From concept to delivery: a yeast-expressed recombinant protein-based COVID-19 vaccine technology suitable for global access.

INTRODUCTION: The development of a yeast-expressed recombinant protein-based vaccine technology co-developed with LMIC vaccine producers and suitable as a COVID-19 vaccine for global access is described. The proof-of-concept for developing a SARS-CoV-2 spike protein receptor-binding domain (RBD) antigen as a yeast-derived recombinant protein vaccine technology is described. AREAS COVERED: Genetic Engineering: The strategy is presented for the design and genetic modification used during cloning and expression in the yeast system. Process and Assay Development: A summary is presented of how a scalable, reproducible, and robust production process for the recombinant protein COVID-19 vaccine antigen was developed. Formulation and Pre-clinical Strategy: We report on the pre-clinical and formulation strategy used for the proof-of-concept evaluation of the SARS-CoV-2 RBD vaccine antigen. Technology Transfer and Partnerships: The process used for the technology transfer and co-development with LMIC vaccine producers is described. Clinical Development and Delivery: The approach used by LMIC developers to establish the industrial process, clinical development, and deployment is described. EXPERT OPINION: Highlighted is an alternative model for developing new vaccines for emerging infectious diseases of pandemic importance starting with an academic institution directly transferring their technology to LMIC vaccine producers without the involvement of multinational pharma companies.

Factors Associated with the Underestimation of Manual CPAP Titration Pressure.

During the SARS-CoV-2 pandemic, the use of in-laboratory positive airway pressure (PAP) titration studies was not routinely suggested. PAP pressure prediction calculations are emerging as alternative methods for the treatment of these patients. The underestimation of PAP titration pressure usually leads to unsatisfactory results for PAP therapy. This study aimed to evaluate the factors associated with the underestimation of PAP titration pressure when using PAP pressure prediction equations. Estimated PAP pressure formulas based on body mass index (BMI) and apnea-hypopnea index (AHI) were chosen to validate the accuracy of equations in the successful prediction of titration pressure. Among 341 adult patients diagnosed with obstructive sleep apnea (OSA) by overnight polysomnography (PSG) and who received overnight PAP titration in order to select a successful pressure, the mean age of the total subjects was 55.4 years old and 78.9% of patients were male. The average BMI and AHI scores were 27.1 ± 4.8 and 37 ± 21.7, respectively. After multivariate stepwise regression analysis, the odds ratio of participants with a pretitration AHI was 1.017 (95% CI: 1.005-1.030). Only the severity of OSA was significantly different between the underestimated group and the adequately assessed group. In conclusion, a high AHI, but not BMI, is associated with an underestimated CPAP titration pressure in adult patients with OSA.

The safety of digestive tract cancer surgery during COVID-19: A living systematic review and meta-analysis.

Surgery is the primary curative treatment of solid cancers. However, its safety has been compromised by the outbreak of COVID-19. Therefore, it is necessary to evaluate the safety of digestive tract cancer surgery in the context of COVID-19. We used the Review Manager software (v.5.4) and Stata software (version 16.0) for meta-analysis and statistical analysis. Sixteen retrospective studies involving 17,077 patients met the inclusion criteria. The data indicates that performing digestive tract cancer surgery during the COVID-19 pandemic led to increased blood loss(MD = -11.31, 95%CI:-21.43 to -1.20, P = 0.03), but did not increase postoperative complications(OR = 1.03, 95%CI:0.78 to1.35, P = 0 0.86), anastomotic leakage (OR = 0.96, 95%CI:0.52 to1.77, P = 0 0.89), postoperative mortality (OR = 0.65, 95%CI:0.40 to1.07, P = 0 0.09), number of transfusions (OR = 0.74, 95%CI:0.30 to 1.80, P = 0.51), number of patients requiring ICU care(OR = 1.37, 95%CI:0.90 to 2.07, P = 0.14), postoperative 30-d readmission (OR = 0.94, 95%CI:0.82 to 1.07, P = 0 0.33), total hospital stay (MD = 0.11, 95%CI:-2.37 to 2.59, P = 0.93), preoperative waiting time(MD = - 0.78, 95%CI:-2.34 to 0.79, P = 0.33), postoperative hospital stay(MD = - 0.44, 95%CI:-1.61 to 0.74, P = 0.47), total operation time(MD = -12.99, 95%CI:-28.00 to 2.02, P = 0.09) and postoperative ICU stay (MD = - 0.02, 95%CI:-0.62 to 0.57, P = 0.94). Digestive tract cancer surgery can be safely performed during the COVID-19.

