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MeSH Disease


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    Th1 Dominant Nucleocapsid and Spike Antigen-Specific CD4+ and CD8+ Memory T Cell Recall MESHD Recall SERO Induced by hAd5 S-Fusion + N-ETSD Infection of Autologous Dendritic Cells from Patients Previously Infected with SARS-CoV-2

    Authors: Peter Sieling; Lise Zakin; Annie Shin; Brett Morimoto; Helty Adisetiyo; Hermes Garban; Philip Liu; Adrian Rice; Justin Taft; Roosheel Patel; Sofija Buta; Marta Martin-Fernandez; Dusan Bogunovic; Elizabeth Gabitzsch; Jeffrey T. Safrit; Lennie Sender; Patricia Spilman; Shahrooz Rabizadeh; Kayvan Niazi; Patrick Soon-Shiong; Marina Botto; Michelle Willicombe; David C Thomas; James E. Peters; Benny Chain; Mahdad Noursadeghi; James C Moon

    doi:10.1101/2020.11.04.20225417 Date: 2020-11-06 Source: medRxiv

    To address the need for a safe, efficacious vaccine against SARS-CoV-2 infection MESHD with the critical properties of enabling both blocking viral entry into cells and clearing virus from cells already infected, we have developed a bivalent, human adenovirus serotype 5 (hAd5) SARS-CoV-2 S MESHD-Fusion + N-ETSD vaccine that is currently in clinical testing. This vaccine uses the next-generation hAd5 [E1-, E2b-, E3-] platform previously used successfully in cancer MESHD patients with pre-existing adenovirus immunity, engineered to express both SARS-CoV-2 spike MESHD (S) protein modified to improve the generation of neutralizing antibodies SERO to block entry of the virus, and nucleocapsid (N) protein with an Enhanced T cell Stimulation Domain (ETSD) to activate CD4+ and CD8+ T cells to clear the virus and block replication by killing infected cells. The targeting of N to endosomes and lysosomes to enhance CD4+ and CD8+ T-cell responses distinguishes our vaccine. In our previously reported pre-clinical studies we showed that in mice, the hAd5 S-Fusion + N-ETSD vaccine elicits both humoral and T-cell responses that are robust and T helper cell 1 (Th1) dominant. Here we report that the hAd5 S-Fusion + N-ETSD vaccine is recognized by anti-sera and T cells from previously SARS-CoV-2 infected MESHD patients, and that the presence of N is vital for T-cell recall SERO. The findings presented herein: i. demonstrate specific recognition of hAd5 S-Fusion + N-ETSD infected MESHD cells by plasma SERO antibodies SERO from previously SARS-CoV-2 infected MESHD patients, but not antibodies SERO from virus-naive subjects; ii. show enhanced binding of plasma SERO SARS-CoV-2 antibodies SERO from previously infected MESHD patients to monocyte-derived dendritic cells (MoDCs) expressing the hAd5 S-Fusion + N-ETSD vaccine as compared to hAd5 S-Fusion alone; iii. reveal N-ETSD localizes to vesicles associated with MHC class II antigen presentation, including endosomes, lysosomes, and autophagosomes in MoDCs; iv. demonstrate endosome/lysosome-targeted N-ETSD elicits higher interferon-gamma T-cell responses than cytoplasm-localized N; and v. N-ETSD alone or in the hAd5 S-Fusion + N-ETSD construct induces both CD4+ and CD8+ T cell memory recall MESHD recall SERO. This recognition of hAd5 S-Fusion + N-ETSD vaccine antigens by T cells from previously SARS-CoV-2 infected MESHD patients, together with the ability of this vaccine candidate to elicit de novo immune responses in naive mice suggests that it re-capitulates the natural immune response to SARS-CoV-2 to activate both B and T cells towards viral neutralization and recognition of infected cells, critical for prevention of COVID-19 MESHD disease. Intriguingly, our hAd5 S-Fusion + N-ETSD T-cell biased vaccine has the potential to not only provide protection for uninfected individuals, but also to be utilized as a therapeutic for already infected MESHD patients to induce rapid clearance of the virus by activating T cells to kill the virus-infected cells, thereby reducing viral replication and lateral transmission TRANS.

