Use of the FebriDx point-of-care assay as part of a triage algorithm for medical admissions with possible COVID-19

BackgroundPatients admitted to hospital with COVID-19 need rapid identification and isolation to prevent nosocomial transmission. However, isolation facilities are often limited, and SARS-CoV-2 RT-PCR results are often not available when discharged from the emergency department. We evaluated a triage algorithm to isolate patients with suspected COVID-19 using simple clinical criteria and the FebriDx assay. DesignRetrospective observational cohort SettingLarge acute care hospital in London, UK ParticipantsAll medical admissions from the ED between 10th August 2020 and 4th November 2020 with valid SARS-CoV-2 RT-PCR. InterventionsMedical admissions were triaged as likely, possible or unlikely COVID-19 based on clinical criteria. Patients triaged as possible COVID-19 underwent FebriDx lateral flow assay on capillary blood, and those positive for MxA were managed as likely COVID-19. Primary Outcome measuresDiagnostic accuracy (sensitivity, specificity and predictive values) of the algorithm and the FebriDx assay compared to SARS-CoV-2 RT-PCR from nasopharyngeal swabs as the reference standard. Results4.0% (136/3,443) of medical admissions had RT-PCR confirmed COVID-19. Prevalence of COVID-19 was 45.7% (80/175) in those triaged as likely, 4.1% (50/1,225) in possible and 0.3% (6/2,033) in unlikely COVID-19. Compared to SARS-CoV-2 RT-PCR, clinical triage had sensitivity of 95.6% (95%CI: 90.5% - 98.0%) and specificity of 61.5% (95%CI: 59.8% - 63.1%), whilst the triage algorithm including FebriDx had sensitivity of 92.6% (95%CI: 86.8% - 96.0%) and specificity of 86.4% (95%CI: 85.2% - 87.5%). The triage algorithm reduced the need for 2,859 patients to be admitted to isolation rooms. Ten patients missed by the algorithm had mild or asymptomatic COVID-19. ConclusionsA triage algorithm including FebriDx assay had good sensitivity and was useful to rule-out COVID-19 among medical admissions to hospital. STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIPragmatic study including a large cohort of consecutive medical admissions providing routine clinical care. C_LIO_LIA single SARS-CoV-2 RT-PCR is an imperfect reference standard for COVID-19. Multiple RT-PCR platforms used, with different PCR targets and performance. C_LIO_LIA higher prevalence of COVID-19 or other respiratory pathogens might alter performance. C_LIO_LICriteria for likely and possible COVID-19 groups changed subtly during the study period. C_LI

Diagnostic accuracy and utility of SARS-CoV-2 antigen lateral flow assays in medical admissions with possible COVID-19

We evaluated diagnostic accuracy of the Innova SARS-CoV-2 Antigen Rapid Qualitative Test compared to SARS-CoV-2 RT-PCR from nasopharyngeal swabs in adult admissions who met the COVID-19 case definition at a busy acute hospital in the UK. We found the Innova SARS-CoV-2 Antigen Rapid Qualitative Test had a good specificity in patients with symptoms of COVID-19 presenting to hospital. The Innova LFA can be used to rapidly identify COVID-19 cases amongst hospital admissions meeting the COVID-19 case definition, allowing patients to be allocated to COVID-19 cohort areas.

Capturing open ocean biodiversity: Comparing environmental DNA metabarcoding to the continuous plankton recorder.

Environmental DNA (eDNA) metabarcoding is emerging as a novel, objective tool for monitoring marine metazoan biodiversity. Zooplankton biodiversity in the vast open ocean is currently monitored through continuous plankton recorder (CPR) surveys, using ship-based bulk plankton sampling and morphological identification. We assessed whether eDNA metabarcoding (2 L filtered seawater) could capture similar Southern Ocean zooplankton biodiversity as conventional CPR bulk sampling (~1,500 L filtered seawater per CPR sample). We directly compared eDNA metabarcoding with (a) conventional morphological CPR sampling and (b) bulk DNA metabarcoding of CPR collected plankton (two transects for each comparison, 40 and 44 paired samples, respectively). A metazoan-targeted cytochrome c oxidase I (COI) marker was used to characterize species-level diversity. In the 2 L seawater eDNA samples, this marker amplified large amounts of non-metazoan picoplanktonic algae, but eDNA metabarcoding still detected up to 1.6 times more zooplankton species than morphologically analysed bulk CPR samples. COI metabarcoding of bulk DNA samples mostly avoided nonmetazoan amplifications and recovered more zooplankton species than eDNA metabarcoding. However, eDNA metabarcoding detected roughly two thirds of metazoan species and identified similar taxa contributing to community differentiation across the subtropical front separating transects. We observed a diurnal pattern in eDNA data for copepods which perform diel vertical migrations, indicating a surprisingly short temporal eDNA signal. Compared to COI, a eukaryote-targeted 18S ribosomal RNA marker detected a higher proportion, but lower diversity, of metazoans in eDNA. With refinement and standardization of methodology, eDNA metabarcoding could become an efficient tool for monitoring open ocean biodiversity.

