Heterologous prime-boost immunisation with mRNA- and AdC68-based 2019-nCoV variant vaccines induces broad-spectrum immune responses in mice.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV) variants has been associated with the transmission and pathogenicity of COVID-19. Therefore, exploring the optimal immunisation strategy to improve the broad-spectrum cross-protection ability of COVID-19 vaccines is of great significance. Herein, we assessed different heterologous prime-boost strategies with chimpanzee adenovirus vector-based COVID-19 vaccines plus Wuhan-Hu-1 (WH-1) strain (AdW) and Beta variant (AdB) and mRNA-based COVID-19 vaccines plus WH-1 strain (ARW) and Omicron (B.1.1.529) variant (ARO) in 6-week-old female BALB/c mice. AdW and AdB were administered intramuscularly or intranasally, while ARW and ARO were administered intramuscularly. Intranasal or intramuscular vaccination with AdB followed by ARO booster exhibited the highest levels of cross-reactive IgG, pseudovirus-neutralising antibody (PNAb) responses, and angiotensin-converting enzyme-2 (ACE2)-binding inhibition rates against different 2019-nCoV variants among all vaccination groups. Moreover, intranasal AdB vaccination followed by ARO induced higher levels of IgA and neutralising antibody responses against live 2019-nCoV than intramuscular AdB vaccination followed by ARO. A single dose of AdB administered intranasally or intramuscularly induced broader cross-NAb responses than AdW. Th1-biased cellular immune response was induced in all vaccination groups. Intramuscular vaccination-only groups exhibited higher levels of Th1 cytokines than intranasal vaccination-only and intranasal vaccination-containing groups. However, no obvious differences were found in the levels of Th2 cytokines between the control and all vaccination groups. Our findings provide a basis for exploring vaccination strategies against different 2019-nCoV variants to achieve high broad-spectrum immune efficacy.

Vaccine inequity-induced COVID-19 dilemma: Time to sober up.

UNSTRUCTURED: The ongoing coronavirus disease 2019 pandemic has not only posed a serious threat to public health but has also imposed a heavy burden on medical systems and global economies. To combat this challenge, unprecedented efforts have been made by governments and the scientific community in the development and production of vaccines. As a result, less than a year elapsed between identification of a novel pathogen sequence and large-scale vaccine rollout. However, much of the focus and debate has increasingly shifted to the looming risk of global vaccine inequity and whether we could do more to modify this risk. In this paper, we first outline the scope of inequitable vaccine distribution and identify its truly catastrophic consequences. Then, from the perspectives of political will, free markets and profit-driven enterprises based on patent and intellectual property protection, we analyze in-depth the root causes why this phenomenon is so difficult to combat. Apart from these, some specific and crucial solutions that should be undertaken in the long term were also put forward, in order to provide a useful reference for the authorities, stakeholders and researchers involved in addressing this global crisis and the next one.

Dynamic behavior analysis of an SVIR epidemic model with two time delays associated with the COVID-19 booster vaccination time.

Since the outbreak of COVID-19, there has been widespread concern in the community, especially on the recent heated debate about when to get the booster vaccination. In order to explore the optimal time for receiving booster shots, here we construct an SVIR model with two time delays based on temporary immunity. Second, we theoretically analyze the existence and stability of equilibrium and further study the dynamic properties of Hopf bifurcation. Then, the statistical analysis is conducted to obtain two groups of parameters based on the official data, and numerical simulations are carried out to verify the theoretical analysis. As a result, we find that the equilibrium is locally asymptotically stable when the booster vaccination time is within the critical value. Moreover, the results of the simulations also exhibit globally stable properties, which might be more beneficial for controlling the outbreak. Finally, we propose the optimal time of booster vaccination and predict when the outbreak can be effectively controlled.

Diagnostic Accuracy of Liquid Biomarkers in Airway Diseases: Toward Point-of-Care Applications.

