BIO-CXRNET: a robust multimodal stacking machine learning technique for mortality risk prediction of COVID-19 patients using chest X-ray images and clinical data.

Nowadays, quick, and accurate diagnosis of COVID-19 is a pressing need. This study presents a multimodal system to meet this need. The presented system employs a machine learning module that learns the required knowledge from the datasets collected from 930 COVID-19 patients hospitalized in Italy during the first wave of COVID-19 (March-June 2020). The dataset consists of twenty-five biomarkers from electronic health record and Chest X-ray (CXR) images. It is found that the system can diagnose low- or high-risk patients with an accuracy, sensitivity, and F1-score of 89.03%, 90.44%, and 89.03%, respectively. The system exhibits 6% higher accuracy than the systems that employ either CXR images or biomarker data. In addition, the system can calculate the mortality risk of high-risk patients using multivariate logistic regression-based nomogram scoring technique. Interested physicians can use the presented system to predict the early mortality risks of COVID-19 patients using the web-link: Covid-severity-grading-AI. In this case, a physician needs to input the following information: CXR image file, Lactate Dehydrogenase (LDH), Oxygen Saturation (O2%), White Blood Cells Count, C-reactive protein, and Age. This way, this study contributes to the management of COVID-19 patients by predicting early mortality risk. Supplementary Information: The online version contains supplementary material available at 10.1007/s00521-023-08606-w.

Dynamics of Anti-S IgG Antibodies Titers after the Second Dose of COVID-19 Vaccines in the Manual and Craft Worker Population of Qatar.

There is limited seroepidemiological evidence on the magnitude and long-term durability of antibody titers of mRNA and non-mRNA vaccines in the Qatari population. This study was conducted to generate evidence on long-term anti-S IgG antibody titers and their dynamics in individuals who have completed a primary COVID-19 vaccination schedule. A total of 300 male participants who received any of the following vaccines BNT162b2/Comirnaty, mRNA-1273, ChAdOx1-S/Covishield, COVID-19 Vaccine Janssen/Johnson, or BBIBP-CorV or Covaxin were enrolled in our study. All sera samples were tested by chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of IgG antibodies to SARS-CoV-2, receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2. Antibodies against SARS-CoV-2 nucleocapsid (SARS-CoV-2 N-protein IgG) were also determined. Kaplan-Meier survival curves were used to compare the time from the last dose of the primary vaccination schedule to the time by which anti-S IgG antibody titers fell into the lowest quartile (range of values collected) for the mRNA and non-mRNA vaccines. Participants vaccinated with mRNA vaccines had higher median anti-S IgG antibody titers. Participants vaccinated with the mRNA-1273 vaccine had the highest median anti-S-antibody level of 13,720.9 AU/mL (IQR 6426.5 to 30,185.6 AU/mL) followed by BNT162b2 (median, 7570.9 AU/mL; IQR, 3757.9 to 16,577.4 AU/mL); while the median anti-S antibody titer for non-mRNA vaccinated participants was 3759.7 AU/mL (IQR, 2059.7-5693.5 AU/mL). The median time to reach the lowest quartile was 3.53 months (IQR, 2.2-4.5 months) and 7.63 months (IQR, 6.3-8.4 months) for the non-mRNA vaccine recipients and Pfizer vaccine recipients, respectively. However, more than 50% of the Moderna vaccine recipients did not reach the lowest quartile by the end of the follow-up period. This evidence on anti-S IgG antibody titers should be considered for informing decisions on the durability of the neutralizing activity and thus protection against infection after the full course of primary vaccination in individuals receiving different type (mRNA verus non-mRNA) vaccines and those with natural infection.

An Adjuvanted Inactivated SARS-CoV-2 Microparticulate Vaccine Delivered Using Microneedles Induces a Robust Immune Response in Vaccinated Mice.