FebriDx point-of-care test in patients with suspected COVID-19: a pooled diagnostic accuracy study

BackgroundWe conducted a systematic review and individual patient data (IPD) meta-analysis to evaluate the diagnostic accuracy of a commercial point-of-care test, the FebriDx lateral flow device (LFD), in adult patients with suspected COVID-19. The FebriDx LFD is designed to distinguish between viral and bacterial respiratory infection. MethodsWe searched MEDLINE, EMBASE, PubMed, Google Scholar, LitCovid, ClinicalTrials.gov and preprint servers on the 13th of January 2021 to identify studies reporting diagnostic accuracy of FebriDx (myxovirus resistance protein A component) versus real time reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 in adult patients suspected of COVID-19. IPD were sought from studies meeting the eligibility criteria. Studies were screened for risk of bias using the QUADAS-2 tool. A bivariate linear mixed model was fitted to the data to obtain a pooled estimate of sensitivity and specificity with 95% confidence intervals (95% CIs). A summary receiver operating characteristic (SROC) curve of the model was constructed. A sub-group analysis was performed by meta-regression using the same modelling approach to compare pooled estimates of sensitivity and specificity between patients with a symptom duration of 0 to 7 days and >7 days, and patients aged between 16 to 73 years and >73 years. ResultsTen studies were screened, and three studies with a total of 1481 patients receiving hospital care were included. FebriDx produced an estimated pooled sensitivity of 0.911 (95% CI: 0.855-0.946) and specificity of 0.868 (95% CI: 0.802-0.915) compared to RT-PCR. There were no significant differences between the sub-groups of 0 to 7 days and >7 days in estimated pooled sensitivity (p = 0.473) or specificity (p = 0.853). There were also no significant differences between the sub-groups of 16 to 73 years of age and >73 years of age in estimated pooled sensitivity (p = 0.946) or specificity (p = 0.486). ConclusionsBased on the results of three studies, the FebriDx LFD had high diagnostic accuracy for COVID-19 in a hospital setting, however, the pooled estimates of sensitivity and specificity should be interpreted with caution due to the small number of studies included, risk of bias, and inconsistent reference standards. Further research is required to confirm these findings, and determine how FebriDx would perform in different healthcare settings and patient populations. Trial registrationThis study was conducted at pace as part of the COVID-19 National Diagnostic Research and Evaluation Platform (CONDOR) national test evaluation programme (https://www.condor-platform.org), and as a result, no protocol was developed, and the study was not registered. Lay summaryTests to diagnose COVID-19 are crucial to help control the spread of the disease and to guide treatment. Over the last few months, tests have been developed to diagnose COVID-19 either by detecting the presence of the virus or by detecting specific markers linked to the virus being active in the body. These tests use complex machines in laboratories accepting samples from large geographical areas. Sometimes it takes days for test results to come back. So, to reduce the wait for results, new portable tests are being developed. These point-of-care (POC) tests are designed to work close to where patients require assessment and care such as hospital emergency departments, GP surgeries or care homes. For these new POC tests to be useful, they should ideally be as good as standard laboratory tests. In this study we looked at published research into a new test called FebriDx. FebriDx is a POC test that detects the bodys response to infection, and is claimed to be able to detect the presence of any viral infection, including infections due to the SARS-CoV-2 virus which causes COVID-19, as well as bacterial infections which can have similar symptoms. The FebriDx result was compared with standard laboratory tests for COVID-19 performed on the same patients throat and nose swab sample. We were able to analyse data from three studies with a total of 1481 adult patients who were receiving hospital care with symptoms of COVID-19 during the UK pandemic. Approximately one fifth of the patients were diagnosed as positive for SARS-CoV-2 virus using standard laboratory tests for COVID-19. Our analysis demonstrated that FebriDx correctly identified 91 out of 100 patients who had COVID-19 according to the standard laboratory test. FebriDx also correctly identified 87 out of 100 patients who did not have COVID-19 according to the standard laboratory test. These results have important implications for how these tests could be used. As there were slightly fewer FebriDx false results when the results of the standard laboratory test were positive (9 out of 100) than when the results of the standard laboratory test were negative (13 out of 100), we can have slightly more confidence in a positive test result using FebriDx than a negative FebriDx result. Overall, we have shown that the FebriDx POC test performed well during the UK COVID-19 pandemic when compared with laboratory tests, especially when COVID-19 was indicated. For the future, this means that the FebriDx POC test might be helpful in making a quick clinical decision on whether to isolate a patient with COVID-19-like symptoms arriving in a busy emergency department. However, our results indicate it would not completely replace the need to conduct a laboratory test in certain cases to confirm COVID-19. There are limitations to our findings. For example, we do not know if FebriDx will work in a similar way with patients in different settings such as in the community or care homes. Similarly, we do not know whether other viral and bacterial infections which cause similar COVID-19 symptoms, and are more common in the autumn and winter months, could influence the FebriDx test accuracy. Our findings are also only based on three studies.