Background: Liquid biomarkers have shown increasing utility in the clinical management of airway diseases. Salivary and blood samples are particularly amenable to point-of-care (POC) testing due to simple specimen collection and processing. However, very few POC tests have successfully progressed to clinical application due to the uncertainty and unpredictability surrounding their diagnostic accuracy. Objective: To review liquid biomarkers of airway diseases with well-established diagnostic accuracies and discuss their prospects for future POC applications. Methodology: A literature review of publications indexed in Medline or Embase was performed to evaluate the diagnostic accuracy of liquid biomarkers for chronic obstructive pulmonary disease (COPD), asthma, laryngopharyngeal reflux (LPR), and COVID-19. Results: Of 3,628 studies, 71 fulfilled the inclusion criteria. Sputum and blood eosinophils were the most frequently investigated biomarkers for the management of asthma and COPD. Salivary pepsin was the only biomarker with a well-documented accuracy for the diagnosis of LPR. Inflammatory blood biomarkers (e.g., CRP, D-dimers, ferritin) were found to be useful to predict the severity, complications, and mortality related to COVID-19 infection. Conclusion: Multiple liquid biomarkers have well-established diagnostic accuracies and are thus amenable to POC testing in clinical settings.

Therapeutic Polypeptides and Peptidomimetics: Powerful Tools for COVID-19 Treatment.

The coronavirus disease 2019 (COVID-19) pandemic has swept the whole world and brought about a public health crisis of unprecedented proportions. To combat the rapid transmission and possible deaths due to the disease, researchers and companies around the world are developing all possible strategies. Due to the advantages of safety, specificity, and fewer adverse effects, polypeptide and peptidomimetic drugs are considered promising strategies. This review comprehensively summarizes and discusses the progress in development of peptide drugs for use in the treatment of COVID-19. Based on the latest results in this field, we divided them into clinically approved drugs, clinical trial drugs, and clinically ineffective drugs, and outlined the molecular targets and mechanisms of action one by one to reveal their feasibility as promising therapeutic agents for COVID-19. Notably, monoclonal antibodies have shown beneficial effects in the early stages of infection, while Paxlovid can significantly reduce hospitalization and mortality among non-vaccinated patients. Among clinical experimental drugs, both the interleukin-1 receptor antagonist anakinra and the bradykinin B2 receptor antagonist icatibant are well tolerated and effective in patients with COVID-19, but long-term trials are needed to confirm the durability of efficacy.

A Nitrocellulose Paper-Based Multi-Well Plate for Point-of-Care ELISA.

Low-cost diagnostic tools for point-of-care immunoassays, such as the paper-based enzyme-linked immunoassay (ELISA), have become increasingly important, especially so in the recent COVID-19 pandemic. ELISA is the gold-standard antibody/antigen sensing method. This paper reports an easy-to-fabricate nitrocellulose (NC) paper plate, coupled with a desktop scanner for ELISA, which provides a higher protein immobilization efficiency than the conventional cellulose paper-based ELISA platforms. The experiments were performed using spiked samples for the direct ELISA of rabbit IgG with a limit of detection (LOD) of 1.016 µg/mL, in a measurement range of 10 ng/mL to 1 mg/mL, and for the sandwich ELISA of sperm protein (SP-10) with an LOD of 88.8 ng/mL, in a measurement range of 1 ng/mL to 100 µg/mL. The described fabrication method, based on laser-cutting, is a highly flexible one-step laser micromachining process, which enables the rapid production of low-cost NC paper-based multi-well plates with different sizes for the ELISA measurements.

Primary care provider's job satisfaction and organizational commitment after COVID-19 restrictions ended: A mixed-method study using a mediation model.

Objectives: More and more countries have decided to cancel most or even all COVD-19 restrictions. However, it is unclear how ending of restrictions will affect primary care providers' job satisfaction and organizational commitment. Our objectives are to explore the current status and possible change in primary care providers' job satisfaction and organizational commitment after massive restriction policies ended in China. Methods: This was a mixed-method study that utilized structured questionnaires and semi-structured qualitative individual interviews. The 20-item Minnesota Satisfaction Questionnaire (MSQ) and 25-item organizational commitment survey were adopted to assess job satisfaction and organization commitment. Descriptive statistics and mediation models, as well as inductive thematic analysis, were used to analyze quantitative and qualitative data. Results: A total of 18 interviews and 435 valid survey responses were included in our analysis. The average scores for job satisfaction and organizational commitment were 80.6 and 90.8. The thematic analysis revealed one major theme: ethical and moral responsibility to provide care as primary care providers, on which we established a mediation model. The mediation analysis revealed that normative commitment could positively affect the other four dimensions of organizational commitment and job satisfaction. The direct effect of affective commitment on job satisfaction was significant (LLCI = 0.11, ULCI = 0.31), and the mediators were identified to have a partial mediating effect instead of a total mediating effect. Conclusion: After COVID-19 restrictions end, the job satisfaction and organizational commitment of primary care providers will return to levels before the pandemic and during this estimated process, a brief rise in resignation is predictable. The normative commitment positively affects the other four dimensions of organizational commitment and job satisfaction for primary care providers, which suggests a possible way to motivate primary care providers when restrictions end.

