Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein.

Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor ß receptor I (TßRI), to disrupt the interaction of TßRI-FK506 Binding Protein12 (FKBP12), which led to activation of TßRI to phosphorylate Smad3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to Smad3 to disrupt TßRI-induced Smad3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting Smad3.

Biomarkers for Lipid and Albumin Metabolism in Hospitalized Patients with Underlying Diseases and Community-Acquired Pneumonia Caused by Bacterial or SARS-CoV-2 Infection.

Background: To look at the differences and similarities in albumin and lipid metabolism in non-severe COVID-19 infection, non-severe community-acquired pneumonia, and severe community pneumonia with underlying diseases, as well as the relationship between albumin and lipid metabolism and inflammatory mediators. Methods: This retrospective analysis comprised 253 individuals with bacterial pneumonia and COVID-19 infection (1 May 2021-1 May 2022). Routine blood examination, blood lipid levels, albumin level, C-reactive protein (CRP) levels, coagulation function, cardiac enzymes, liver function, renal function, immunological function, and bacterial culture were also collected. Correlation analysis was performed using Spearman's test for lipid parameter and Inflammatory factors in the blood. Furthermore, the multiple linear regression (MLR) analysis was employed to analyze the multicollinearity in lipidomics data. The statistical analysis was performed using SPSS statistic version 19.0. Results: There were 63 (24.90%) non-severe community-acquired pneumonia patients (NSCAP), 48 (18.97%) severe community-acquired pneumonia patients (SCAP), 112 (44.27%) non-severe COVID-19 infection patients (NSCOV), and 30 (11.86%) healthy volunteers (HV). In all, 45.59% (116/253) of the patients had underlying diseases. Patients with community-acquired pneumonia had lower albumin and cholesterol levels than those with non-severe COVID-19 infection and healthy controls (t = -3.81, -2.09, P = 0.00, 0.04). Albumin, triglyceride, cholesterol, and LDL-C levels in peripheral blood were considerably lower in the SCAP group than in the NSCAP group. Albumin, cholesterol, HDL-C, LDL-C, and aop-A were all inversely connected with CRP in the SCAP with underlying illness group, but cholesterol level was favorably correlated with lymphocyte count (R = 0.36, P = 0.01). Hypoproteinemia, hypotriglyceridemia, and an elevated neutrophil-to-lymphocyte count ratio are all risk factors for severe community-acquired pneumonia. Conclusion: Hypoalbuminemia and abnormal lipid metabolism are important indicators of bacterial infection, especially severe bacterial pneumonia.

Field-effect transistor antigen/antibody-TMDs sensors for the detection of COVID-19 samples.

We fabricated sensors by modifying the surface of MoS2 and WS2 with COVID-19 antibodies and investigated their characteristics, including stability, reusability, sensitivity, and selectivity. Thiols and disulfanes in antibodies strongly interact with vacant Mo or W sites of MoS2 or WS2, yielding durable devices that are stable for several days in the air or water. More importantly, detachment of the antibodies is suppressed even during the aggressive cleaning process of the devices at pH 3, which allows reusing the same device in several experiments without appreciable loss of sensitivity. Therefore, the nanodevice may be employed in samples of different patients. Further, we found a limit of detection (LOD) of 1 fg ml-1 at room temperature, time responses of 1 second, and selectivity against interferences such as KLH protein or Albumin.

Open Innovation in Times of Crisis: An Overview of the Healthcare Sector in Response to the COVID-19 Pandemic

The COVID-19 pandemic has caused huge and disruptive technological changes in the healthcare sector, transforming the way businesses and societies function. To respond to the global health crisis, there have been numerous innovation projects in the healthcare sector, including the fast design and manufacturing of personal protective equipment (PPE) and medical devices, and testing, treatment, and vaccine technologies. Many of these innovative activities happen beyond organizational boundaries with collaboration and open innovation. In this paper, we review the current literature on open innovation strategy during the pandemic and adopt the co-evolution view of business ecosystems to address the context of change. Based on a detailed exploration of the COVID-19-related technologies in the UK and global healthcare sectors, we identify the key emerging themes of open innovation in crisis. Further discussions are conducted in relation to each theme. Our results and analysis can help provide policy recommendations for the healthcare sector, businesses, and society to recover from the crisis.