In Situ Vibrational Probes of Epoxy Gelation.

This paper presents an efficient way to measure the curing kinetics and gel point, αgel, in epoxy resins from one single experiment. The epoxy curing reaction is herein monitored using in situ and time-resolved near-infrared absorption spectroscopy (NIR). The curing profiles over different isothermal conditions are in good agreement with DSC. Furthermore, the increase of the NIR absorption bands of aromatic rings (unreactive throughout curing) probe the cure shrinkage, as more and more aromatic rings are localized within the fixed sample volume. Therefore, the gel point is determined using the onset of the aromatic absorption increase. The results are in good agreement with the theoretical gel point, as well as DMA results. This innovative approach enables gelation measurements on epoxy neat resins and film composites with an easy-to-perform, accurate, robust, and versatile method.

Diurnally Fluctuating pCO2 Modifies the Physiological Responses of Coral Recruits Under Ocean Acidification.

Diurnal pCO2 fluctuations have the potential to modulate the biological impact of ocean acidification (OA) on reef calcifiers, yet little is known about the physiological and biochemical responses of scleractinian corals to fluctuating carbonate chemistry under OA. Here, we exposed newly settled Pocillopora damicornis for 7 days to ambient pCO2, steady and elevated pCO2 (stable OA) and diurnally fluctuating pCO2 under future OA scenario (fluctuating OA). We measured the photo-physiology, growth (lateral growth, budding and calcification), oxidative stress and activities of carbonic anhydrase (CA), Ca-ATPase and Mg-ATPase. Results showed that while OA enhanced the photochemical performance of in hospite symbionts, it also increased catalase activity and lipid peroxidation. Furthermore, both OA treatments altered the activities of host and symbiont CA, suggesting functional changes in the uptake of dissolved inorganic carbon (DIC) for photosynthesis and calcification. Most importantly, only the fluctuating OA treatment resulted in a slight drop in calcification with concurrent up-regulation of Ca-ATPase and Mg-ATPase, implying increased energy expenditure on calcification. Consequently, asexual budding rates decreased by 50% under fluctuating OA. These results suggest that diel pCO2 oscillations could modify the physiological responses and potentially alter the energy budget of coral recruits under future OA, and that fluctuating OA is more energetically expensive for the maintenance of coral recruits than stable OA.

Effect of genetic deletion or pharmacological antagonism of tumor necrosis factor alpha on colitis-associated carcinogenesis in mice.

BACKGROUND: Intestinal inflammation in inflammatory bowel diseases is driven by abnormal levels of proinflammatory cytokines, where tumor necrosis factor (TNF)-α seems to be particularly important. Chronic inflammatory signaling in the colon increases the risk of colorectal cancer, so we sought to evaluate the role of TNF-α in a mouse model of this condition. METHODS: TNF mice were treated with azoxymethane/dextran sulfate sodium to induce inflammation and tumorigenesis. Etanercept was used to produce pharmacological ablation of TNF-α in wild-type mice. Subsequent activation of procarcinogenic transcription factor NF-κB and relevant proinflammatory cytokines of the TNF superfamily were measured through immunohistochemistry and quantitative polymerase chain reaction methods. RESULTS: Results showed that the severity of colitis, as assessed by mortality, histological scoring, and cytokine expression levels, was similar or slightly higher in mice lacking TNF-α than in control mice. Activation levels of NF-κB were not influenced by the presence of TNF-α. We also observed upregulated expression of TNF family member TNF-ß, TNF receptors 1 and 2 and a variety of other proinflammatory factors in colitis-associated tumors of TNF mice, compared with levels in tumors of control mice. Neither genetic ablation of TNF-α nor pharmacological inhibition of the TNF family using etanercept reduced tumor number. CONCLUSIONS: Our results reveal a redundant role for TNF-α in a mouse model of colitis-associated tumorigenesis, indicating a high degree of redundancy in proinflammatory cytokine networks in this model.