An unusual injury mechanism of atlantoaxial dislocation: illustrative case

BACKGROUND Atlantoaxial dislocation (AAD) is a rare and potentially life-threatening condition. Various underlying mechanisms of injury are described in the literature. Here, the authors report an unusual nontraumatic injury mechanism of AAD in a 12-year-old patient. OBSERVATIONS A 12-year-old boy presented with intolerable neck pain and numbness in both upper limbs. The patient’s symptoms had started 2 months after the initiation of online classes during the coronavirus disease 2019 pandemic without a history of trauma. He used a computer for personal study and online classes for prolonged hours with no respite. On physical and radiological evaluation, he was diagnosed with AAD. Before surgery, skull traction was applied to reduce the dislocation and posterior C1 lateral mass screw and C2 pedicle screw fixation was performed. An optimal clinical outcome was achieved with no postoperative complications. A preoperative visual analog scale score of 8.0 was reduced to 0 postoperatively. LESSONS A prolonged fixed neck posture is an unusual underlying cause of AAD. Posterior C1 lateral mass and C2 pedicle screw fixation results in an optimal clinical outcome.

Mathematical modeling and stability analysis of the time-delayed SAIM model for COVID-19 vaccination and media coverage.

Since the COVID-19 outbreak began in early 2020, it has spread rapidly and threatened public health worldwide. Vaccination is an effective way to control the epidemic. In this paper, we model a SAIM equation. Our model involves vaccination and the time delay for people to change their willingness to be vaccinated, which is influenced by media coverage. Second, we theoretically analyze the existence and stability of the equilibria of our model. Then, we study the existence of Hopf bifurcation related to the two equilibria and obtain the normal form near the Hopf bifurcating critical point. Third, numerical simulations based two groups of values for model parameters are carried out to verify our theoretical analysis and assess features such as stable equilibria and periodic solutions. To ensure the appropriateness of model parameters, we conduct a mathematical analysis of official data. Next, we study the effect of the media influence rate and attenuation rate of media coverage on vaccination and epidemic control. The analysis results are consistent with real-world conditions. Finally, we present conclusions and suggestions related to the impact of media coverage on vaccination and epidemic control.

Combining intramuscular and intranasal homologous prime-boost with a chimpanzee adenovirus-based COVID-19 vaccine elicits potent humoral and cellular immune responses in mice.

The efficacy of many coronavirus disease 2019 (COVID-19) vaccines has been shown to decrease to varying extents against new severe acute respiratory syndrome coronavirus 2 variants, which are responsible for the continuing COVID-19 pandemic. Combining intramuscular and intranasal vaccination routes is a promising approach for achieving more potent immune responses. We evaluated the immunogenicity of prime-boost protocols with a chimpanzee adenovirus serotype 68 vector-based vaccine, ChAdTS-S, administered via both intranasal and intramuscular routes in BALB/c mice. Intramuscular priming followed by an intranasal booster elicited the highest levels of IgG, IgA, and pseudovirus neutralizing antibody titres among all the protocols tested at day 42 after prime immunization compared with the intranasal priming/intramuscular booster and prime-boost protocols using only one route. In addition, intramuscular priming followed by an intranasal booster induced high T-cell responses, measured using the IFN-γ ELISpot assay, that were similar to those observed upon intramuscular vaccination. All ChAdTS-S vaccination groups induced Th1-skewing of the T-cell response according to intracellular cytokine staining and Meso Scale Discovery cytokine profiling assays on day 56 after priming. This study provides reference data for assessing vaccination schemes of adenovirus-based COVID-19 vaccines with high immune efficacy.

Diagnostic Accuracy of Liquid Biomarkers in Airway Diseases: Toward Point-of-Care Applications

Background Liquid biomarkers have shown increasing utility in the clinical management of airway diseases. Salivary and blood samples are particularly amenable to point-of-care (POC) testing due to simple specimen collection and processing. However, very few POC tests have successfully progressed to clinical application due to the uncertainty and unpredictability surrounding their diagnostic accuracy. Objective To review liquid biomarkers of airway diseases with well-established diagnostic accuracies and discuss their prospects for future POC applications. Methodology A literature review of publications indexed in Medline or Embase was performed to evaluate the diagnostic accuracy of liquid biomarkers for chronic obstructive pulmonary disease (COPD), asthma, laryngopharyngeal reflux (LPR), and COVID-19. Results Of 3,628 studies, 71 fulfilled the inclusion criteria. Sputum and blood eosinophils were the most frequently investigated biomarkers for the management of asthma and COPD. Salivary pepsin was the only biomarker with a well-documented accuracy for the diagnosis of LPR. Inflammatory blood biomarkers (e.g., CRP, D-dimers, ferritin) were found to be useful to predict the severity, complications, and mortality related to COVID-19 infection. Conclusion Multiple liquid biomarkers have well-established diagnostic accuracies and are thus amenable to POC testing in clinical settings.

