Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus' evolution.

Recommendations and guidelines for the diagnosis and management of Coronavirus Disease-19 (COVID-19) associated bacterial and fungal infections in Taiwan.

Coronavirus disease-19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2 that has rapidly evolved into a pandemic to cause over 600 million infections and more than 6.6 million deaths up to Nov 25, 2022. COVID-19 carries a high mortality rate in severe cases. Co-infections and secondary infections with other micro-organisms, such as bacterial and fungus, further increases the mortality and complicates the diagnosis and management of COVID-19. The current guideline provides guidance to physicians for the management and treatment of patients with COVID-19 associated bacterial and fungal infections, including COVID-19 associated bacterial infections (CABI), pulmonary aspergillosis (CAPA), candidiasis (CAC) and mucormycosis (CAM). Recommendations were drafted by the 7th Guidelines Recommendations for Evidence-based Antimicrobial agents use Taiwan (GREAT) working group after review of the current evidence, using the grading of recommendations assessment, development, and evaluation (GRADE) methodology. A nationwide expert panel reviewed the recommendations in March 2022, and the guideline was endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline includes the epidemiology, diagnostic methods and treatment recommendations for COVID-19 associated infections. The aim of this guideline is to provide guidance to physicians who are involved in the medical care for patients with COVID-19 during the ongoing COVID-19 pandemic.

The first imported case of monkeypox in Taiwan.

he first imported case of monkeypox in Taiwan was diagnosed in an Asian man with HIV-1 infection and asymptomatic COVID-19, returning from Germany. Atypical presentations included asynchronous skin lesions, anogenital lesions and prominent inguinal lymphadenopathy. Whole genomic sequence alignment indicate that the Taiwan strain clustered together with human monkeypox virus West African clade B.1, currently circulating in Europe. Prompt diagnosis and infection control measures are crucial to mitigate the spread of monkeypox.

Real-Time Monitoring of Infectious Disease Outbreaks with a Combination of Google Trends Search Results and the Moving Epidemic Method: A Respiratory Syncytial Virus Case Study.

The COVID-19 pandemic has disrupted the seasonal patterns of several infectious diseases. Understanding when and where an outbreak may occur is vital for public health planning and response. We usually rely on well-functioning surveillance systems to monitor epidemic outbreaks. However, not all countries have a well-functioning surveillance system in place, or at least not for the pathogen in question. We utilized Google Trends search results for RSV-related keywords to identify outbreaks. We evaluated the strength of the Pearson correlation coefficient between clinical surveillance data and online search data and applied the Moving Epidemic Method (MEM) to identify country-specific epidemic thresholds. Additionally, we established pseudo-RSV surveillance systems, enabling internal stakeholders to obtain insights on the speed and risk of any emerging RSV outbreaks in countries with imprecise disease surveillance systems but with Google Trends data. Strong correlations between RSV clinical surveillance data and Google Trends search results from several countries were observed. In monitoring an upcoming RSV outbreak with MEM, data collected from both systems yielded similar estimates of country-specific epidemic thresholds, starting time, and duration. We demonstrate in this study the potential of monitoring disease outbreaks in real time and complement classical disease surveillance systems by leveraging online search data.

Safety and Efficacy of Oral administrated Cepharathine in Non-hospitalized, asymptomatic or mild COVID-19 patients: A Double-blind, Randomized, Placebo-controlled Trial (preprint)