Clinical Phenotype Prediction From Single-cell RNA-seq Data using Attention-Based Neural Networks (preprint)

Motivation: A patient's disease phenotype can be driven and determined by specific groups of cells whose marker genes are either unknown, or can only be detected at late-stage using conventional bulk assays such as RNA-Seq technology. Recent advances in single-cell RNA sequencing (scRNA-seq) enable gene expression profiling in cell-level resolution, and therefore have the potential to identify those cells driving the disease phenotype even while the number of these cells is small. However, most existing methods rely heavily on accurate cell type detection, and the number of available annotated samples is usually too small for training deep learning predictive models. Results: Here we propose the method ScRAT for clinical phenotype prediction using scRNA-seq data. To train ScRAT with a limited number of samples of different phenotypes, such as COVID and non-COVID, ScRAT first applies a mixup module to increase the number of training samples. A multi-head attention mechanism is employed to learn the most informative cells for each phenotype without relying on a given cell type annotation. Using three public COVID datasets, we show that ScRAT outperforms other phenotype prediction methods. The performance edge of ScRAT over its competitors increases as the number of training samples decreases, indicating the efficacy of our sample mixup. Critical cell types detected based on high-attention cells also support novel findings in the original papers and the recent literature. This suggests that ScRAT overcomes the challenge of missing marker genes and limited sample number with great potential revealing novel molecular mechanisms and/or therapies.

Boosting Convolution with Efficient MLP-Permutation for Volumetric Medical Image Segmentation (preprint)

Recently, the advent of vision Transformer (ViT) has brought substantial advancements in 3D dataset benchmarks, particularly in 3D volumetric medical image segmentation (Vol-MedSeg). Concurrently, multi-layer perceptron (MLP) network has regained popularity among researchers due to their comparable results to ViT, albeit with the exclusion of the resource-intensive self-attention module. In this work, we propose a novel permutable hybrid network for Vol-MedSeg, named PHNet, which capitalizes on the strengths of both convolution neural networks (CNNs) and MLP. PHNet addresses the intrinsic isotropy problem of 3D volumetric data by employing a combination of 2D and 3D CNNs to extract local features. Besides, we propose an efficient multi-layer permute perceptron (MLPP) module that captures long-range dependence while preserving positional information. This is achieved through an axis decomposition operation that permutes the input tensor along different axes, thereby enabling the separate encoding of the positional information. Furthermore, MLPP tackles the resolution sensitivity issue of MLP in Vol-MedSeg with a token segmentation operation, which divides the feature into smaller tokens and processes them individually. Extensive experimental results validate that PHNet outperforms the state-of-the-art methods with lower computational costs on the widely-used yet challenging COVID-19-20 and Synapse benchmarks. The ablation study also demonstrates the effectiveness of PHNet in harnessing the strengths of both CNNs and MLP.

Cannabis as antivirals.

Cannabis is a plant notorious for its psychoactive effect, but when used correctly, it provides a plethora of medicinal benefits. With more than 400 active compounds that have therapeutic properties, cannabis has been accepted widely as a medical treatment and for recreational purposes in several countries. The compounds exhibit various clinical benefits, which include, but are not limited to, anticancer, antimicrobial, and antioxidant properties. Among the vast range of compounds, multiple research papers have shown that cannabinoids, such as cannabidiol and delta-9-tetrahydrocannabinol, have antiviral effects. Recently, scientists found that both compounds can reduce severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection by downregulating ACE2 transcript levels and by exerting anti-inflammatory properties. These compounds also act as the SARS-CoV-2 main protease inhibitors that block viral replication. Apart from cannabinoids, terpenes in cannabis plants have also been widely explored for their antiviral properties. With particular emphasis on four different viruses, SARS-CoV-2, human immunodeficiency virus, hepatitis C virus, and herpes simplex virus-1, this review discussed the role of cannabis compounds in combating viral infections and the potential of both cannabinoids and terpenes as novel antiviral therapeutics.