SARS-CoV-2, the causal agent of COVID-19, is a contagious respiratory virus that frequently mutates, giving rise to variant strains and leading to reduced vaccine efficacy against the variants. Frequent vaccination against the emerging variants may be necessary; thus, an efficient vaccination system is needed. A microneedle (MN) vaccine delivery system is non-invasive, patient-friendly, and can be self-administered. Here, we tested the immune response produced by an adjuvanted inactivated SARS-CoV-2 microparticulate vaccine administered via the transdermal route using a dissolving MN. The inactivated SARS-CoV-2 vaccine antigen and adjuvants (Alhydrogel® and AddaVax™) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) polymer matrices. The resulting MP were approximately 910 nm in size, with a high percentage yield and percent encapsulation efficiency of 90.4%. In vitro, the vaccine MP was non-cytotoxic and increased the immunostimulatory activity measured as nitric oxide release from dendritic cells. The adjuvant MP potentiated the immune response of the vaccine MP in vitro. In vivo, the adjuvanted SARS-CoV-2 MP vaccine induced high levels of IgM, IgG, IgA, IgG1, and IgG2a antibodies and CD4+ and CD8+ T-cell responses in immunized mice. In conclusion, the adjuvanted inactivated SARS-CoV-2 MP vaccine delivered using MN induced a robust immune response in vaccinated mice.

High-temporal resolution profiling reveals distinct immune trajectories following the first and second doses of COVID-19 mRNA vaccines.

Knowledge of the mechanisms underpinning the development of protective immunity conferred by mRNA vaccines is fragmentary. Here, we investigated responses to coronavirus disease 2019 (COVID-19) mRNA vaccination via high-temporal resolution blood transcriptome profiling. The first vaccine dose elicited modest interferon and adaptive immune responses, which peaked on days 2 and 5, respectively. The second vaccine dose, in contrast, elicited sharp day 1 interferon, inflammation, and erythroid cell responses, followed by a day 5 plasmablast response. Both post-first and post-second dose interferon signatures were associated with the subsequent development of antibody responses. Yet, we observed distinct interferon response patterns after each of the doses that may reflect quantitative or qualitative differences in interferon induction. Distinct interferon response phenotypes were also observed in patients with COVID-19 and were associated with severity and differences in duration of intensive care. Together, this study also highlights the benefits of adopting high-frequency sampling protocols in profiling vaccine-elicited immune responses.

Prognostic Model of ICU Admission Risk in Patients with COVID-19 Infection Using Machine Learning.

With the onset of the COVID-19 pandemic, the number of critically sick patients in intensive care units (ICUs) has increased worldwide, putting a burden on ICUs. Early prediction of ICU requirement is crucial for efficient resource management and distribution. Early-prediction scoring systems for critically ill patients using mathematical models are available, but are not generalized for COVID-19 and Non-COVID patients. This study aims to develop a generalized and reliable prognostic model for ICU admission for both COVID-19 and non-COVID-19 patients using best feature combination from the patient data at admission. A retrospective cohort study was conducted on a dataset collected from the pulmonology department of Moscow City State Hospital between 20 April 2020 and 5 June 2020. The dataset contains ten clinical features for 231 patients, of whom 100 patients were transferred to ICU and 131 were stable (non-ICU) patients. There were 156 COVID positive patients and 75 non-COVID patients. Different feature selection techniques were investigated, and a stacking machine learning model was proposed and compared with eight different classification algorithms to detect risk of need for ICU admission for both COVID-19 and non-COVID patients combined and COVID patients alone. C-reactive protein (CRP), chest computed tomography (CT), lung tissue affected (%), age, admission to hospital, and fibrinogen parameters at hospital admission were found to be important features for ICU-requirement risk prediction. The best performance was produced by the stacking approach, with weighted precision, sensitivity, F1-score, specificity, and overall accuracy of 84.45%, 84.48%, 83.64%, 84.47%, and 84.48%, respectively, for both types of patients, and 85.34%, 85.35%, 85.11%, 85.34%, and 85.35%, respectively, for COVID-19 patients only. The proposed work can help doctors to improve management through early prediction of the risk of need for ICU admission of patients during the COVID-19 pandemic, as the model can be used for both types of patients.

PCovNet: A presymptomatic COVID-19 detection framework using deep learning model using wearables data.