Cepharanthine (CEP) is a natural remedy that potently inhibits SARS-CoV-2 activity both in vitro and in vivo. We conducted a proof-of-concept, double-blind, randomized, placebo-controlled trial among adults with asymptomatic or mild coronavirus disease 2019 (COVID-19). Patients were stratified randomly to de novo infection or viral rebound, and assigned in a 1:1:1 ratio to receive 60 mg/day or 120 mg/day of CEP or placebo. Primary outcome the time from randomization to negative nasopharyngeal swab, and safety were evaluated. A total of 262 de novo infected and 124 viral rebound patients underwent randomization. In the 188 de novo patients included in modified intention-to-treat (mITT) population, when compared with placebo, 60 mg/day CEP slightly shortened the time to negative (difference=-0.77 days, hazard ratio (HR)=1.40, 95% CI 0.97 to 2.01, p=0.072), and 120 mg/day CEP did not show the trend. Among de novo patients in the per-protocol set (PPS), 60 mg/day CEP significantly shortened the time to negative (difference=-0.87 days, HR=1.56, 95% CI 1.03 to 2.37, p=0.035). Among viral rebound patients in the mITT population, neither 120 mg/day nor 60 mg/day CEP significantly shortened the time to negative compared to placebo. Adverse events were not different among the three groups, and no serious adverse events occurred. Treatment of asymptomatic or mild Covid-19 with 120 mg/day or 60 mg/day CEP did not shorten the time to negative compared with placebo, without evident safety concerns. Among de novo infected patients with good compliance, 60 mg/day CEP significantly shortened the time to negative compared with placebo ( NCT05398705 ).

Flexible analytic model to inform multi-stakeholder pediatric vaccine scheduling decisions.

BACKGROUND: Pediatric immunization is important for preventing potentially life-threatening diseases in children. Over time, the number of recommended pediatric vaccines has increased and is likely to increase further as new vaccines are developed. Given the different number of doses for available vaccines and various constraints (e.g., the appropriate age for each dose of a vaccine or the time between doses), it is challenging to develop a recommended vaccination schedule or a catch-up schedule when a child falls behind on one or more vaccinations. METHODS: We developed an integer programming optimization model, enabled by Python programming and embedded into an Excel-based decision tool, to recommend childhood vaccination schedules or personalized catch-up schedules. The model recommends a vaccination schedule that balances the goal of being as close as possible to the clinically-indicated dosing schedules and the goal of minimizing clinic visits, and gives users the ability to trade off between these two goals. We illustrated the broad applicability of our proposed model with commonly-faced vaccine scheduling challenges in the United States. RESULTS: The illustrative computational case study confirms our model's ability to create personalized schedules based on each child's age and vaccination history, and to adjust appropriately when a new vaccine becomes available. CONCLUSIONS: The model presented in this paper fills the need for an easy-to-use tool to recommend vaccination schedules for de novo and catch-up purposes. It provides straightforward recommendations that can be easily used by physicians, is flexible to handle the requirements varying by region, and can be updated as new vaccines are approved for use.

A Positive Legacy of Trauma? The Role of Perceived Social Support on Mental Health Among Earthquake Survivors During the COVID-19 Outbreak.

Background: People with prior experience of severe trauma may be particularly vulnerable in the face of the COVID-19 pandemic. However, little is known about mental health problems among prior trauma survivors during the pandemic outbreak. Methods: A total of 362 Wenchuan earthquake survivors were assessed using Patient Health Questionnaire, Generalized Anxiety Disorder Scale, as well as Multidimensional Scale of Perceived Social Support, as part of an online survey between February 3 and 10, 2020. Results: Our results showed that 6.6 and 4.7% of the participants experienced depression and anxiety during the COVID-19 outbreak, respectively. Perceived social support was negatively associated with depressive and anxiety symptoms. Earthquake exposure has no direct effect on current depressive and anxiety symptoms, but it would moderate the direct relationship between perceived social support and psychological symptoms. Conclusions: Our findings suggested that trauma exposure may lead to salutogenic outcomes. The protective effect of perceived social support on psychological symptoms was greater in people with a higher level of trauma exposure than in a lower one.

Clinical features and effectiveness of Chinese medicine in patients with COVID-19 from overseas: A retrospective study in Xiamen, China.