Dynamic Analysis of a COVID-19 Vaccination Model with a Positive Feedback Mechanism and Time-Delay

As the novel coronavirus pandemic has spread globally since 2019, most countries in the world are conducting vaccination campaigns. First, based on the traditional SIR infectious disease model, we introduce a positive feedback mechanism associated with the vaccination rate, and consider the time delay from antibody production to antibody disappearance after vaccination. We establish an UVaV model for COVID-19 vaccination with a positive feedback mechanism and time-delay. Next, we verify the existence of the equilibrium of the formulated model and analyze its stability. Then, we analyze the existence of the Hopf bifurcation, and use the multiple time scales method to derive the normal form of the Hopf bifurcation, further determining the direction of the Hopf bifurcation and the stability of the periodic solution of the bifurcation. Finally, we collect the parameter data of some countries and regions to determine the reasonable ranges of multiple parameters to ensure the authenticity of simulation results. Numerical simulations are carried out to verify the correctness of the theoretical results. We also give the critical time for controllable widespread antibody failure to provide a reference for strengthening vaccination time. Taking two groups of parameters as examples, the time of COVID-19 vaccine booster injection should be best controlled before 38.5 weeks and 35.3 weeks, respectively. In addition, study the impact of different expiration times on epidemic prevention and control effectiveness. We further explore the impact of changes in vaccination strategies on trends in epidemic prevention and control effectiveness. It could be concluded that, under the same epidemic vaccination strategy, the existence level of antibody is roughly the same, which is consistent with the reality.

A deep fuzzy model for diagnosis of COVID-19 from CT images.

From early 2020, a novel coronavirus disease pneumonia has shown a global "pandemic" trend at an extremely fast speed. Due to the magnitude of its harm, it has become a major global public health event. In the face of dramatic increase in the number of patients with COVID-19, the need for quick diagnosis of suspected cases has become particularly critical. Therefore, this paper constructs a fuzzy classifier, which aims to detect infected subjects by observing and analyzing the CT images of suspected patients. Firstly, a deep learning algorithm is used to extract the low-level features of CT images in the COVID-CT dataset. Subsequently, we analyze the extracted feature information with attribute reduction algorithm to obtain features with high recognition. Then, some key features are selected as the input for the fuzzy diagnosis model to the training model. Finally, several images in the dataset are used as the test set to test the trained fuzzy classifier. The obtained accuracy rate is 94.2%, and the F1-score is 93.8%. Experimental results show that, compared with the deep learning diagnosis methods widely used in medical image analysis, the proposed fuzzy model improves the accuracy and efficiency of diagnosis, which consequently helps to curb the spread of COVID-19.

SPEEDS: A portable serological testing platform for rapid electrochemical detection of SARS-CoV-2 antibodies.

The COVID-19 pandemic has resulted in a worldwide health crisis. Rapid diagnosis, new therapeutics and effective vaccines will all be required to stop the spread of COVID-19. Quantitative evaluation of serum antibody levels against the SARS-CoV-2 virus provides a means of monitoring a patient's immune response to a natural viral infection or vaccination, as well as evidence of a prior infection. In this paper, a portable and low-cost electrochemical immunosensor is developed for the rapid and accurate quantification of SARS-CoV-2 serum antibodies. The immunosensor is capable of quantifying the concentrations of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies against the SARS-CoV-2 spike protein in human serum. For IgG and IgM, it provides measurements in the range of 10.1 ng/mL - 60 µg/mL and 1.64 ng/mL - 50 µg/mL, respectively, both with an assay time of 13 min. We also developed device stabilization and storage strategies to achieve stable performance of the immunosensor over 24-week storage at room temperature. We evaluated the performance of the immunosensor using COVID-19 patient serum samples collected at different time points after symptom onset. The rapid and sensitive detection of IgG and IgM provided by our immunosensor fulfills the need of rapid COVID-19 serological testing for both point-of-care diagnosis and population immunity screening.

