Rapid diagnostic tests (RDTs) developed for point of care detection of SARS-CoV-2 antigen are recommended by WHO to use trained health care workers to collect samples. We hypothesised that self-taken ...samples are non-inferior for use with RDTs to diagnose COVID-19. We designed a prospective diagnostic evaluation comparing self-taken and healthcare worker (HCW)-taken throat/nasal swabs to perform RDTs for SARS-CoV-2, and how these compare to RT-PCR.
Eligible participants 18 years or older with symptoms of COVID-19. 250 participants recruited at the NHS Test and Trace drive-through community PCR testing site (Liverpool, UK); one withdrew before analysis. Self-administered throat/nasal swab for the Covios® RDT, a trained HCW taken throat/nasal sample for PCR and HCW comparison throat/nasal swab for RDT were collected. RDT results were compared to RT-PCR, as the reference standard, to calculate sensitivity and specificity.
Seventy-five participants (75/249, 30.1%) were positive by RT-PCR. RDTs with self-taken swabs had a sensitivity of 90.5% (67/74, 95% CI: 83.9-97.2), compared to 78.4% (58/74, 95% CI: 69.0-87.8) for HCW-taken swabs (absolute difference 12.2%, 95% CI: 4.7-19.6, p = 0.003). Specificity for self-taken swabs was 99.4% (173/174, 95% CI: 98.3-100.0), versus 98.9% (172/174, 95% CI: 97.3-100.0) for HCW-taken swabs (absolute difference 0.6%, 95% CI: 0.5-1.7, p = 0.317). The PPV of self-taken RDTs (98.5%, 67/68, 95% CI: 95.7-100.0) and HCW-taken RDTs (96.7%, 58/60, 95% CI 92.1-100.0) were not significantly different (p = 0.262). However, the NPV of self-taken swab RDTs was significantly higher (96.1%, 173/180, 95% CI: 93.2-98.9) than HCW-taken RDTs (91.5%, 172/188, 95% CI 87.5-95.5, p = 0.003).
In conclusion, self-taken swabs for COVID-19 testing offer an accurate alternative to healthcare worker taken swabs for use with RDTs. Our results demonstrate that, with no training, self-taken throat/nasal samples can be used by lay individuals as part of rapid testing programmes for symptomatic adults. This is especially important where the lack of trained healthcare workers restricts access to testing.
In order to generate independent performance data regarding accuracy of COVID-19 antigen-based rapid diagnostic tests (Ag-RDTs), prospective diagnostic evaluation studies across multiple sites are ...required to evaluate their performance in different clinical settings. This report describes the clinical evaluation the GENEDIA W COVID-19 Ag Device (Green Cross Medical Science Corp., Chungbuk, Korea) and the ActiveXpress+ COVID-19 Complete Testing Kit (Edinburgh Genetics Ltd, UK), in two testing sites Peru and the United Kingdom.
Nasopharyngeal swabs collected from 456 symptomatic patients at primary points of care in Lima, Peru and 610 symptomatic participants at a COVID-19 Drive-Through testing site in Liverpool, England were analyzed by Ag-RDT and compared to RT-PCR. Analytical evaluation of both Ag-RDTs was assessed using serial dilutions of direct culture supernatant of a clinical SARS-CoV-2 isolate from the B.1.1.7 lineage.
For GENEDIA brand, the values of overall sensitivity and specificity were 60.4% 95% CI 52.4-67.9%, and 99.2% 95% CI 97.6-99.7% respectively; and for Active Xpress+ the overall values of sensitivity and specificity were 66.2% 95% CI 54.0-76.5%, and 99.6% 95% CI 97.9-99.9% respectively. The analytical limit of detection was determined at 5.0 x 102 pfu/ml what equals to approximately 1.0 x 104 gcn/ml for both Ag-RDTs. The UK cohort had lower median Ct values compared to that of Peru during both evaluations. When split by Ct, both Ag-RDTs had optimum sensitivities at Ct<20 (in Peru; 95% 95% CI 76.4-99.1% and 100.0% 95% CI 74.1-100.0% and in the UK; 59.2% 95% CI 44.2-73.0% and 100.0% 95% CI 15.8-100.0%, for the GENDIA and the ActiveXpress+, respectively).
Whilst the overall clinical sensitivity of the Genedia did not meet WHO minimum performance requirements for rapid immunoassays in either cohort, the ActiveXpress+ did so for the small UK cohort. This study illustrates comparative performance of Ag-RDTs across two global settings and considers the different approaches in evaluation methods.
Chest pain is one of the most common reasons for emergency ambulance calls. Patients are routinely transported to the hospital to prevent acute myocardial infarction (AMI). We evaluated the ...diagnostic accuracy of clinical pathways in the out-of-hospital environment. The Troponin-only Manchester Acute Coronary Syndromes decision aid and History, ECG, Age, Risk Factors, Troponin score require cardiac troponin (cTn) measurement, whereas the History and ECG-only Manchester Acute Coronary Syndromes decision aid and History, ECG, Age, Risk Factors score do not.