Clinical features, treatment, and survival of patients with colorectal cancer with or without inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) increases the risk of colorectal cancer (CRC), indicating that inflammation might alter tumor characteristics and potentially affect treatment and survival. Published data on this topic are inconclusive, so we conducted a population-based study in Ireland to address it. METHODS: We used the National Cancer Registry to collect data on all patients diagnosed with CRC in Ireland from 1994 to 2005 (n = 22,335) and identified those who also had IBD (n = 170). The clinical characteristics, treatment, and survival of patients with IBD and CRC were compared with those of patients with CRC without IBD. RESULTS: Patients with CRC and IBD were, on average, 7.7 years younger than those without IBD at diagnosis of CRC (P = .001), and were less likely to smoke (P = .002). Fewer CRCs in patients with IBD were stage 4 at diagnosis (12% vs 22% in non-IBD patients; P < .001). There was no significant difference in CRC treatment modalities between patients with or without IBD (P = .57). The median survival time of CRC patients with IBD was about 3 years longer than that of patients without IBD (P < .001). However, Cox proportional hazards analysis revealed that IBD was not a significant prognostic factor for CRC (P = .97). However, older age, male sex, smoking, and advanced grade and stage all were associated independently with shorter survival time. When propensity score matching was used to analyze outcomes, the survival times of CRC patients with and without IBD did not differ significantly. CONCLUSIONS: The features of patients with CRC and IBD differ significantly from those of CRC patients without IBD, but each group of patients receive similar treatment and have similar patterns of disease progression after diagnosis.

How to manage the risk of colorectal cancer in ulcerative colitis.

There is a strong association between chronic inflammation and cancer formation. This correlation has been well observed in patients with long standing inflammatory bowel disease (IBD) who are at high risk of colorectal cancer (CRC). At present, there is a lack of good markers for predicting the progression from normal to neoplastic mucosa in patients with IBD. IBD patients who are 'at-risk' of CRC should be identified, evaluated and should also be enrolled in surveillance program, regardless of their disease activity. Early identification of dysplasia and its appropriate management using endoscopic techniques or surgery are essential in patients with long-standing IBD, to minimize CRC morbidity and mortality. Gastroenterologists should work along with experienced, specialised gastrointestinal pathologists, surgeons and with fully informed and compliant IBD patients' to ensure the success of surveillance programme in early detection of CRC.

Regulation of NF-kappaB responses by epigenetic suppression of IkappaBalpha expression in HCT116 intestinal epithelial cells.

Intestinal epithelial cells play critical roles in regulating mucosal immunity. Since epigenetic factors such as DNA methylation and histone modifications are implicated in aging, carcinogenesis, and immunity, we set out to assess any role for epigenetic factors in the regulation of intestinal epithelial cell immune responses. Experiments were conducted using the HCT116 cell line, and a subclone was genetically engineered to lack DNA methyltransferases (DNMT). The induction of the chemokine interleukin-8 and the antiapoptotic protein cFLIP by tumor necrosis factor-alpha were markedly less in HCT116 cells lacking DNMT than in parental cells. These effects were accompanied by lower monocyte chemotaxis and higher caspase signaling in HCT116 cells lacking DNMT than parental cells. Tumor necrosis factor-alpha-induced NF-kappaB activation was blocked and IkappaBalpha expression was higher in HCT116 cells lacking DNMT than in parental cells. A CpG island in the IkappaBalpha gene promoter region was found to contain variable levels of methylation in parental HCT116 cells. Chromatin immunoprecipitation analysis of histone proteins bound to the IkappaBalpha gene promoter revealed that higher levels of IkappaBalpha expression in HCT116 cells lacking DNMT compared with parental cells were accompanied by more chromatin marks permissive to gene transcription. These findings show that epigenetic factors influence the NF-kappaB system in intestinal epithelial cells, resulting in a previously unrecognized mechanism of innate immune regulation.