Enhancing the performance of paper-based electrochemical impedance spectroscopy nanobiosensors: An experimental approach.

Accurate, rapid, and low-cost molecular diagnostics is essential in managing outbreaks of infectious diseases, such as the pandemic of coronavirus disease 2019 (COVID-19). Accordingly, microfluidic paper-based analytical devices (µPADs) have emerged as promising diagnostic tools. Among the extensive efforts to improve the performance and usability of diagnostic tools, biosensing mechanisms based on electrochemical impedance spectroscopy (EIS) have shown great promise because of their label-free operation and high sensitivity. However, the method to improve EIS biosensing on µPADs is less explored. Here, we present an experimental approach to enhancing the performance of paper-based EIS biosensors featuring zinc oxide nanowires (ZnO NWs) directly grown on working electrodes (WEs). Through a comparison of different EIS settings and an examination of ZnO-NW effects on EIS measurements, we show that ZnO-NW-enhanced WEs function reliably with Faradaic processes utilizing iron-based electron mediators. We calibrate paper-based EIS biosensors with different morphologies of ZnO NWs and achieve a low limit of detection (0.4 pg ml-1) in detecting p24 antigen as a marker for human immunodeficiency virus (HIV). Through microscopic imaging and electrochemical characterization, we reveal that the morphological and the electrochemical surface areas of ZnO-NW-enhanced WEs indicate the sensitivities and sensing ranges of the EIS nanobiosensors. Finally, we report that the EIS nanobiosensors are capable of differentiating the concentrations (blank, 10 ng ml-1, 100 ng ml-1, and 1 µg ml-1) of IgG antibody (CR3022) to SARS-CoV-2 in human serum samples, demonstrating the efficacy of these devices for COVID-19 diagnosis. This work provides a methodology for the rational design of high-performance EIS µPADs and has the potential to facilitate diagnosis in pandemics.

Efficacy and safety of Shufeng Jiedu capsule for coronavirus disease 2019 (COVID-19): A protocol for systematic review and meta-analysis.

BACKGROUND: From the end of 2019 to the present, coronavirus disease 2019 (COVID-19) has put considerable pressure on the worlds medical system and caused significant mortality and economic losses around the world. In China, the Shufeng Jiedu capsule has been widely used in the treatment of COVID-19, but there is still a lack of evidence-based medical evaluation. METHODS: According to the retrieval strategies, randomized controlled trials (RCTs) on the Shufeng Jiedu capsule for COVID-19 were obtained from CNKI, WanFang, VIP, PubMed, Embase and Cochrane Library, regardless of publication date, or language. Studies were screened based on inclusion and exclusion criteria, and the Cochrane risk bias assessment tool was used to evaluate the quality of the studies. The meta-analysis was performed using RevMan 5.3 and STATA 14.2 software. Ultimately, the evidentiary grade for the results will be evaluated. RESULTS: This study will evaluate the efficacy and safety of the Shufeng Jiedu capsule in the treatment of COVID-19 and provide a more reasonable choice of medication in clinical practice. CONCLUSION: Our findings will provide references for future clinical decision and guidance development. REGISTRATION: INPLASY registration number: INPLASY202070024.

Fighting COVID-19: Integrated Micro- and Nanosystems for Viral Infection Diagnostics.

The pandemic of coronavirus disease 2019 (COVID-19) highlights the importance of rapid and sensitive diagnostics of viral infection that enables the efficient tracing of cases and the implementation of public health measures for disease containment. The immediate actions from both academia and industry have led to the development of many COVID-19 diagnostic systems that have secured fast-track regulatory approvals and have been serving our healthcare frontlines since the early stage of the pandemic. On diagnostic technologies, many of these clinically validated systems have significantly benefited from the recent advances in micro- and nanotechnologies in terms of platform design, analytical method, and system integration and miniaturization. The continued development of new diagnostic platforms integrating micro- and nanocomponents will address some of the shortcomings we have witnessed in the existing COVID-19 diagnostic systems. This Perspective reviews the previous and ongoing research efforts on developing integrated micro- and nanosystems for nucleic acid-based virus detection, and highlights promising technologies that could provide better solutions for the diagnosis of COVID-19 and other viral infectious diseases. With the summary and outlook of this rapidly evolving research field, we hope to inspire more research and development activities to better prepare our society for future public health crises.