    Development and Validation of Early Warning Score Systems for COVID-19 MESHD Patients

    Authors: Alexey Youssef; Samaneh Kouchaki; Farah Shamout; Jacob Armstrong; Rasheed El-Bouri; Thomas Taylor; Drew Birrenkott; Baptiste Vasey; Andrew Soltan; Tingting Zhu; David A Clifton; David W Eyre; Joseph M Gibbons; Wing Yiu J Lee; Meleri Jones; Dylan M Williams; Jonathan Lambourne; Marianna Fontana; - COVIDsortium Investigators; Daniel M Altmann; Rosemary Boyton; Mala K Maini; Aine McKnight; Timothy Brooks; Benny Chain; Mahdad Noursadeghi; James C Moon

    doi:10.1101/2020.11.04.20225904 Date: 2020-11-06 Source: medRxiv

    COVID-19 MESHD is a major, urgent, and ongoing threat to global health. Globally more than 24 million have been infected and the disease MESHD has claimed more than a million lives as of October 2020. Predicting which patients will need respiratory support is important to guiding individual patient treatment and also to ensuring sufficient resources are available. We evaluated the ability of six common Early Warning Scores (EWS) to identify respiratory deterioration MESHD defined as the need for advanced respiratory support (high-flow nasal oxygen, continuous positive airways pressure, non-invasive ventilation, intubation) within a prediction window of 24 hours. We show these scores perform sub-optimally at this specific task. Therefore, we develop an alternative Early Warning Score based on a Gradient Boosting Trees (GBT) algorithm that is able to predict deterioration within the next 24 hours with high AUROC 94% and an accuracy, sensitivity SERO and specificity of 70%, 96%, 70%, respectively. Our GBT model outperformed the best EWS (LDTEWS:NEWS), increasing the AUROC by 14%. Our GBT model makes the prediction based on the current and baseline measures of routinely available vital signs and blood SERO tests.

    Real-life performances SERO of a novel antigen detection test on nasopharyngeal specimens for SARS-CoV-2 infection MESHD diagnosis: a prospective study

    Authors: Laura Courtellemont; jerome Guinard; Clemence Guillaume; Susanna Giache; Vincent Rzepecki; Aymeric Seve; Camelia Gubavu; Kim Baud; Heidi Doize; Claire Le Helloco; Clemence Lebegue; Elom A Tay; Guy Cassuto; Gilles Pialoux; Laurent Hocqueloux; thierry prazuck

    doi:10.1101/2020.10.28.20220657 Date: 2020-11-03 Source: medRxiv

    Introduction The SARS-CoV-2 pandemic has become a major public health issue worldwide. Developing and evaluating rapid and easy-to-perform diagnostic tests is an absolute priority. The current prospective study was designed to assess diagnostic performances SERO of an antigen-based rapid detection test (COVID-VIRO) in a real-life setting. Methods Two nasopharyngeal specimens of symptomatic or asymptomatic TRANS adult TRANS patients hospitalized in the Infectious Diseases Department or voluntarily accessing the COVID-19 MESHD Screening Department of the Regional Hospital of Orleans, France, were concurrently collected. COVID VIRO diagnostic specificity and sensitivity SERO were assessed in comparison to real-time reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) results. A subgroup of patients underwent an additional oropharyngeal and/or a saliva swab for rapid testing SERO. Results 121 patients already having a confirmed infection TRANS and 127 patients having no evidence of recent or ongoing infection MESHD were enrolled, for a total of 248 couple of nasopharyngeal swab specimens. Overall COVID-VIRO sensitivity SERO was 96.7% (IC: 93.5%-99.9%). In asymptomatic TRANS patients, patients having symptoms for more than 4 days and those having a RT-qPCR Cycle threshold value >32, sensitivity SERO was of 100%, 95.8% and 96.9% respectively. The concordance between RT-qPCR and COVID VIRO rapid test SERO was 100% for the 127 patients with no SARS-CoV-2 infection MESHD. Conclusion COVID-VIRO test had 100% specificity and above 95% sensitivity SERO, better than WHO recommendations (specificity [≥]97-100%, sensitivity SERO [≥]80%). These rapid tests SERO are particularly interesting for large-scale screening in Emergency Department, low resource settings and airports.