A new model to monitor the virological efficacy of antiretroviral treatment in resource-poor countries.

Monitoring the efficacy of antiretroviral treatment in developing countries is difficult because these countries have few laboratory facilities to test viral load and drug resistance. Those that exist are faced with a shortage of trained staff, unreliable electricity supply, and costly reagents. Not only that, but most HIV patients in resource-poor countries do not have access to such testing. We propose a new model for monitoring antiretroviral treatment in resource-limited settings that uses patients' clinical and treatment history, adherence to treatment, and laboratory indices such as haemoglobin level and total lymphocyte count to identify virological treatment failure, and offers patients future treatment options. We believe that this model can make an accurate diagnosis of treatment failure in most patients. However, operational research is needed to assess whether this strategy works in practice.

First-line antiretroviral therapy in Africa--how evidence-base are our recommendations?

According to the World Health Organization guidelines, a non-nucleoside reverse transcriptase inhibitor (NNRTI) along with two nucleoside reverse transcriptase inhibitors (NRTI) is the treatment of choice as first-line antiretroviral therapy. The results of the 2NN and different cohort studies performed in developed countries do not provide sufficient evidence by which to select between nevirapine and efavirenz as the first-line NNRTI for antiretroviral therapy in Africa. The current first-line NNRTI-containing antiretroviral therapy regimens used in Africa are certainly not ideal. Nevirapine interacts with rifampicin and therefore is not indicated in patients with tuberculosis. On the other hand, efavirenz should not be given to pregnant women. NNRTI-containing regimens may be less effective in women who received nevirapine monotherapy at delivery. Stavudine, used in the nucleoside backbone, may lead to lipoatrophy, lactic acidosis and polyneuritis. Zidovudine may cause serious anemia. Mainly because of cost considerations, the generic fixed-drug combination of nevirapine plus two NRTI seems at the moment to be the best choice. It is clear, however, that antiretroviral programs should not rely only on this combination for initial antiretroviral treatment. Most importantly, more HIV clinical trials need to be conducted in Africa, and African cohorts of patients on antiretroviral therapy need to be established in order to develop recommendations that are evidence based.

Stricter ozone ambient air quality standard has beneficial effect on ponderosa pine in California.

Ambient air quality standards and control strategies are implemented to protect humans and vegetation from adverse effects. We used a process-based tree-growth model (TREGRO) to show that over the past 37 years, changes in O(3) exposure, with accompanying variation in climate, are reflected in changes in the growth of Pinus ponderosa Dougl. ex Laws. in the San Bernardino Mountains near Los Angeles, California, USA. Despite variation in temperature and precipitation over the study period (1963-1999), O(3) exposure consistently reduced simulated tree growth. Simulated growth reductions increased concurrent with increasing O(3) exposure. The maximum growth reduction occurred in 1979. As O(3) exposures decreased during the 1980s and 1990s, effects on growth also decreased. This implies that emission control strategies taken to reduce exposures to attain O(3) standards benefited P. ponderosa growth in the San Bernardino Mountains. This modeling approach provides a powerful tool for solving the difficult problem of evaluating regulatory effectiveness by simulating plant response using long-term climate and air pollution exposure records for a given region.

Ozone and natural systems: understanding exposure, response, and risk.

Research aimed at understanding the response of plants to ozone has been conducted for over four decades but little of it has addressed intact natural systems. Even so, there is sufficient scientific information at this time to support air quality standards that will protect natural terrestrial ecosystems from ozone. What is unknown is the risk associated with continued exposure of natural systems, including both above- and below-ground components, in combination with other stresses including changing temperature and precipitation, elevated carbon dioxide, pests and pathogens, invasive species, and other activities that may fragment the landscape. Research to support an assessment of the ecological risk associated with ozone as it exists, in a milieu of stresses, must include endpoints beyond those addressed in the past, primarily productivity and species composition. To estimate the risk to society of ozone impacts on natural systems, endpoints such as the integrity of soil food webs, the quantity and quality of water supplied from terrestrial ecosystems, wildlife and recreational values, and the transfer and fate of carbon, nutrients, and water within the systems must be quantified. Not only will this research provide the basis for a sound estimate of risk, but also it will improve our understanding of fundamental ecosystem processes.