Development of Disaster Response Strategies for Multi-Disasters (preprint)

The purpose of this research is to develop a disaster response strategy that can be used when more than one disaster happens at the same time. When different types of disasters occur at the same time, disaster response operations will become extremely complex. It is difficult for responders to directly perform response operations based on a single standard operation procedure. This research used flooding events that occurred in Taiwan during the COVID pandemic as an example case to develop the response strategies. The standard operating procedures before and after the pandemic were first reviewed. The authors also joined the response operations to have close observations on how responders execute response operations under restrictions of the pandemic. User interviews were then conducted to collect feedback from four responders. Finally, the multi-disaster response strategies, coined as OPERATE, was developed based on results of procedure review, field observations, and user interviews. OPERATE was developed for disaster response teams to smoothly execute response operations when multiple disasters occur simultaneously. It includes seven perspectives: simplified operation, flexible procedures, adjustable environment, personalized reminder, positive attitude, well-developed decision support tool, and preparatory education. OPERATE is developed to reduce the impact of multi-disasters on response teams, including the impact of the disaster itself and orders issued by other government departments in response to other disasters. Following the developed strategies, disaster response teams are expected to conduct stable and efficient operations in the context of multiple disasters.

Liver injury in COVID-19: Clinical features, potential mechanisms, risk factors and clinical treatments.

The coronavirus disease 2019 (COVID-19) pandemic has been a serious threat to global health for nearly 3 years. In addition to pulmonary complications, liver injury is not uncommon in patients with novel COVID-19. Although the prevalence of liver injury varies widely among COVID-19 patients, its incidence is significantly increased in severe cases. Hence, there is an urgent need to understand liver injury caused by COVID-19. Clinical features of liver injury include detectable liver function abnormalities and liver imaging changes. Liver function tests, computed tomography scans, and ultrasound can help evaluate liver injury. Risk factors for liver injury in patients with COVID-19 include male sex, preexisting liver disease including liver transplantation and chronic liver disease, diabetes, obesity, and hypertension. To date, the mechanism of COVID-19-related liver injury is not fully understood. Its pathophysiological basis can generally be explained by systemic inflammatory response, hypoxic damage, ischemia-reperfusion injury, and drug side effects. In this review, we systematically summarize the existing literature on liver injury caused by COVID-19, including clinical features, underlying mechanisms, and potential risk factors. Finally, we discuss clinical management and provide recommendations for the care of patients with liver injury.

Historical Evolutionary Dynamics and Phylogeography Analysis of Transmissible Gastroenteritis Virus and Porcine Deltacoronavirus: Findings from 59 Suspected Swine Viral Samples from China.

Since the beginning of the 21st century, humans have experienced three coronavirus pandemics, all of which were transmitted to humans via animals. Recent studies have found that porcine deltacoronavirus (PDCoV) can infect humans, so swine enteric coronavirus (SeCoV) may cause harm through cross-species transmission. Transmissible gastroenteritis virus (TGEV) and PDCoV have caused tremendous damage and loss to the pig industry around the world. Therefore, we analyzed the genome sequence data of these two SeCoVs by evolutionary dynamics and phylogeography, revealing the genetic diversity and spatiotemporal distribution characteristics. Maximum likelihood and Bayesian inference analysis showed that TGEV could be divided into two different genotypes, and PDCoV could be divided into four main lineages. Based on the analysis results inferred by phylogeography, we inferred that TGEV might originate from America, PDCoV might originate from Asia, and different migration events had different migration rates. In addition, we also identified positive selection sites of spike protein in TGEV and PDCoV, indicating that the above sites play an essential role in promoting membrane fusion to achieve adaptive evolution. In a word, TGEV and PDCoV are the past and future of SeCoV, and the relatively smooth transmission rate of TGEV and the increasing transmission events of PDCoV are their respective transmission characteristics. Our results provide new insights into the evolutionary characteristics and transmission diversity of these SeCoVs, highlighting the potential for cross-species transmission of SeCoV and the importance of enhanced surveillance and biosecurity measures for SeCoV in the context of the COVID-19 epidemic.