    Using Automated-Machine Learning to Predict COVID-19 MESHD Patient Survival: Identify Influential Biomarkers

    Authors: Kenji Ikemura; Doctor Y Goldstein; James Szymanski; Eran Bellin; Lindsay Stahl; Yukako Yagi; Mahmoud Saada; Katelyn Simone; Morayma Reyes Gil; Catherine Biggs; Carl Marincowitz; Jose Schutter; Sarah Connelly; Elena Sheldon; Jamie Hall; Emma Young; Andrew Bentley; Kirsty Challen; Chris Fitzsimmons; Tim Harris; Fiona Lecky; Andrew Lee; Ian Maconochie; Darren Walter

    doi:10.1101/2020.10.12.20211086 Date: 2020-10-14 Source: medRxiv

    Background: In a pandemic, it is important for clinicians to stratify patients and decide who receives limited medical resources. In this study, we used automated machine learning (autoML) to develop and compare between multiple machine learning ( ML MESHD) models that predict the chance of patient survival from COVID-19 MESHD infection and identified the best-performing model. In addition, we investigated which biomarkers are the most influential in generating an accurate model. We believe an ML model such as this could be a useful tool for clinicians stratifying hospitalized SARS-CoV-2 patients. Methods: The data was retrospectively collected from Clinical Looking Glass (CLG) on all patients testing positive for COVID-19 MESHD through a nasopharyngeal specimen by real-time RT-PCR and admitted between 3/1/2020-7/3/2020 (4376 patients) at our institution. We collected 47 biomarkers from each patient within 36 hours before or after the index time: RT-PCR positivity, and tracked whether a patient survived or not for one month following this time. We utilized the autoML from, an open source package for R language. The autoML generated 20 ML models and ranked them by area under the precision- recall SERO curve (AUCPR) on the test set. We selected the best model (model_var_47) and chose a threshold probability that maximized F2 score to make a binary classifier: dead or alive. Subsequently, we ranked the relative importance of variables that generated model_var_47 and chose the 10 most influential variables. Next, we reran the autoML with these 10 variables and likewise selected the model with the best AUCPR on the test set (model_var_10). Again, threshold probability that maximized F2 score for model_var_10 was chosen to make a binary classifier. We calculated and compared the sensitivity SERO, specificity, and positive predicate value (PPV) for model_var_10 and model_var_47. Results: The best model that autoML generated using all 47 variables was the stacked ensemble model of all models (AUCPR = 0.836). The most influential variables were: systolic and diastolic blood SERO pressure, age TRANS, respiratory rate, pulse oximetry, blood SERO urea nitrogen, lactate dehydrogenase, d-dimer, troponin, and glucose. When the autoML was retrained with these 10 most important variables, it did not significantly affect the performance SERO (AUCPR= 0.828). For the binary classifiers, sensitivity SERO, specificity, and PPV of model_var_47 was 83.6%, 87.7%, and 69.8% respectively, while for model_var_10 they were 90.9%, 71.1%, and 51.8% respectively. Conclusions: By using autoML, we developed high-performing models that predict patient mortality from COVID-19 MESHD infection. In addition, we identified the most important biomarkers correlated with mortality. This ML model can be used as a decision supporting tool for medical practitioners to efficiently triage COVID-19 MESHD infected MESHD patients. From our literature review, this will be the largest COVID-19 MESHD patient cohort to train ML models and the first to utilize autoML. The COVID-19 MESHD survival calculator based on this study can be found at Keywords: Automated machine learning; COVID-19 MESHD; Biomarkers; Ranking; Decision support tool. Corresponding author: Kenji Ikemura (