Long-term Consequences of COVID-19: Chemosensory Disorders.

PURPOSE OF REVIEW: A number of sequelae after acute coronavirus disease 2019 (COVID-19) significantly affect the quality of life of patients. The chemosensory disorders including olfactory dysfunction (OD) and gustatory dysfunction (GD) are two of the commonest symptoms complained by patients with COVID-19. Although chemosensory function has been reported improved in over 60% of COVID-19 patients in a short time after acute infection, it may last as a major symptom for patients with long COVID-19. This narrative review discussed current literatures on OD and GD in long COVID-19 including the prevalence, risk factors, possible mechanisms, and potential therapies. RECENT FINDINGS: Although the prevalence of OD and GD has declined continuously after acute COVID-19, a considerable number of patients had persistent chemosensory disorders 3 months to 2 years after symptom onset. Female gender, initial severity of dysfunction, nasal congestion, emotional distress and depression, and SARS-CoV-2 variants have been identified as risk factors for persistent OD and GD in long COVID-19. The pathogenesis of OD and GD in long COVID-19 remains unknown, but may be analogous to the persistent OD and GD post common respiratory viral infection. Corticosteroids and olfactory training might be a potential choice regarding the treatment of lasting OD and GD after SARS-CoV-2 infection; however, more studies are needed to prove it. OD and GD are common long-term consequences of COVID-19 and influenced by gender, initial severity of dysfunction, emotional distress and depression, and SARS-CoV-2 variants. More studies are needed to illustrate their pathogenesis and to establish therapeutic strategies.

Biparatopic antibody BA7208/7125 effectively neutralizes SARS-CoV-2 variants including Omicron BA.1-BA.5.

SARS-CoV-2 Omicron subvariants have demonstrated extensive evasion from monoclonal antibodies (mAbs) developed for clinical use, which raises an urgent need to develop new broad-spectrum mAbs. Here, we report the isolation and analysis of two anti-RBD neutralizing antibodies BA7208 and BA7125 from mice engineered to produce human antibodies. While BA7125 showed broadly neutralizing activity against all variants except the Omicron sublineages, BA7208 was potently neutralizing against all tested SARS-CoV-2 variants (including Omicron BA.1-BA.5) except Mu. By combining BA7208 and BA7125 through the knobs-into-holes technology, we generated a biparatopic antibody BA7208/7125 that was able to neutralize all tested circulating SARS-CoV-2 variants. Cryo-electron microscopy structure of these broad-spectrum antibodies in complex with trimeric Delta and Omicron spike indicated that the contact residues are highly conserved and had minimal interactions with mutational residues in RBD of current variants. In addition, we showed that administration of BA7208/7125 via the intraperitoneal, intranasal, or aerosol inhalation route showed potent therapeutic efficacy against Omicron BA.1 and BA.2 in hACE2-transgenic and wild-type mice and, separately, effective prophylaxis. BA7208/7125 thus has the potential to be an effective candidate as an intervention against COVID-19.

Chinese Guideline on Allergen Immunotherapy for Allergic Rhinitis: The 2022 Update.

In the last few decades, there has been a progressive increase in the prevalence of allergic rhinitis (AR) in China, where it now affects approximately 250 million people. AR prevention and treatment include allergen avoidance, pharmacotherapy, allergen immunotherapy (AIT), and patient education, among which AIT is the only curative intervention. AIT targets the disease etiology and may potentially modify the immune system as well as induce allergen-specific immune tolerance in patients with AR. In 2017, a team of experts from the Chinese Society of Allergy (CSA) and the Chinese Allergic Rhinitis Collaborative Research Group (C2AR2G) produced the first English version of Chinese AIT guidelines for AR. Since then, there has been considerable progress in basic research of and clinical practice for AIT, especially regarding the role of follicular regulatory T (TFR) cells in the pathogenesis of AR and the use of allergen-specific immunoglobulin E (sIgE) in nasal secretions for the diagnosis of AR. Additionally, potential biomarkers, including TFR cells, sIgG4, and sIgE, have been used to monitor the incidence and progression of AR. Moreover, there has been a novel understanding of AIT during the coronavirus disease 2019 pandemic. Hence, there was an urgent need to update the AIT guideline for AR by a team of experts from CSA and C2AR2G. This document aims to serve as professional reference material on AIT for AR treatment in China, thus improving the development of AIT across the world.