Effective approaches to disaster evacuation during a COVID-like pandemic (preprint)

Since COVID-19 vaccines became available, no studies have quantified how different disaster evacuation strategies can mitigate pandemic risks in shelters. Therefore, we applied an age-structured epidemiological model, known as the Susceptible-Exposed-Infectious-Recovered (SEIR) model, to investigate to what extent different vaccine uptake levels and the Diversion protocol implemented in Taiwan decrease infections and delay pandemic peak occurrences. Taiwan's Diversion protocol involves diverting those in self-quarantine due to exposure, thus preventing them from mingling with the general public at a congregate shelter. The Diversion protocol, combined with sufficient vaccine uptake, can decrease the maximum number of infections and delay outbreaks relative to scenarios without such strategies. When the diversion of all exposed people is not possible, or vaccine uptake is insufficient, the Diversion protocol is still valuable. Furthermore, a group of evacuees that consists primarily of a young adult population tends to experience pandemic peak occurrences sooner and have up to 180% more infections than does a majority elderly group when the Diversion protocol is implemented. However, when the Diversion protocol is not enforced, the majority elderly group suffers from up to 20% more severe cases than the majority young adult group.

A Perspective on the Influence of National Corporate Governance Institutions and Government's Political Ideology on the Speed to Lockdown as a Means of Protection Against Covid-19.

This first wave study of the Covid-19 pandemic investigates why the governments of different countries proceeded to lockdown at different speeds. We draw upon the literature on Corporate Governance Institutions (CGIs) to theorize that governments' decision-making is undertaken in the light of prevailing beliefs, norms, and rules of the collectivity, as portrayed by the focal country's CGIs, in their effort to maintain legitimacy. In addition, drawing on motivated cognition we posit that the government's political ideology moderates this relationship because decision-makers are biased when assessing the impact of lockdown on commerce. Running negative binomial regressions on a sample of 125 countries, we find that the more shareholder-oriented the CGIs, the slower the governmental response in shutting down the economy to protect from the pandemic. Moreover, the main relationship is stronger the more right-leaning the government's ideology. Our study contributes to the research on corporate governance institutions and political ideology and illustrates how societal and ideological biases affect government decision-making, especially when important decisions about public welfare are taken with little information on hand.

SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl- accumulation in respiratory epithelium.

SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl- is a crucial regulator of host defense, whereas the role of Cl- signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl- concentration ([Cl-]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl-]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl-]i. Our findings suggested that Cl- acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl- signaling pathway might be a novel therapeutic strategy for COVID-19.

Viral Vector Vaccine Development and Application during the COVID-19 Pandemic.

With the accumulation of mutations in SARS-CoV-2 and the continuous emergence of new variants, the importance of developing safer and effective vaccines has become more prominent in combating the COVID-19 pandemic. Both traditional and genetically engineered vaccines have contributed to the prevention and control of the pandemic. However, in recent years, the trend of vaccination research has gradually transitioned from traditional to genetically engineered vaccines, with the development of viral vector vaccines attracting increasing attention. Viral vector vaccines have several unique advantages compared to other vaccine platforms. The spread of Omicron has also made the development of intranasal viral vector vaccines more urgent, as the infection site of Omicron is more prominent in the upper respiratory tract. Therefore, the present review focuses on the development of viral vector vaccines and their application during the COVID-19 pandemic.

Mobile health applications: awareness, attitudes, and practices among medical students in Malaysia.

BACKGROUND: The popularity of mobile health (mHealth) applications (or apps) in the field of health and medical education is rapidly increasing, especially since the COVID-19 pandemic. We aimed to assess awareness, attitudes, practices, and factors associated with the mHealth app usage among medical students. METHODS: We conducted a cross-sectional study involving medical students at a government university in Sarawak, Malaysia, from February to April 2021. Validated questionnaires were administered to all consenting students. These questionnaires included questions on basic demographic information as well as awareness, attitude toward, and practices with mHealth apps concerned with medical education, health and fitness, and COVID-19 management. RESULTS: Respondents had favorable attitudes toward mHealth apps (medical education [61.8%], health and fitness [76.3%], and COVID-19 management [82.7%]). Respondents' mean attitude scores were four out of five for all three app categories. However, respondents used COVID-19 management apps more frequently (73.5%) than those for medical education (35.7%) and fitness (39.0%). Usage of all three app categories was significantly associated with the respondent's awareness and attitude. Respondents in the top 20% in term of household income and study duration were more likely to use medical education apps. The number of respondents who used COVID-19 apps was higher in the top 20% household income group than in the other income groups. The most common barrier to the use of apps was uncertainty regarding the most suitable apps to choose. CONCLUSION: Our study highlighted a discrepancy between awareness of mHealth apps and positive attitudes toward them and their use. Recognition of barriers to using mHealth apps by relevant authorities may be necessary to increase the usage of these apps.