COVID-19, referred to as new coronary pneumonia, is an acute infectious disease caused by a new type of coronavirus SARS-CoV-2. To evaluate the effect of integrated Chinese medicine and Western medicine in patients with COVID-19 from overseas. Data were collected from 178 COVID-19 patients overseas at First Affiliated Hospital of Xiamen University from April 1, 2021 to July 31, 2021. These patients received therapy of integrated Chinese medicine and western medicine. Demographic data and clinical characteristics were extracted and analyzed. In addition, the prescription which induced less length of PCR positive days and hospitalization days than the median value was obtained. The top 4 frequently used Chinese medicine and virus-related genes were analyzed by network pharmacology and bioinformatics analysis. According to the chest computed tomography (CT) measurement, abnormal lung findings were observed in 145 subjects. The median length of positive PCR/hospitalization days was 7/7 days for asymptomatic subjects, 14/24 days for mild subjects, 10/15 days for moderate subjects, and 14/20 days for severe subjects. The most frequently used Chinese medicine were Scutellaria baicalensis (Huangqin), Glycyrrhiza uralensis (Gancao), Bupleurum chinense (Chaihu), and Pinellia ternata (Banxia). The putative active ingredients were baicalin, stigmasterol, sigmoidin-B, cubebin, and troxerutin. ACE, SARS-CoV-2 3CL, SARS-CoV-2 Spike, SARS-CoV-2 ORF7a, and caspase-6 showed good binding properties to active ingredients. In conclusion, the clinical results showed that integrated Chinese medicine and Western medicine are effective in treating COVID-19 patients from overseas. Based on the clinical outcomes, the putative ingredients from Chinese medicine and the potential targets of SARS-CoV-2 were provided, which could provide a reference for the clinical application of Chinese medicine in treating COVID-19 worldwide.

A triple-RBD-based mucosal vaccine provides broad protection against SARS-CoV-2 variants of concern.

The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broad-spectrum protection against the initial infection and thereby curb the transmission potential. Here, we designed a chimeric triple-RBD immunogen, 3Ro-NC, harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold. 3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern. Notably, intranasal immunization with 3Ro-NC plus the mucosal adjuvant KFD (3Ro-NC + KFDi.n) elicits coordinated mucosal IgA and higher neutralizing antibody specificity (closer antigenic distance) against the Omicron variant. In Omicron-challenged human ACE2 transgenic mice, 3Ro-NC + KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung (85.7-fold) and the nasal turbinate (13.6-fold). Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies. Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection, pathology and transmission potential.

Predicting and preventing COVID-19 outbreaks in indoor environments: an agent-based modeling study.

How to mitigate the spread of infectious diseases like COVID-19 in indoor environments remains an important research question. In this study, we propose an agent-based modeling framework to evaluate facility usage policies that aim to lower the probability of outbreaks. The proposed framework is individual-based, spatially-resolved with time resolution of up to 1 s, and takes into detailed account specific floor layouts, occupant schedules and movement. It enables decision makers to compute realistic contact networks and generate risk profiles of their facilities without relying on wearable devices, smartphone tagging or surveillance cameras. Our demonstrative modeling results indicate that not all facility occupants present the same risk of starting an outbreak, where the driver of outbreaks varies with facility layouts as well as individual occupant schedules. Therefore, generic mitigation strategies applied across all facilities should be considered inferior to tailored policies that take into account individual characteristics of the facilities of interest. The proposed modeling framework, implemented in Python and now available to the public in an open-source platform, enables such strategy evaluation.

A Granulation Tissue Detection Model to Track Chronic Wound Healing in DM Foot Ulcers

Diabetes mellitus (DM) foot ulcer is a chronic wound and is highly related to the mortality and morbidity of infection, and might induce sepsis and foot amputation, especially during the isolation stage of the COVID-19 pandemic. Visual observation when changing dressings is the most common and traditional method of detecting wound healing. The formation of granulation tissues plays an important role in wound healing. In the complex pathophysiology of excess and unhealthy granulation induced by infection, oxygen supply may explain the wound healing process in DM patients with multiple complicated wounds. Thus, advanced and useful tools to observe the condition of wound healing are very important for DM patients with extremities ulcers. For this purpose, we developed an artificial intelligence (AI) detection model to identify the growth of granulation tissue of the wound bed. We recruited 100 patients to provide 219 images of wounds at different healing stages from 2 hospitals. This was performed to understand the wound images of inconsistent size, and to allow self-inspection on mobile devices, having limited computing resources. We segmented those images into 32 ×32 blocks and used a reduced ResNet-18 model to test them individually. Furthermore, we conducted a learning method of active learning to improve the efficiency of model training. Experimental results reveal that our model can identify the region of granulation tissue with an Intersection-over-Union (IOU) rate higher than 0.5 compared to the ground truth. Multiple cross-repetitive validations also confirm that the detection results of our model may serve as an auxiliary indicator for assessing the progress of wound healing. The preliminary findings may help to identify the granulation tissue of patients with DM foot ulcer, which may lead to better long-term home care during the COVID-19 pandemic. The current limit of our model is an IOU of about 0.6. If more actual data are available, the IOU is expected to improve. We can continue to use the currently established active learning process for subsequent training.