The relationship between online courses and mental health among Chinese children

Background Previous studies on the association of online courses and mental health were mainly conducted in universities, and no study investigated the relationship between characteristics of online courses and children’s mental health in primary and secondary school. This study aimed to explore the association of online courses and children’s mental health in primary and secondary school. Methods A cross-sectional study was conducted through an online survey among 540 primary and secondary school students and their parents in the eastern, central and western region of China from April to May in 2020. Children’s mental health was assessed by the Strengths and Difficulties Questionnaire (SDQ). Borderline mental health problems (SDQ total difficulties score ≥ 16) and mental health problems (SDQ total difficulties score ≥ 20) were defined according to Goodman’s standard. Multivariable linear and logistic regression models were used to examine the association between online courses and children’s mental health. Results Compared with those who did not have problems of online courses, children having the difficulty in understanding the content of online courses had a higher SDQ total difficulties score [β = 1.80, 95% confidence interval (CI): 0.89, 2.71] and a higher risk of borderline mental health problems [odds ratio (OR) = 1.93, 95%CI: 1.07, 3.49], while device or internet connection problems were not significantly associated with children’s mental health. Compared with children who had live courses, those having video-recorded courses had a higher SDQ total difficulties score (β = 0.90, 95%CI: 0.01, 1.80). Children who spent more than 4 h on online courses had a higher SDQ total difficulties score than those of less than or equal to 4 h (β = 0.95, 95%CI: 0.09, 1.81). Conclusion We found that online courses with inappropriate characteristics were associated with children’s mental health. The findings called for the efforts to optimize the online courses and improve children’s mental health. Supplementary Information The online version contains supplementary material available at 10.1186/s12888-022-03976-2.

SARS-CoV-2 tetrameric RBD protein blocks viral infection and induces potent neutralizing antibody response.

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed serious threats to global health and economy and calls for the development of safe treatments and effective vaccines. The receptor-binding domain in the spike protein (S^RBD) of SARS-CoV-2 is responsible for its binding to angiotensin-converting enzyme 2 (ACE2) receptor. It contains multiple dominant neutralizing epitopes and serves as an important antigen for the development of COVID-19 vaccines. Here, we showed that dimeric S^RBD-Fc and tetrameric 2xS^RBD-Fc fusion proteins bind ACE2 with different affinity and block SARS-CoV-2 pseudoviral infection. Immunization of mice with S^RBD-Fc fusion proteins elicited high titer of RBD-specific antibodies with robust neutralizing activity against pseudoviral infections. As such, our study indicates that the polymeric S^RBD-Fc fusion protein can serve as a treatment agent as well as a vaccine for fighting COVID-19.

The relationship between online courses and mental health among Chinese children.

BACKGROUND: Previous studies on the association of online courses and mental health were mainly conducted in universities, and no study investigated the relationship between characteristics of online courses and children's mental health in primary and secondary school. This study aimed to explore the association of online courses and children's mental health in primary and secondary school. METHODS: A cross-sectional study was conducted through an online survey among 540 primary and secondary school students and their parents in the eastern, central and western region of China from April to May in 2020. Children's mental health was assessed by the Strengths and Difficulties Questionnaire (SDQ). Borderline mental health problems (SDQ total difficulties score ≥ 16) and mental health problems (SDQ total difficulties score ≥ 20) were defined according to Goodman's standard. Multivariable linear and logistic regression models were used to examine the association between online courses and children's mental health. RESULTS: Compared with those who did not have problems of online courses, children having the difficulty in understanding the content of online courses had a higher SDQ total difficulties score [ß = 1.80, 95% confidence interval (CI): 0.89, 2.71] and a higher risk of borderline mental health problems [odds ratio (OR) = 1.93, 95%CI: 1.07, 3.49], while device or internet connection problems were not significantly associated with children's mental health. Compared with children who had live courses, those having video-recorded courses had a higher SDQ total difficulties score (ß = 0.90, 95%CI: 0.01, 1.80). Children who spent more than 4 h on online courses had a higher SDQ total difficulties score than those of less than or equal to 4 h (ß = 0.95, 95%CI: 0.09, 1.81). CONCLUSION: We found that online courses with inappropriate characteristics were associated with children's mental health. The findings called for the efforts to optimize the online courses and improve children's mental health.