The Advances of Broad-Spectrum and Hot Anti-Coronavirus Drugs.

Coronaviruses, mainly including severe acute respiratory syndrome virus, severe acute respiratory syndrome coronavirus 2, Middle East respiratory syndrome virus, human coronavirus OC43, chicken infectious bronchitis virus, porcine infectious gastroenteritis virus, porcine epidemic diarrhea virus, and murine hepatitis virus, can cause severe diseases in humans and livestock. The severe acute respiratory syndrome coronavirus 2 is infecting millions of human beings with high morbidity and mortality worldwide, and the multiplicity of swine epidemic diarrhea coronavirus in swine suggests that coronaviruses seriously jeopardize the safety of public health and that therapeutic intervention is urgently needed. Currently, the most effective methods of prevention and control for coronaviruses are vaccine immunization and pharmacotherapy. However, the emergence of mutated viruses reduces the effectiveness of vaccines. In addition, vaccine developments often lag behind, making it difficult to put them into use early in the outbreak. Therefore, it is meaningful to screen safe, cheap, and broad-spectrum antiviral agents for coronaviruses. This review systematically summarizes the mechanisms and state of anti-human and porcine coronavirus drugs, in order to provide theoretical support for the development of anti-coronavirus drugs and other antivirals.

The global response: How cities and provinces around the globe tackled Covid-19 outbreaks in 2021.

Background: Tackling the spread of COVID-19 remains a crucial part of ending the pandemic. Its highly contagious nature and constant evolution coupled with a relative lack of immunity make the virus difficult to control. For this, various strategies have been proposed and adopted including limiting contact, social isolation, vaccination, contact tracing, etc. However, given the heterogeneity in the enforcement of these strategies and constant fluctuations in the strictness levels of these strategies, it becomes challenging to assess the true impact of these strategies in controlling the spread of COVID-19. Methods: In the present study, we evaluated various transmission control measures that were imposed in 10 global urban cities and provinces in 2021- Bangkok, Gauteng, Ho Chi Minh City, Jakarta, London, Manila City, New Delhi, New York City, Singapore, and Tokyo. Findings: Based on our analysis, we herein propose the population-level Swiss cheese model for the failures and pitfalls in various strategies that each of these cities and provinces had. Furthermore, whilst all the evaluated cities and provinces took a different personalized approach to managing the pandemic, what remained common was dynamic enforcement and monitoring of breaches of each barrier of protection. The measures taken to reinforce the barriers were adjusted continuously based on the evolving epidemiological situation. Interpretation: How an individual city or province handled the pandemic profoundly affected and determined how the entire country handled the pandemic since the chain of transmission needs to be broken at the very grassroot level to achieve nationwide control. Funding: The present study did not receive any external funding.

Swine Enteric Coronavirus: Diverse Pathogen-Host Interactions.

Swine enteric coronavirus (SeCoV) causes acute gastroenteritis and high mortality in newborn piglets. Since the last century, porcine transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) have swept farms all over the world and caused substantial economic losses. In recent years, porcine delta coronavirus (PDCoV) and swine acute diarrhea syndrome coronavirus (SADS-CoV) have been emerging SeCoVs. Some of them even spread across species, which made the epidemic situation of SeCoV more complex and changeable. Recent studies have begun to reveal the complex SeCoV-host interaction mechanism in detail. This review summarizes the current advances in autophagy, apoptosis, and innate immunity induced by SeCoV infection. These complex interactions may be directly involved in viral replication or the alteration of some signal pathways.