While the advanced diagnostic tools and healthcare management protocols have been struggling to contain the COVID-19 pandemic, the spread of the contagious viral pathogen before the symptom onset acted as the Achilles' heel. Although reverse transcription-polymerase chain reaction (RT-PCR) has been widely used for COVID-19 diagnosis, they are hardly administered before any visible symptom, which provokes rapid transmission. This study proposes PCovNet, a Long Short-term Memory Variational Autoencoder (LSTM-VAE)-based anomaly detection framework, to detect COVID-19 infection in the presymptomatic stage from the Resting Heart Rate (RHR) derived from the wearable devices, i.e., smartwatch or fitness tracker. The framework was trained and evaluated in two configurations on a publicly available wearable device dataset consisting of 25 COVID-positive individuals in the span of four months including their COVID-19 infection phase. The first configuration of the framework detected RHR abnormality with average Precision, Recall, and F-beta scores of 0.946, 0.234, and 0.918, respectively. However, the second configuration detected aberrant RHR in 100% of the subjects (25 out of 25) during the infectious period. Moreover, 80% of the subjects (20 out of 25) were detected during the presymptomatic stage. These findings prove the feasibility of using wearable devices with such a deep learning framework as a secondary diagnosis tool to circumvent the presymptomatic COVID-19 detection problem.

QUCoughScope: An Intelligent Application to Detect COVID-19 Patients Using Cough and Breath Sounds.

Problem-Since the outbreak of the COVID-19 pandemic, mass testing has become essential to reduce the spread of the virus. Several recent studies suggest that a significant number of COVID-19 patients display no physical symptoms whatsoever. Therefore, it is unlikely that these patients will undergo COVID-19 testing, which increases their chances of unintentionally spreading the virus. Currently, the primary diagnostic tool to detect COVID-19 is a reverse-transcription polymerase chain reaction (RT-PCR) test from the respiratory specimens of the suspected patient, which is invasive and a resource-dependent technique. It is evident from recent researches that asymptomatic COVID-19 patients cough and breathe in a different way than healthy people. Aim-This paper aims to use a novel machine learning approach to detect COVID-19 (symptomatic and asymptomatic) patients from the convenience of their homes so that they do not overburden the healthcare system and also do not spread the virus unknowingly by continuously monitoring themselves. Method-A Cambridge University research group shared such a dataset of cough and breath sound samples from 582 healthy and 141 COVID-19 patients. Among the COVID-19 patients, 87 were asymptomatic while 54 were symptomatic (had a dry or wet cough). In addition to the available dataset, the proposed work deployed a real-time deep learning-based backend server with a web application to crowdsource cough and breath datasets and also screen for COVID-19 infection from the comfort of the user's home. The collected dataset includes data from 245 healthy individuals and 78 asymptomatic and 18 symptomatic COVID-19 patients. Users can simply use the application from any web browser without installation and enter their symptoms, record audio clips of their cough and breath sounds, and upload the data anonymously. Two different pipelines for screening were developed based on the symptoms reported by the users: asymptomatic and symptomatic. An innovative and novel stacking CNN model was developed using three base learners from of eight state-of-the-art deep learning CNN algorithms. The stacking CNN model is based on a logistic regression classifier meta-learner that uses the spectrograms generated from the breath and cough sounds of symptomatic and asymptomatic patients as input using the combined (Cambridge and collected) dataset. Results-The stacking model outperformed the other eight CNN networks with the best classification performance for binary classification using cough sound spectrogram images. The accuracy, sensitivity, and specificity for symptomatic and asymptomatic patients were 96.5%, 96.42%, and 95.47% and 98.85%, 97.01%, and 99.6%, respectively. For breath sound spectrogram images, the metrics for binary classification of symptomatic and asymptomatic patients were 91.03%, 88.9%, and 91.5% and 80.01%, 72.04%, and 82.67%, respectively. Conclusion-The web-application QUCoughScope records coughing and breathing sounds, converts them to a spectrogram, and applies the best-performing machine learning model to classify the COVID-19 patients and healthy subjects. The result is then reported back to the test user in the application interface. Therefore, this novel system can be used by patients in their premises as a pre-screening method to aid COVID-19 diagnosis by prioritizing the patients for RT-PCR testing and thereby reducing the risk of spreading of the disease.

Mortality Prediction Utilizing Blood Biomarkers to Predict the Severity of COVID-19 Using Machine Learning Technique.