A New iNKT-Cell Agonist-Adjuvanted SARS-CoV-2 Subunit Vaccine Elicits Robust Neutralizing Antibody Responses.

Adjuvants are essential components of vaccines. Invariant natural killer T (iNKT) cells are a distinct subset of T cells that function to bridge the innate and adaptive immunities and are capable of mediating strong and rapid responses to a range of diseases, including cancer and infectious disease. An increasing amount of evidence suggests that iNKT cells can help fight viral infection. In particular, iNKT-secreting IL-4 is a key mediator of humoral immunity and has a positive correlation with the levels of neutralizing antibodies. As iNKT cell agonists, αGC glycolipid (α-galactosylceramide, or KRN7000) and its analogues as vaccine adjuvants have begun to provide vaccinologists with a new toolset. Herein we found that a new iNKT-cell agonist αGC-CPOEt elicited a strong cytokine response with increased IL-4 production. Remarkably, after three immunizations, SARS-CoV-2 RBD-Fc adjuvanted by αGC-CPOEt evoked robust neutralizing antibody responses that were about 5.5-fold more than those induced by αGC/RBD-Fc and 25-fold greater than those induced by unadjuvanted RBD-Fc. These findings imply that αGC-CPOEt could be investigated further as a new COVID-19 vaccine adjuvant to prevent current and future infectious disease outbreaks.

Interrupted-time-series analysis of the immediate impact of COVID-19 mitigation measures on preterm birth in China.

Preliminary evidence from China and other countries has suggested that coronavirus disease 2019 (COVID-19) mitigation measures have caused a decline in preterm births, but evidence is conflicting. Utilising a national representative data of 11,714,947 pregnant women in China, we explored the immediate changes in preterm birth rates during the COVID-19 mitigation period using an interrupted-time-series analysis. We defined the period prior to February 1, 2020 as the baseline, followed by the COVID-19 mitigation stage. In the first month of the COVID-19 mitigation, a significant absolute decrease in preterm birth rates of 0.68% (95%CI:-1.10% to -0.26%) in singleton, and of 2.80% (95%CI:-4.51% to -1.09%) in multiple births was noted. This immediate decline in Wuhan was greater than that at the national level among singleton births [-2.21% (95%CI:-4.09% to -0.34% vs. -0.68%)]. Here we report an immediate impact of COVID-19 mitigation measures on preterm birth in China.

Development of a Genetically Engineered Bivalent Vaccine against Porcine Epidemic Diarrhea Virus and Porcine Rotavirus.

Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus that causes acute diarrhea, vomiting, dehydration, and a high mortality rate in neonatal piglets. In recent years, PEDV has been associated with co-infections with other swine enteric viruses, including porcine rotavirus (PoRV), resulting in increased mortality among newborn piglets. In this paper, we developed a bivalent vaccine against PEDV and PoRV by constructing a recombinant PEDV encoding PoRV VP7 (rPEDV-PoRV-VP7). The recombinant virus was constructed by replacing the entire open reading frame 3 (ORF3) in the genome of an attenuated PEDV strain YN150 with the PoRV VP7 gene using reverse genetic systems. Similar plaque morphology and replication kinetics were observed in Vero cells with the recombinant PEDV compared to the wild-type PEDV. It is noteworthy that the VP7 protein could be expressed stably in rPEDV-PoRV-VP7-infected cells. To evaluate the immunogenicity and safety of rPEDV-PoRV-VP7, 10-day-old piglets were vaccinated with the recombinant virus. After inoculation, no piglet displayed clinical symptoms such as vomiting, diarrhea, or anorexia. The PoRV VP7- and PEDV spike-specific IgG in serum and IgA in saliva were detected in piglets after rPEDV-PoRV-VP7 vaccination. Moreover, both PoRV and PEDV neutralizing antibodies were produced simultaneously in the inoculated piglets. Collectively, we engineered a recombinant PEDV expressing PoRV VP7 that could be used as an effective bivalent vaccine against PEDV and PoRV.