Rational design of AAVrh10-vectored ACE2 functional domain to broadly block the cell entry of SARS-CoV-2 variants.

The frequently emerging SARS-CoV-2 variants have weakened the effectiveness of existing COVID-19 vaccines and neutralizing antibody therapy. Nevertheless, the infections of SARS-CoV-2 variants still depend on angiotensin-converting enzyme 2 (ACE2) receptor-mediated cell entry, and thus the soluble human ACE2 (shACE2) is a potential decoy for broadly blocking SARS-CoV-2 variants. In this study, we firstly generated the recombinant AAVrh10-vectored shACE2 constructs, a kind of adeno-associated virus (AAV) serotype with pulmonary tissue tropism, and then validated its inhibition capacity against SARS-CoV-2 infection. To further optimize the minimized ACE2 functional domain candidates, a comprehensive analysis was performed to clarify the interactions between the ACE2 orthologs from various species and the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein. Based on the key interface amino acids, we designed a series of truncated ACE2 orthologs, and then assessed their potential affinity to bind to SARS-CoV-2 variants RBD in silico. Of note, we found that the 24-83aa fragment of dog ACE2 (dACE224-83) had a higher affinity to the RBD of SARS-CoV-2 variants than that of human ACE2. Importantly, AAVrh10-vectored shACE2 or dACE224-83 constructs exhibited a broadly blockage breadth against SARS-CoV-2 prototype and variants in vitro and ex vivo. Collectively, these data highlighted a promising therapeutic strategy against SARS-CoV-2 variants.

Distinct immune responses in the early phase to natural SARS-CoV-2 infection or vaccination.

Immune responses elicited by viral infection or vaccination play key roles in the viral elimination and the prevention of reinfection, as well as the protection of healthy persons. As one of the most widely used Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, there have been increasing concerns about the necessity of additional doses of inactivated vaccines, due to the waning immune response several months after vaccination. To further optimize inactivated SARS-CoV-2 vaccines, we compared immune responses to SARS-CoV-2 elicited by natural infection and immunization with inactivated vaccines in the early phase. We observed the lower antibody levels against SARS-CoV-2 spike (S) and nucleocapsid (N) proteins in the early phase of postvaccination with a slow increase, compared to the acute phase of SARS-CoV-2 natural infection. Specifically, IgA antibodies have the most significant differences. Moreover, we further analyzed cytokine expression between these two groups. A wide variety of cytokines presented high expression in the infected individuals, while a few cytokines were elicited by inactivated vaccines. The differences in antibody responses and cytokine levels between natural SARS-CoV-2 infection and vaccination with the inactivated vaccines may provide implications for the optimization of inactivated SARS-CoV-2 vaccines and the additional application of serological tests.

Comparative global B cell receptor repertoire difference induced by SARS-CoV-2 infection or vaccination via single-cell V(D)J sequencing.

Dynamic changes of the paired heavy and light chain B cell receptor (BCR) repertoire provide an essential insight into understanding the humoral immune response post-SARS-CoV-2 infection and vaccination. However, differences between the endogenous paired BCR repertoire kinetics in SARS-CoV-2 infection and previously recovered/naïve subjects treated with the inactivated vaccine remain largely unknown. We performed single-cell V(D)J sequencing of B cells from six healthy donors with three shots of inactivated SARS-CoV-2 vaccine (BBIBP-CorV), five people who received the BBIBP-CorV vaccine after having recovered from COVID-19, five unvaccinated COVID-19 recovered patients and then integrated with public data of B cells from four SARS-CoV-2-infected subjects. We discovered that BCR variable (V) genes were more prominently used in the SARS-CoV-2 exposed groups (both in the group with active infection and in the group that had recovered) than in the vaccinated groups. The VH gene that expanded the most after SARS-CoV-2 infection was IGHV3-33, while IGHV3-23 in the vaccinated groups. SARS-CoV-2-infected group enhanced more BCR clonal expansion and somatic hypermutation than the vaccinated healthy group. A small proportion of public clonotypes were shared between the SARS-CoV-2 infected, vaccinated healthy, and recovered groups. Moreover, several public antibodies had been identified against SARS-CoV-2 spike protein. We comprehensively characterize the paired heavy and light chain BCR repertoire from SARS-CoV-2 infection to vaccination, providing further guidance for the development of the next-generation precision vaccine.