    Sero- prevalence SERO of anti- SARS-CoV-2 Antibodies SERO in Addis Ababa, Ethiopia

    Authors: Berhanu Nega; Adamu Addissie; Gemechis Mamo; Negussie Deyessa; Tamrat Abebe; Abdulnasir Abagero; Wondimu Ayele; Workeabeba Abebe; Tewodros Haile; Rahel Argaw; Wondwossen Amogne; Ayele Belachew; Zelalem Desalegn; Brhanu Teka; Eva Kantelhardt; Mesfin Wossen; Saro Abdella; Getachew Tollera; Lia Tadesse; Shaun Pennington; Giancarlo Biagini; Andrew Owen; Julian Alexander Hiscox; James P Stewart; Jinghe Huang; Auke C Reidinga; Daisy Rusch; Kim CE Sigaloff; Renee A Douma; Lianne de Haan; Egill A Fridgeirsson; Niels C Gritters van de Oever; Roger JMW Rennenberg; Guido van Wingen; Marcel JH Aries; Martijn Beudel

    doi:10.1101/2020.10.13.337287 Date: 2020-10-13 Source: bioRxiv

    Background: Anti- SARS-CoV-2 antibody SERO tests are being increasingly used for sero-epidemiological purposes to provide better understanding of the extent of the infection in the community, and monitoring the progression of the COVID-19 MESHD epidemic. We conducted sero- prevalence SERO study to estimate prior infection with with SARS-CoV-2 in Addis Ababa. Methods: A cross-sectional study was done from April 23 to 28, 2020 among 301 randomly selected residents of Addis Ababa; with no known history of contact with confirmed COVID-19 MESHD person. Interviews on socio demographic and behavioural risk factor followed by serological tests SERO were performed for SARS-CoV-2 IgM, and IgG antibodies SERO, using COVID-19 MESHD IgG/IgM Rapid Test SERO Cassette. The test has sensitivity SERO of 87{middle dot}9% and specificity of 100% for lgM; and a sensitivity SERO of 97{middle dot}2% and specificity of 100% for IgG. RT-PCR test was also done on combined nasopharyngeal and oropharengeal swabs as an important public health consideration. Findings: The unadjusted antibody SERO-based crude SARS-CoV-2 prevalence SERO was 7{middle dot}6% and the adjusted true SARS-CoV-2 prevalence SERO was estimated at 8{middle dot}8% (95% CI 5{middle dot}5%-11{middle dot}6%) for the study population. Higher sero- prevalence SERO were observed for males TRANS (9.0%), age TRANS below 50 years (8.2%), students and unemployed (15.6%), those with primary education (12.1%), smokers (7.8%), alcohol consumers (8.6%), chatt-chewers (13.6%) and shish smokers (18.8%). Seroprevalence SERO was not significantly associated neither with socio-demographic not behavioral characteristics. According to the findings, possibly more individuals had been infected in Addis Ababa MESHD than what was being detected and reported by RT-PCR test suggestive of community transmission TRANS. The use of serological test SERO for epidemiological estimation of the extent of SARS-CoV-2 epidemic MESHD gives a more precise estimate of magnitude which would be used for further monitoring and surveillance of the magnitude of the SARS CoV-2 infection MESHD.

    Experience of Clinical Screening for Elective Orthopedic Surgery in The Midst of The COVID-19 MESHD Pandemic: An Alternative Proposal.