Innovation in crisis: The role of 'exaptive relations' for medical device development in response to COVID-19.

The COVID-19 pandemic has resulted in huge disruption to the healthcare sector. In response to this, there have been collaborative efforts between many different public and private organizations to foster medical innovations. The effect of crisis upon innovation, particularly medical innovation, remains a debatable subject. In addition, the role of inter-personal relations is becoming more widely acknowledged as a critical feature of innovation. Drawing upon exaptation literature, the study aims to understand the nature of the micro-relations within medical innovations that are undertaken in response to COVID-19. The findings of this paper contribute to the limited literature that examines the performance of medical innovation in response to crisis. In addition to confirming the importance of exaptive pools, exaptive events, and exaptive forums in fostering serendipitous developments, the study makes a contribution to theory by identifying a further form of serendipitous encounter that is 'exaptive relations'.

Induction of Broadly Cross-Reactive Antibody Responses to SARS-CoV-2 Variants by S1 Nanoparticle Vaccines.

Despite the rapid deployment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, the emergence of SARS-CoV-2 variants and reports of their immune evasion characteristics have led to an urgent need for novel vaccines that confer potent cross-protective immunity. In this study, we constructed three different SARS-CoV-2 spike S1-conjugated nanoparticle vaccine candidates that exhibited high structural homogeneity and stability. Notably, these vaccines elicited up to 50-times-higher neutralizing antibody titers than the S1 monomer in mice. Crucially, it was found that the S1-conjugated nanoparticle vaccine could elicit comparable levels of neutralizing antibodies against wild-type or emerging variant SARS-CoV-2, with cross-reactivity to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), the effect of which could be further enhanced using our designed nanoparticles. Our results indicate that the S1-conjugated nanoparticles are promising vaccine candidates with the potential to elicit potent and cross-reactive immunity against not only wild-type SARS-CoV-2, but also its variants of concern, variants of interest, and even other pathogenic betacoronaviruses. IMPORTANCE The emergence of SARS-CoV-2 variants led to an urgent demand for a broadly effective vaccine against the threat of variant infection. The spike protein S1-based nanoparticle designed in our study could elicit a comprehensive humoral response toward different SARS-CoV-2 variants of concern and variants of interest and will be helpful to combat COVID-19 globally.

Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial.

OBJECTIVE: To evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma. DESIGN: Multicentre, randomised, double blind, phase 3 trial. SETTING: 66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021. PARTICIPANTS: 659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment. INTERVENTION: Participants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m2 continuous infusion on days 1-5). MAIN OUTCOME MEASURES: Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1. RESULTS: 659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P<0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P<0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively. CONCLUSIONS: Compared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising. TRIAL REGISTRATION: ClinicalTrials.gov NCT03748134.

Nine-month outcomes of tracheostomy in patients with COVID-19: A retrospective study.

PURPOSE: The outcome of performing a tracheostomy in patients with coronavirus disease (COVID-19) seems promising based on the reported 30-day survival rate. However, long-term outcomes are still lacking. Therefore, our aim in this study was to evaluate the long-term outcomes of tracheostomy performed in critically ill COVID-19 patients. METHODS: This was a retrospective analysis of 27 COVID-19 patients on whom tracheostomy was performed between February 28, 2020, and April 7, 2020, at Tongji Hospital (Wuhan, China). Patients' clinical characteristics, complications, and outcomes were analyzed. RESULTS: All patients underwent successful bedside tracheostomy. Thirteen patients (48.1%) were successfully weaned off ventilation within 1 month. The survival rate at one, three, and nine months after tracheostomy were 63.0%, 37.0%, and 29.6%, respectively. At nine months after tracheostomy, 8/27 patients had survived, with five (62.5%) being discharged home while the remaining were dependent on nursing care. CONCLUSION: The survival rate of COVID-19 patients who underwent tracheotomy decreased markedly from 1 to 3 months after tracheotomy, remaining stable between 3 and 9 months. Medical support is much needed for COVID-19 patients over the first 90 days after tracheotomy.