Healthcare researchers have been working on mortality prediction for COVID-19 patients with differing levels of severity. A rapid and reliable clinical evaluation of disease intensity will assist in the allocation and prioritization of mortality mitigation resources. The novelty of the work proposed in this paper is an early prediction model of high mortality risk for both COVID-19 and non-COVID-19 patients, which provides state-of-the-art performance, in an external validation cohort from a different population. Retrospective research was performed on two separate hospital datasets from two different countries for model development and validation. In the first dataset, COVID-19 and non-COVID-19 patients were admitted to the emergency department in Boston (24 March 2020 to 30 April 2020), and in the second dataset, 375 COVID-19 patients were admitted to Tongji Hospital in China (10 January 2020 to 18 February 2020). The key parameters to predict the risk of mortality for COVID-19 and non-COVID-19 patients were identified and a nomogram-based scoring technique was developed using the top-ranked five parameters. Age, Lymphocyte count, D-dimer, CRP, and Creatinine (ALDCC), information acquired at hospital admission, were identified by the logistic regression model as the primary predictors of hospital death. For the development cohort, and internal and external validation cohorts, the area under the curves (AUCs) were 0.987, 0.999, and 0.992, respectively. All the patients are categorized into three groups using ALDCC score and death probability: Low (probability < 5%), Moderate (5% < probability < 50%), and High (probability > 50%) risk groups. The prognostic model, nomogram, and ALDCC score will be able to assist in the early identification of both COVID-19 and non-COVID-19 patients with high mortality risk, helping physicians to improve patient management.

COVID-19 Lesion Segmentation Using Lung CT Scan Images: Comparative Study Based on Active Contour Models

Pneumonia is a lung infection that threatens all age groups. In this paper, we use CT scans to investigate the effectiveness of active contour models (ACMs) for segmentation of pneumonia caused by the Coronavirus disease (COVID-19) as one of the successful methods for image segmentation. A comparison has been made between the performances of the state-of-the-art methods performed based on a database of lung CT scan images. This review helps the reader to identify starting points for research in the field of active contour models on COVID-19, which is a high priority for researchers and practitioners. Finally, the experimental results indicate that active contour methods achieve promising results when there are not enough images to use deep learning-based methods as one of the powerful tools for image segmentation.

Development and Validation of an Early Scoring System for Prediction of Disease Severity in COVID-19 Using Complete Blood Count Parameters.

The coronavirus disease 2019 (COVID-19) after outbreaking in Wuhan increasingly spread throughout the world. Fast, reliable, and easily accessible clinical assessment of the severity of the disease can help in allocating and prioritizing resources to reduce mortality. The objective of the study was to develop and validate an early scoring tool to stratify the risk of death using readily available complete blood count (CBC) biomarkers. A retrospective study was conducted on twenty-three CBC blood biomarkers for predicting disease mortality for 375 COVID-19 patients admitted to Tongji Hospital, China from January 10 to February 18, 2020. Machine learning based key biomarkers among the CBC parameters as the mortality predictors were identified. A multivariate logistic regression-based nomogram and a scoring system was developed to categorize the patients in three risk groups (low, moderate, and high) for predicting the mortality risk among COVID-19 patients. Lymphocyte count, neutrophils count, age, white blood cell count, monocytes (%), platelet count, red blood cell distribution width parameters collected at hospital admission were selected as important biomarkers for death prediction using random forest feature selection technique. A CBC score was devised for calculating the death probability of the patients and was used to categorize the patients into three sub-risk groups: low (<=5%), moderate (>5% and <=50%), and high (>50%), respectively. The area under the curve (AUC) of the model for the development and internal validation cohort were 0.961 and 0.88, respectively. The proposed model was further validated with an external cohort of 103 patients of Dhaka Medical College, Bangladesh, which exhibits in an AUC of 0.963. The proposed CBC parameter-based prognostic model and the associated web-application, can help the medical doctors to improve the management by early prediction of mortality risk of the COVID-19 patients in the low-resource countries.

Microneedles: A New Generation Vaccine Delivery System.