    Authors: Edwarth Soler Peña; Sammy Nicolas Farah Amin; Valeria Patricia Bustos; Sofia Elizabeth Muñoz; Ernesto Martinez; Jairo Fernando Gomez; Carlos Álvarez Moreno

    doi:10.21203/ Date: 2020-10-13 Source: ResearchSquare

    Background:  The COVID-19 MESHD ( Coronavirus disease 2019 MESHD) pandemic is the largest global event of recent times, leaving millions infected MESHD and hundreds of thousands of dead worldwide. Colombia is no stranger to this situation, being subject to massive cancellations of medically necessary surgical procedures categorized as ¨non vital¨. The objective of this study is to show the results of a program of elective essential and non-essential low and medium complexity orthopedic surgeries performed during the mitigation phase of the COVID-19 MESHD pandemic with a pre-surgical clinical protocol, without serological or molecular testing, during April, 2020 in two institutions in Bogotá, Colombia. Methodology​ :​ A multicenter, observational, retrospective, descriptive study of a cohort of patients who underwent elective orthopedic surgery at two institutions in the city of Bogota, Colombia, during April 2020. We performed a preoperative clinical protocol without including serological or molecular tests, an epidemiological survey, describing the type of surgery, their score in the MeNTs (medically necessary time sensitive) scale, and the presence of suggestive symptoms of COVID-19 MESHD postoperatively. Results​ :​ A total of 179 patients underwent orthopedic surgery with an average age TRANS of 47 years (swilk= 0.021) (Shapiro-Wilk) ranging between 18 and 81 years, with a majority of females TRANS (61.5%). As for the surgeries, 86 (48%) were knee operations, 42 (23.5%) hand surgeries, 34 (19%) shoulder surgeries, and 17 (9.5%) foot and ankle surgeries. The average MeNTS of all patients was 44.6 points. During the two weeks after surgery, four patients were considered suspects for COVID-19 MESHD for presenting at least two symptoms associated with the disease representing an incidence of 2.3%. Two (1.1%) of these four patients consulted an emergency department where RT-PCR(reverse transcription polymerase chain reaction) type tests were performed, obtaining a negative result for SARSCov-2 MESHD (severe acute respiratory syndrome Coronavirus-2 MESHD). No patients died or were hospitalized for symptoms associated with COVID-19 MESHD. Conclusion​ :​ Through the implementation of a pre-surgical clinical protocol (physical examination, clinical survey inquiring about signs, symptoms and epidemiological contacts), a pre-surgical isolation and without the performance SERO of molecular or serological diagnostic tests, the present study showed good results in the performance SERO of low and medium complexity elective orthopedic surgery at an early stage of the COVID-19 MESHD pandemic. Level of evidence​ :​ IV. 

    Analysis of external quality assessment samples revealed crucial performance SERO differences between commercial RT-PCR assays for SARS-CoV-2 detection when taking extraction methods and real-time-PCR instruments into account

    Authors: Monika Malecki; Jessica Luesebrink; Andreas Wendel; Frauke Mattner; Gert-Jan Godeke; Sabine Yerly; Marieke Hoogerwerf; Nicolas Vuilleumier; Laurent Kaiser; Isabella Eckerle; Chantal Reusken; Peter Gaal; Lisa M Schilling; Spencer SooHoo; Hua Xu; Kai Zheng; Lucila Ohno-Machado; - R2D2 Consortium; Amir Mehrkar; Helen J Curtis; Nicholas J DeVito; Richard Croker; Henry Drysdale; Jonathan Cockburn; John Parry; Frank Hester; Sam Harper; Ian J Douglas; Laurie Tomlinson; Stephen Evans; Richard Grieve; David Harrison; Kathy Rowan; Kamlesh Khunti; Nish Chaturvedi; Liam Smeeth; Ben Goldacre; Ana P M Fernandes; Isabel K F M Santos; Vania L D Bonato; Marcelo Dias-Baruffi; Adriana Malheiro; Ruxana T Sadikot; Cristina R B Cardoso; Lucia H Faccioli; Carlos A Sorgi

