS-CoV-2 (1h, 37degreeC). Virus-plasma mixture were added onto VERO E6/VERO-E6 TMPRSS2 cells for 18h. Percentage infected cells was analysed by automated flow cytometry following trypsinisation,fixation and SARS-CoV-2 Nucleoprotein intracellular staining. Half-maximal Neutralisation Titres (NT50) was determined using four-parameter logistic regression. Our assay was compared to Plaque Reduction Neutralisation Test (PRNT) and validated against WHO anti-SARS-CoV-2 Immunoglobulin Standards. Results. Using WHO Standards with low, medium or high anti-SARS-CoV-2 IgG, both Micro-NT and PRNT achieved comparable NT50 values (Table 1). Micro-NT was found to be highly reproducible (inter-assay CV of 11.39%). Screening 190 convalescent samples and 11 COVID-19 naive controls (AIID cohort) we achieved an assay sensitivity of 90% and specificity of 81%. We demonstrated that Micro-NT has broad dynamic range differentiating NT50s < 1/20 to > 1/5000 (Figure 1). We could also characterise immune-escape VoC, observing up to 10-fold reduction in NT50 against Beta (Figure 2). Table 1: NT50s of Low, Medium and High Titre Anti-SARS-CoV-2 IgG Standards measured against Live SARS-CoV-2 using PRNT and Micro-NT Neutralising Capacity of low, medium and high-titre anti-SARS-CoV-2 IgG (WHO, International Standards) against live SARS-CoV-2 (2019-nCoV/Italy-INMI1) measured using PRNT and Micro-NT Assays on Vero E6 cells, as well as the potency of NAbs in each sample in International Units (IU/ml) as determined by the WHO. Figure 1: Dynamic Range of Micro-NT Micro-NT has a broad Dynamic Range, distinguishing low (A), medium (B) and high (C) neutralising plasma samples against live SARS-CoV-2 (2019-nCoV/Italy-INMI1) from a cohort of COVID-19 convalescent individuals (AIID cohort), as well as negative samples from COVID-19 naive samples (D). Graphs show 3 representative samples of each NT50 range. (E) shows the population distribution of 190 Convalescent plasma samples as measured by Micro-NT on Vero E6 cells. Figure 2: Reduced Neutralisation Capacities measured against SARS-CoV-2 VoC using Micro-NT Low (A), Medium (B) and High (C) anti-SARS-CoV-2 IgG (WHO Standards) show different neutralising capacities against WT (D614G) SARS-CoV-2 and variants Beta and Omicron, measured using Micro-NT on Vero-E6-TMPRSS2 cells. Conclusion. Our flow-cytometry-based Micro-NT is a robust and reliable assay to quantify NAb titres, an important evaluation endpoint in clinical trials. It has higher throughput (96 well format versus 12 well) and reduced infection time (18h vs 48-96h) compared to the gold standard PRNT.
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Background. A wide array of assays to detect the serologic response to SARS-CoV-2 have been developed since the emergence of the pandemic. The majority of these are either qualitative or semi-quantitative, detect antibodies against one antigenic target, and are not adaptable to new antigens. Methods. We developed a new, multiplex immunoassay to detect antibodies against the receptor binding domain, S1 and S2 spike subunits and nucleocapsid (N) antigens of SARS-CoV-2 (the CEPHR SARS-CoV-2 Serology Assay). This assay uses electrochemiluminescence technology which allows for a broad dynamic range, and a linker format which allows for the addition of new antigenic targets. We tested this assay on a series of biobanked samples and validated its performance against the Abbott SARS-CoV-2 IgG and Abbott SARS-CoV-2 IgG II assays, and the MesoScale Diagnostics V-PLEX SARS-CoV-2 Panel 2 Kit. Results. Participant demographics are shown in Table 1. The mean (standard deviation (SD)) intra-assay (within plate) coefficient of variation (CV) of 80 plasma samples run on the same plate was 3.9% (2.9) for N, 3.8% (6.2) for RBD, 3.8% (5.9) for S1 and 3.9% (5.3) for S2. The mean (SD) inter-assay CV derived from 5 samples run across 3 days by two different operators was 11% (6.5) for N, 13% (5.7) for RBD, 14% (8.9) for S1 and 13% (5.1) for S2. In the convalescent group (n=193), overall sensitivity for each assay was;RBD 82% (95% CI 76-87), S1 86% (81-91%), S2 88% (83 - 92%) and N 72% (64 - 78%). Sensitivity improved when analysis included only individuals who were sampled more than 14 days from onset of symptoms (n=166), RBD 87% (81 - 95%), S1 91% (85 - 95%), S2 91% (85 - 95%) but not for the N-target (73% (66-80%)). In vaccinated individuals (n = 58), 100% (94-100%) had both detectable RBD and S1 antibodies. Overall specificity was 96% (87-99%) for RBD, 90% (78-97%) for S1, 94% (84-99%) for S2 and 90% (78-97%) for N. There was excellent correlation between the Abbott IgG II and both CEPHR anti-RBD IgG (rho 0.91) and CEPHR anti-S1 IgG (rho 0.9, both p < 0.001, Figure 1.) and the V-PLEX full spike and both CEPHR RBD IgG (rho 0.83) and S1 IgG (rho 0.82, both p < 0.001, Figure 4). Conclusion. The CEPHR SARS-CoV-2 Serology Assay is a robust, customisable, multiplex serologic assay for the detection of several different IgG specific to SARS-CoV-2.