Transdermal vaccination route using biodegradable microneedles is a rapidly progressing field of research and applications. The fear of painful needles is one of the primary reasons most people avoid getting vaccinated. Therefore, developing an alternative pain-free method of vaccination using microneedles has been a significant research area. Microneedles comprise arrays of micron-sized needles that offer a pain-free method of delivering actives across the skin. Apart from being pain-free, microneedles provide various advantages over conventional vaccination routes such as intramuscular and subcutaneous. Microneedle vaccines induce a robust immune response as the needles ranging from 50 to 900 µm in length can efficiently deliver the vaccine to the epidermis and the dermis region, which contains many Langerhans and dendritic cells. The microneedle array looks like band-aid patches and offers the advantages of avoiding cold-chain storage and self-administration flexibility. The slow release of vaccine antigens is an important advantage of using microneedles. The vaccine antigens in the microneedles can be in solution or suspension form, encapsulated in nano or microparticles, and nucleic acid-based. The use of microneedles to deliver particle-based vaccines is gaining importance because of the combined advantages of particulate vaccine and pain-free immunization. The future of microneedle-based vaccines looks promising however, addressing some limitations such as dosing inadequacy, stability and sterility will lead to successful use of microneedles for vaccine delivery. This review illustrates the recent research in the field of microneedle-based vaccination.

An Early Warning Tool for Predicting Mortality Risk of COVID-19 Patients Using Machine Learning.

COVID-19 pandemic has created an extreme pressure on the global healthcare services. Fast, reliable, and early clinical assessment of the severity of the disease can help in allocating and prioritizing resources to reduce mortality. In order to study the important blood biomarkers for predicting disease mortality, a retrospective study was conducted on a dataset made public by Yan et al. in [1] of 375 COVID-19 positive patients admitted to Tongji Hospital (China) from January 10 to February 18, 2020. Demographic and clinical characteristics and patient outcomes were investigated using machine learning tools to identify key biomarkers to predict the mortality of individual patient. A nomogram was developed for predicting the mortality risk among COVID-19 patients. Lactate dehydrogenase, neutrophils (%), lymphocyte (%), high-sensitivity C-reactive protein, and age (LNLCA)-acquired at hospital admission-were identified as key predictors of death by multi-tree XGBoost model. The area under curve (AUC) of the nomogram for the derivation and validation cohort were 0.961 and 0.991, respectively. An integrated score (LNLCA) was calculated with the corresponding death probability. COVID-19 patients were divided into three subgroups: low-, moderate-, and high-risk groups using LNLCA cutoff values of 10.4 and 12.65 with the death probability less than 5%, 5-50%, and above 50%, respectively. The prognostic model, nomogram, and LNLCA score can help in early detection of high mortality risk of COVID-19 patients, which will help doctors to improve the management of patient stratification.

Exploring the effect of image enhancement techniques on COVID-19 detection using chest X-ray images.

Computer-aided diagnosis for the reliable and fast detection of coronavirus disease (COVID-19) has become a necessity to prevent the spread of the virus during the pandemic to ease the burden on the healthcare system. Chest X-ray (CXR) imaging has several advantages over other imaging and detection techniques. Numerous works have been reported on COVID-19 detection from a smaller set of original X-ray images. However, the effect of image enhancement and lung segmentation of a large dataset in COVID-19 detection was not reported in the literature. We have compiled a large X-ray dataset (COVQU) consisting of 18,479 CXR images with 8851 normal, 6012 non-COVID lung infections, and 3616 COVID-19 CXR images and their corresponding ground truth lung masks. To the best of our knowledge, this is the largest public COVID positive database and the lung masks. Five different image enhancement techniques: histogram equalization (HE), contrast limited adaptive histogram equalization (CLAHE), image complement, gamma correction, and balance contrast enhancement technique (BCET) were used to investigate the effect of image enhancement techniques on COVID-19 detection. A novel U-Net model was proposed and compared with the standard U-Net model for lung segmentation. Six different pre-trained Convolutional Neural Networks (CNNs) (ResNet18, ResNet50, ResNet101, InceptionV3, DenseNet201, and ChexNet) and a shallow CNN model were investigated on the plain and segmented lung CXR images. The novel U-Net model showed an accuracy, Intersection over Union (IoU), and Dice coefficient of 98.63%, 94.3%, and 96.94%, respectively for lung segmentation. The gamma correction-based enhancement technique outperforms other techniques in detecting COVID-19 from the plain and the segmented lung CXR images. Classification performance from plain CXR images is slightly better than the segmented lung CXR images; however, the reliability of network performance is significantly improved for the segmented lung images, which was observed using the visualization technique. The accuracy, precision, sensitivity, F1-score, and specificity were 95.11%, 94.55%, 94.56%, 94.53%, and 95.59% respectively for the segmented lung images. The proposed approach with very reliable and comparable performance will boost the fast and robust COVID-19 detection using chest X-ray images.