Relationship Between Negative Emotions and Job Burnout in Medical Staff During the Prevention and Control of the COVID-19 Epidemic: The Mediating Role of Psychological Resilience.

We herein investigated the relationship between psychological status and the various emotions of medical staff during the prevention and control of coronavirus disease 2019 (COVID-19) epidemic. In this study, the convenience sampling method was used to select medical staff members as participants, and a cross-sectional study design was implemented. The instruments included the Burnout Clinical Subtype Questionnaire (BCSQ-36), the 10-item Connor-Davidson Resilience Scale (CD-RISC-10), the self-rated 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16), and the Self-rating Anxiety Scale (SAS). In total, 876 medical staff members were selected in this study. The CD-RISC-10 was negatively correlated with all other scales (P < 0.01). The hierarchical regression coefficients of the SAS and QIDS-SR16 against the BCSQ-36 mediated by the CD-RISC-10 were P < 0.01, and the significance of the F values in all hierarchical regression equations was P < 0.01 (Sobel test, P < 0.01). Medical staff burnout during the COVID-19 epidemic was affected by anxiety and depression, and psychological resilience had a mediating role. Attending to changes in the negative emotions of medical staff and improving their psychological resilience are beneficial to alleviate job burnout.

ORF8 protein of SARS-CoV-2 reduces male fertility in mice.

As one of the most rapidly evolving proteins of the genus Betacoronavirus, open reading frames (ORF8's) function and potential pathological consequence in vivo are still obscure. In this study, we show that the secretion of ORF8 is dependent on its N-terminal signal peptide sequence and can be inhibited by reactive oxygen species scavenger and endoplasmic reticulum-Golgi transportation inhibitor in cultured cells. To trace the effect of its possible in vivo secretion, we examined the plasma samples of coronavirus disease 2019 (COVID-19) convalescent patients and found that the patients aged from 40 to 60 had higher antibody titers than those under 40. To explore ORF8's in vivo function, we administered the mice with ORF8 via tail-vein injection to simulate the circulating ORF8 in the patient. Although no apparent difference in body weight, food intake, and vitality was detected between vehicle- and ORF8-treated mice, the latter displayed morphological abnormalities of testes and epididymides, as indicated by the loss of the central ductal lumen accompanied by a decreased fertility in 5-week-old male mice. Furthermore, the analysis of gene expression in the testes between vehicle- and ORF8-treated mice identified a decreased expression of Col1a1, the loss of which is known to be associated with mice's infertility. Although whether our observation in mice could be translated to humans remains unclear, our study provides a potential mouse model that can be used to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the human reproductive system.

A Positive Legacy of Trauma? The Role of Perceived Social Support on Mental Health Among Earthquake Survivors During the COVID-19 Outbreak

Background People with prior experience of severe trauma may be particularly vulnerable in the face of the COVID-19 pandemic. However, little is known about mental health problems among prior trauma survivors during the pandemic outbreak. Methods A total of 362 Wenchuan earthquake survivors were assessed using Patient Health Questionnaire, Generalized Anxiety Disorder Scale, as well as Multidimensional Scale of Perceived Social Support, as part of an online survey between February 3 and 10, 2020. Results Our results showed that 6.6 and 4.7% of the participants experienced depression and anxiety during the COVID-19 outbreak, respectively. Perceived social support was negatively associated with depressive and anxiety symptoms. Earthquake exposure has no direct effect on current depressive and anxiety symptoms, but it would moderate the direct relationship between perceived social support and psychological symptoms. Conclusions Our findings suggested that trauma exposure may lead to salutogenic outcomes. The protective effect of perceived social support on psychological symptoms was greater in people with a higher level of trauma exposure than in a lower one.