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Background: Although presence of SARS-CoV-2 neutralising antibodies can provide protection against development of COVID-19, how reflective circulating anti-SARS-CoV-2 antibody levels are of underlying neutralising capacity, and whether a threshold exists to predict sufficient neutralising capacity remains unclear. Methods: In plasma from individuals with PCR-confirmed COVID-19 recruited to the All Ireland Infectious Diseases Cohort Study, we measured IgG concentrations against RBD, Spike protein sub-unit 1 and 2 (S1, S2) and Nucleocapsid (NC) using multiplex electrochemiluminescence (normalised to World Health Organisation reference serum as IU/mL). Neutralising capacity was measured against live SARS-CoV-2 virus (clinical isolate 2019-nCoV/Italy-INMI1) by determining the maximum plasma dilution required to maintain 50% inhibition of infection of Vero E6 cells (50% Neutralisation Titre (NT50)), by flow cytometry-based micro-neutralisation assay. Given that the Beta SARS-CoV-2 variant of concern (VOC) reduces neutralising activity up to six fold, we estimated a NT50 of 1:1000 against wild type SARS-CoV-2 would maintain neutralising activity against VOC. We used Spearman correlation and linear regression to model relationships between NT50 and IgG concentrations. Data are presented as median (IQR) unless specified. Results: In 190 individuals (age 50 (40-64) years, 55% female, time from symptom onset 98 (35-179) days), NT50 most highly correlated with anti-RBD IgG (Rho 0.81 p<0.001, Fig 1a) compared with other IgG classes (S1;Rho 0.8, S2;0.73, NC;0.72, all p<0.001). Median RBD titre was 246 (71-662) but trended lower over time, with a median of 319 (61-1012) IU/ml at 0-90 days, 244 (86-523) IU/ml at 90-180 days and 157 (80-364) IU/ml at >180 days post symptom onset respectively (p=0.08, Fig 1b). RBD IgG titres of 476 IU/ml corresponded to a NT50 of 1:1000. Overall, RBD ≥476 IU/ml predicted NT50 ≥1:1000 with a sensitivity of 77 (95% CI 65-87)% and specificity 89 (95% CI 82-93)%. This improved in an analysis restricted to convalescent samples (>30 days post symptom onset, n=148), with a sensitivity 88% (95% CI 74-96%) and specificity 90% (95%CI 82-95%) respectively. Conclusion: In convalescent plasma, RBD IgG titres ≥476IU/mL is sensitive and specific for predicting robust underlying neutralising capacity. Further research is required to validate these findings in other cohorts and confirm these thresholds in post-vaccinated individuals.
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Background: The SARS-Cov-2 pandemic led to significant ongoing disruptive change in healthcare from 3/2020 to the present. The impact and legacy on a national clinical trials organisation was assessed. Methods: A review was conducted of prospectively acquired communications, team logs and time sheets, trial activation, closure, and accrual, for the period 2019-present. An online survey of the impact of the pandemic on clinical investigators was performed. During lock-down periods hospital sites closed to monitoring visits and remote visits were not always possible due to paper- based health information systems. Overall accrual to academic cancer clinical trials decreased by 49%. Results: In the 9 months after the pandemic was declared clinical trial accrual fell by 54%, radiotherapy trial accrual by 90% and translational studies by 36%. Staff reassignment occurred in 60% of units. Monitoring visits by Clinical Research Associates was reduced by 42% and remote monitoring rose from 5% to 20% of monitoring visits. The opening of new trials fell by 67%. 77% of investigators experienced burnout, 71% had less time for trials and 53% reported less support for trials. Conclusions: The pandemic has had a significant negative impact on cancer clinical trial activity in Ireland with a notable decline in academic-led trial activity compared to pharmaceutical-led trials. Protected staff assignments, electronic records to facilitate remote monitoring and enhanced support for clinical trials staff is needed to increase resilience in the system. Legal entity responsible for the study: Cancer Trials Ireland. Funding: Cancer Trials Ireland. Disclosure: The author has declared no conflicts of interest.