We conducted a prospective diagnostic accuracy study at 4 ambulance services and 12 emergency departments between February 2019 and March 2020. We included patients who received an emergency ambulance response in whom paramedics suspected AMI. Paramedics recorded the data required to calculate each decision aid and took venous blood samples in the out-of-hospital environment. Samples were tested using a point-of-care cTn assay (Roche cobas h232) within 4 hours. The target condition was a diagnosis of type 1 AMI, adjudicated by 2 investigators.
Of 817 included participants, 104 (12.8%) had AMI. Setting the cutoff at the lowest risk group, Troponin-only Manchester Acute Coronary Syndromes had 98.3% sensitivity (95% confidence interval 91.1% to 100%) and 25.5% specificity (21.4% to 29.8%) for type 1 AMI. History, ECG, Age, Risk Factors, Troponin had 86.4% sensitivity (75.0% to 98.4%) and 42.2% specificity (37.5% to 47.0%); History and ECG-only Manchester Acute Coronary Syndromes had 100% sensitivity (96.4% to 100%) and 3.1% specificity (1.9% to 4.7%), whereas History, ECG, Age, Risk Factors had 95.1% sensitivity (88.9% to 98.4%) and 12.1% specificity (9.8% to 14.8%).
With point-of-care cTn testing, decision aids can identify patients at a low risk of type 1 AMI in the out-of-hospital environment. When used alongside clinical judgment, and with appropriate training, such tools may usefully enhance out-of-hospital risk stratification.
IntroductionWithin the UK, chest pain is one of the most common reasons for emergency (999) ambulance calls and the most common reason for emergency hospital admission. Diagnosing acute coronary ...syndromes (ACS) in a patient with chest pain in the prehospital setting by a paramedic is challenging. The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision rule is a validated tool used in the emergency department (ED) to stratify patients with suspected ACS following a single blood test.We are seeking to evaluate the diagnostic accuracy of the T-MACS decision aid algorithm to ‘rule out’ ACS when used in the prehospital environment with point-of-care troponin assays. If successful, this could allow paramedics to immediately rule out ACS for patients in the ‘very low risk’ group and avoid the need for transport to the ED, while also risk stratifying other patients using a single blood sample taken in the prehospital setting.Methods and analysisWe will recruit patients who call emergency (999) ambulance services where the responding paramedic suspects cardiac chest pain. The data required to apply T-MACS will be prospectively recorded by paramedics who are responding to each patient. Paramedics will be required to draw a venous blood sample at the time of arrival to the patient. Blood samples will later be tested in batches for cardiac troponin, using commercially available troponin assays. The primary outcome will be a diagnosis of acute myocardial infarction, established at the time of initial hospital admission. The secondary outcomes will include any major adverse cardiac events within 30 days of enrolment.Ethics and disseminationThe study obtained approval from the National Research Ethics Service (reference: 18/ES/0101) and the Health Research Authority. We will publish our findings in a high impact general medical journal.Trial registration numberRegistration number: ClinicalTrials.gov, study ID: NCT03561051
The Manchester Acute Coronary Syndromes ECG (MACS-ECG) prediction model calculates a score based on objective ECG measurements to give the probability of a non-ST elevation myocardial infarction ...(NSTEMI). The model showed good performance in the emergency department (ED), but its accuracy in the pre-hospital setting is unknown. We aimed to externally validate MACS-ECG in the pre-hospital environment.
We undertook a secondary analysis from the Pre-hospital Evaluation of Sensitive Troponin (PRESTO) study, a multi-centre prospective study to validate decision aids in the pre-hospital setting (26 February 2019 to 23 March 2020). Patients with chest pain where the treating paramedic suspected acute coronary syndrome were included. Paramedics collected demographic and historical data and interpreted ECGs contemporaneously (as 'normal' or 'abnormal'). After completing recruitment, we analysed ECGs to calculate the MACS-ECG score, using both a pre-defined threshold and a novel threshold that optimises sensitivity to differentiate AMI from non-AMI. This was compared with subjective ECG interpretation by paramedics. The diagnosis of AMI was adjudicated by two investigators based on serial troponin testing in hospital.
Of 691 participants, 87 had type 1 AMI and 687 had complete data for paramedic ECG interpretation. The MACS-ECG model had a C-index of 0.68 (95% CI: 0.61 to 0.75). At the pre-determined cut-off, MACS-ECG had 2.3% (95% CI: 0.3% to 8.1%) sensitivity, 99.5% (95% CI: 98.6% to 99.9%) specificity, 40.0% (95% CI: 10.2% to 79.3%) positive predictive value (PPV) and 87.6% (87.3% to 88.0%) negative predictive value (NPV). At the optimal threshold for sensitivity, MACS-ECG had 50.6% sensitivity (39.6% to 61.5%), 83.1% specificity (79.9% to 86.0%), 30.1% PPV (24.7% to 36.2%) and 92.1% NPV (90.4% to 93.5%). In comparison, paramedics had a sensitivity of 71.3% (95% CI: 60.8% to 80.5%) with 53.8% (95% CI: 53.8% to 61.8%) specificity, 19.7% (17.2% to 22.45%) PPV and 93.3% (90.8% to 95.1%) NPV.