    doi:10.1101/2020.09.18.20185744 Date: 2020-09-23 Source: medRxiv

    In limelight of the ongoing pandemic SARS-CoV-2 testing is critical for the diagnosis of infected MESHD patients, contact-tracing TRANS and mitigating the transmission TRANS. Diagnostic laboratories are expected to provide appropriate testing with maximum accuracy. Real-time reverse transcriptase PCR (RT-PCR) is the diagnostic standard yet many commercial diagnostic kits have become available. However, only a handful of studies have reviewed their performance SERO in clinical settings. The aim of this study was to compare the performance SERO of the overall analytical matrix including the extraction kit (BD MAX, Promega, Qiagen), the PCR instrument (Agilent Mx3005P, BD MAX, Qiagen Rotor-Gene, Roche Cobas z 480) and the RT-PCR assay (Altona Diagnostics, CerTest Biotec, R-Biopharm AG) using predefined samples from proficiency testing organizers. The greatest difference of the Ct values between the matrices was 9 cycles. One borderline sample could not be detected by 3 out of 12 analytical matrices and yielded a false negative result. We therefore conclude that diagnostic laboratories should take the complete analytical matrix in addition to the performance SERO values published by the manufacturer for a respective RT-PCR kit into account. With limited resources laboratories have to validate a wide range of kits to determine appropriate analytical matrices for detecting SARS-CoV-2 reliably. The interpretation of clinical results has to be adapted accordingly.

    Disinfection and sterilization methods to reuse face masks and respirators: A systematic review

    Authors: Kirellos Said Abbas; Ngoc Mai Luu; Dao Ngoc Hien Tam; Abdelrahman Gad; Reham Reda; Basant Lashin; Khadiga Nour; Fatmaelzahraa Yasser Ali; Atef Khairy Sharaf; Ranjit Tiwari; Abdelwahap Salem Khalifa Elghezewi; Vinh Dong; Nguyen Tien Huy

    doi:10.21203/ Date: 2020-09-10 Source: ResearchSquare

    Background: In the context of COVID-19 MESHD pandemic, mask, or respirator wearing is considered one of the essential protection measures for healthcare workers to deal with infected MESHD patients. As the demand for face masks strongly increases during the pandemic leading to their shortages, our study aimed to review the current decontamination methods to reuse masks and respirators. Method: On May 18th, 2020, a systematic search for articles reported the methods of disinfection and sterilization for reusing surgical masks or respirators was conducted in eight electronic databases including PubMed, Scopus, Web of Science (ISI), Google Scholar, Cochrane, WHO Global Health Library (GHL), Clinicaltrials and Virtual Health Library (VHL). Manual search was further performed by screening references of included articles and relevant reviews and their related articles in PubMed and Google Scholar. We excluded unreliable extracted data, non-original or secondary research, not available full texts or abstract only. Results: There were 52 articles included in the qualitative synthesis. While hydrogen peroxide gas plasma SERO (HPGP) (59%) degraded the mask filtration performance SERO, vapor hydrogen peroxide (VHP) at varying concentrations and ethylene oxide (EtO) did not affect this. Moist heat incubation (MHI) (at 65 ± 5°C for 20 minutes) and microwave generated steam (MGS) (2 -3 minutes) caused > 4 log reduction of the H5N1 virus and did not degrade the mask filtration performance SERO, while autoclave (at 121°C, 103 kPas) strongly affected this. The mask filtration efficacy was significantly reduced by ethanol 70% but recovered to 86% after the recharge process. Ultraviolet germicidal irradiation (UVGI) (4.32 – 7.2 J/cm2) showed good biocidal efficacy and no degradation of filtration performance SERO but had a poor effect with a dose of 3J/cm2 and degraded the mask with a dose of 18 J/cm2. Conclusion: MHI and UVGI could be highly recommended decontamination methods for reusing masks. VHP could be considered but less effective due to the possible degradation in physical appearances. 