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Background: In December 2019 a cluster of pneumonias, later identified as SARS-CoV-2 (CoV), were reported in China. The first case in Ireland was reported February 29th 2020. The first community acquired case in Ireland was reported March 5th. The World Health Organisation declared CoV a pandemic March 11th. Lockdown measures were implemented in Ireland March 27th. Cork University Hospital is a large acute hospital and a tertiary referral center for cancer care. We undertook an audit of unscheduled medical oncology admissions over a 3 month period with a view to assess the impact of CoV on the centre. Method(s): From 1st February to 30th April we audited unscheduled medical oncology admissions. Parameters included presenting time, location and complaint, CoV status and average length of hospital stay (aLOS). Data was organised into 3 phases: four week period prior to a confirmed case of CoV in Ireland (phase I), four week period from confirmed case to lockdown implementation (phase 2) and four week period during lockdown (phase 3). After the outbreak of CoV we developed a separate medical oncology assessment facility (AOS) with an admission pathway. A hospital CoV pathway (CoVp) for potential CoV cases was also implemented. Result(s): A total of 162 medical oncology patients had unscheduled admissions during this period. Over half (57%) were receiving anticancer systemic treatment. The most common presenting complaints were pain (21%), pyrexia (17%) and dyspnoea (14%). The underlying diagnosis was cancer-related in 51%, treatment-related toxicity in 10% and non-cancer related in 39%. One patient was CoV positive. Unscheduled hospital admissions, source of admission and aLOS are outlined in the Table. [Formula presented]. Conclusion(s): A reduction in aLOS and ED admissions was paralleled by increasing use of alternative pathways. Processes which facilitate urgent assessment of oncology patients in specialized units avoid ED attendance and accelerate discharge planning in the care of cancer patients in the face of a pandemic and beyond. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Copyright © 2020
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Aim Deaths of doctors during the COVID-19 pandemic prompted an assessment of financial resilience among doctors in training in Ireland Methods In 2020, a 27-item online survey of demographics, work practices and finances was circulated nationally. The results were assessed using multiple correspondence analysis to develop a financial resilience framework. Results 161 responses were received. Only 26 (16.1%) respondents had income insurance, 10 (6.2%) had composed a will, and 41 (25.5%) had life insurance. 135 (83.9%) had not sought financial guidance and 153 (95%) were not aware of employer supports in event of death/disability. 105 (65.2%) would be considered financially fragile based on their median savings. Using a multiple correspondence analysis, 74 (46%) of the cohort were financially insecure. In the event of death 44/70 (62.9%) of those with dependents, felt that their dependents would not be looked after. Conclusion The majority of doctors in training lack both financial resilience and knowledge, nor are they aware of financial support structures. Financial management should be incorporated into medical education.
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Introduction There is little described in the current COVID-19 literature about the outcomes of patients discharged from hospital following COVID-19 pneumonia. We describe the rapid establishment of a 'virtual ward' (VW) for followup of patients with a suspected or confirmed diagnosis of COVID-19 pneumonia or pneumonitis upon hospital discharge, characteristics and outcomes for the first 300 patient referrals. Methods Admitted patients with a confirmed/suspected diagnosis of COVID-19 pneumonia/pneumonitis were referred electronically to the VW on discharge. Pulse oximeters were provided if oxygen saturations were <92%. The 'tracking board' was reviewed daily and phone calls carried out to assess patients for symptom improvement, stability or deterioration. If cause for concern was raised, same-day review for the patient at home was arranged via predetermined community pathways or patients were transferred urgently to hospital. Results The M:F ratio was 2:1 and 25% of patients were of black and minority ethnic origin. 71% of patients had at least 1 co-morbidity. 31% of patients were SARS-CoV-2 PCR negative on respiratory tract samples but had high clinical suspicion of COVID-19. 70% of patients had radiological changes on CXR/CT formally reported as being consistent with COVID-19. Median Length of stay (LOS) on the VW was 3.5 days [range 0-19], 85% of patients had a LOS £7 days. Around half (158, 53%) of patients had required oxygen during admission. Pulse oximeters were provided to 31 (10%) of patients. Outcomes are shown in figure 1. Thirty-eight (13%) patients re-attended the Emergency Department;28 were readmitted;of these, 3 were ventilated for respiratory failure, 5 had increasing oxygen requirements and 8 had confirmed pulmonary embolism. 12 had other reasons for admission. 2 patients readmitted by the VW died, both had underlying terminal diagnoses. Conclusions To our knowledge, this is the first description of the characteristics of patients discharged from UK hospitals with COVID-19. We have demonstrated that a virtual COVID-19 ward allowed early discharge of patients, offering a safety net and reassurance for patients and clinicians at the time of discharge. Use of pulse oximeters allowed for early identification of clinical deterioration, enabling prompt readmission when required.