Neither MACS-ECG nor paramedic ECG interpretation had a sufficiently high PPV or NPV to 'rule in' or 'rule out' NSTEMI alone.
COVID-19 rapid diagnostics: practice review Reynard, Charles; Allen, Joy A; Shinkins, Bethany ...
Emergency medicine journal : EMJ,
01/2022, Volume:
39, Issue:
1
Journal Article
Peer reviewed
Open access
Point-of-care tests for SARS-CoV-2 could enable rapid rule-in and/or rule-out of COVID-19, allowing rapid and accurate patient cohorting and potentially reducing the risk of nosocomial transmission. ...As COVID-19 begins to circulate with other more common respiratory viruses, there is a need for rapid diagnostics to help clinicians test for multiple potential causative organisms simultaneously.However, the different technologies available have strengths and weaknesses that must be understood to ensure that they are used to the benefit of the patient and healthcare system. Device performance is related to the deployed context, and the diagnostic characteristics may be affected by user experience.This practice review is written by members of the UK's COVID-19 National Diagnostic Research and Evaluation programme. We discuss relative merits and test characteristics of various commercially available technologies. We do not advocate for any given test, and our coverage of commercially supplied tests is not intended to be exhaustive.
Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth ...tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.
•DNA methylation within the ANRIL promoter region was predictive of measures of adiposity in four independent cohorts.•DNA methylation may be a marker for late gestation fetal undernutrition, followed by rapid postnatal weight gain.•Altered DNA methylation associated with p16INK4a and p14ARF expression.•ERα may bind at the ANRIL promoter, and in vitro E2 treatment stimulated expression of ANRIL, while reducing p14 expression.
The quality of the early life environment before birth can affect susceptibility to metabolic disease later in the lifecourse, with epigenetic regulation of gene function thought to be one mechanism through which early life environmental factors induce persistent phenotypic changes. In this study, using DNA from the Southampton Women's Survey (SWS), we identified changes in DNA methylation levels at birth that associated with adiposity later in childhood within the promoter of ANRIL, a gene with strong disease associations that is involved in regulatiing cellular growth. This finding was replicated in several independent cohorts, and functionally validated in adipocyte cells.
As the population is becoming more aged, osteoporosis is becoming more prevalent and the number of fragility fractures that are occurring is increasing. One of the main predictors of developing ...osteoporosis in later life is a bone mineral density that is greater than 2.5 standard deviations below the young adult sex-matched mean, though studies have only been able to explain 5% of the variance seen in bone mineral densities between individuals. There is now increasing evidence that the development of osteoporosis can begin in utero and that epigenetic processes, such as DNA methylation, may be central to the mechanism by which early development influences bone mineral density and later bone health. Previous work within the group has identified associations of a 300bp differentially methylated region within the CDKN2A locus with bone mineral content, bone area and areal bone mineral density in offspring from the Southampton Women’s Survey(SWS) cohort. As methylation of CDKN2A increases, bone mineral content, bone area and areal bone mineral density all decrease at both 4 and 6 years of age. The two cell cycle regulators p16INK4A and p14ARF are transcribed from this gene as well as the lncRNA ANRIL. Various techniques were used to determine whether this differentially methylated region has a functional role in osteoblasts or whether it is just a potential marker for predicting bone mineral density. It was shown that there was specific binding in the osteoblast-like SaOS-2 cell line to this region and that methylation of these CpGs led to a decrease in transcription factor binding. Treatment of both SaOS-2 cells and primary osteoblasts with siRNAs against ANRIL caused a decrease in cell number, a decrease in cell proliferation, an increase in cells in G0/G1 phase of the cell cycle and, in SaOS-2 cells, caused an increase in the expression of bone differentiation markers RUNX2 and ALP. Knock down of ANRIL expression also caused a change in genes that have roles in osteoblast specific pathways as well as genes that were involved in molecular functions such as nuclear regulation and acetylation. Associations were found between CpG methylation in RXRA and offspring bone outcomes at birth in both the SWS and MAVIDOS cohorts. Daily maternal cholecalciferol supplementation was also shown to decrease the methylation of CpG loci within RXRA in offspring umbilical cord and further investigation showed that this effect of maternal supplementation was only seen in children born during the winter months. Together, these findings suggest that the association between CDKN2A methylation at birth and later bone health could indicate a potential role for CDKN2A in bone development and function and raises the possibility that differential methylation of CDKN2A may allow the identification of individuals at increased risk of osteoporosis in later life. Due to the effect of ANRIL knock down in primary osteoblasts, which could not be explained through normal cell cycle pathways, results suggest that ANRIL has potential trans-regulatory functions in these cells. These findings suggest that ANRIL could potentially play a role in bone differentiation, cell proliferation and metabolism and that dysregulation of the expression of this lncRNA could have adverse effects on bone health, potentially increasing the risk of individuals developing osteoporosis in later life.
PDF