    Rapid 'mix and read' assay for scalable detection of SARS-CoV-2 antibodies SERO in patient plasma SERO

    Authors: Hong Yue; Radosław P Nowak; Daan Overwijn; N Connor Payne; Stephanie Fischinger; Caroline Atyeo; Lindsey R Baden; Eric James Nilles; Elizabeth W Karlson; Xu G Yu; Jonathan Z Li; Galit Alter; Ralph Mazitschek; Eric S Fischer; Caroline Marshall; Brenda Clemente; Jerel Vega; Scott Roberts; Jose A. Gonzalez; Marciano Sablad; Rodrigo Yelin; Wendy Taylor; Kiyoshi Tachikawa; Suezanne Parker; Priya Karmali; Jared Davis; Sean M Sullivan; Steve G. Hughes; Pad Chivukula; Eng Eong Ooi

    doi:10.1101/2020.09.01.20184101 Date: 2020-09-03 Source: medRxiv

    The human beta coronavirus SARS-CoV-2, causative virus of COVID-19 MESHD, has infected more than 15 million people globally and continues to spread. Widespread, population level testing to detect active and past infections is critical to curb the COVID-19 MESHD pandemic. Antibody SERO ( serological) testing SERO is the only option for detecting past infections outside the narrow window accessible to nucleic acid-based tests. However, currently available serological assays SERO commonly lack scalability. Here, we describe the development of a rapid homogenous serological assay SERO for the detection of antibodies to SARS-CoV-2 SERO in patient plasma SERO. We show that the fluorescence-based assay accurately detects seroconversion in COVID-19 MESHD patients from less than 1 microliter of plasma SERO. Using a cohort of samples from COVID-19 MESHD infected MESHD or healthy individuals, we demonstrate detection with 100% sensitivity SERO and specificity. This assay addresses an important need for a robust, low barrier to implementation, and scalable serological assay SERO with complementary strengths to currently available serological platforms.

    Real-time Prediction of COVID-19 MESHD related Mortality using Electronic Health Records

    Authors: Patrick Schwab; Arash Mehrjou; Sonali Parbhoo; Leo Anthony Celi; Jürgen Hetzel; Markus Hofer; Bernhard Schölkopf; Stefan Bauer

    id:2008.13412v1 Date: 2020-08-31 Source: arXiv

    Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) is an emerging respiratory disease MESHD caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with rapid human-to-human transmission TRANS and a high case fatality rate particularly in older patients. Due to the exponential growth of infections, many healthcare systems across the world are under pressure to care for increasing amounts of at-risk patients. Given the high number of infected MESHD patients, identifying patients with the highest mortality risk early is critical to enable effective intervention and optimal prioritisation of care. Here, we present the COVID-19 MESHD Early Warning System (CovEWS), a clinical risk scoring system for assessing COVID-19 MESHD related mortality risk. CovEWS provides continuous real-time risk scores for individual patients with clinically meaningful predictive performance SERO up to 192 hours (8 days) in advance, and is automatically derived from patients' electronic health records (EHRs) using machine learning. We trained and evaluated CovEWS using de-identified data from a cohort of 66430 COVID-19 MESHD positive patients seen at over 69 healthcare institutions in the United States (US), Australia, Malaysia and India amounting to an aggregated total of over 2863 years of patient observation time. On an external test cohort of 5005 patients, CovEWS predicts COVID-19 MESHD related mortality from $78.8\%$ ($95\%$ confidence interval [CI]: $76.0$, $84.7\%$) to $69.4\%$ ($95\%$ CI: $57.6, 75.2\%$) specificity at a sensitivity SERO greater than $95\%$ between respectively 1 and 192 hours prior to observed mortality events - significantly outperforming existing generic and COVID-19 MESHD specific clinical risk scores. CovEWS could enable clinicians to intervene at an earlier stage, and may therefore help in preventing or mitigating COVID-19 MESHD related mortality.

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