Algorithm for Optimized mRNA Design Improves Stability and Immunogenicity.

Messenger RNA (mRNA) vaccines are being used to contain COVID-19 (1, 2, 3), but still suffer from the critical limitation of mRNA instability and degradation, which is a major obstacle in the storage, distribution, and efficacy of the vaccine products (4). Previous work showed that increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression (5). Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, due to synonymous codons, the mRNA design space is prohibitively large (e.g., ~10632 candidates for the SARS-CoV-2 Spike protein), which poses insurmountable computational challenges. Here we provide a simple and unexpected solution using a classical concept in computational linguistics, where finding the optimal mRNA sequence is akin to identifying the most likely sentence among similar sounding alternatives (6). Our algorithm LinearDesign takes only 11 minutes for the Spike protein, and can jointly optimize stability and codon usage. On both COVID-19 and varicella-zoster virus mRNA vaccines, LinearDesign substantially improves mRNA half-life and protein expression, and dramatically increases antibody titer by up to 128× in vivo, compared to the codon-optimization benchmark. This surprising result reveals the great potential of principled mRNA design, and enables the exploration of previously unreachable but highly stable and efficient designs. Our work is a timely tool not only for vaccines but also for mRNA medicine encoding all therapeutic proteins (e.g., monoclonal antibodies and anti-cancer drugs (7, 8)).

The association between online learning, parents' marital status, and internet addiction among adolescents during the COVID-19 pandemic period: A cross-lagged panel network approach.

INTRODUCTION: Previous research has identified the association between online learning and Internet addiction (IA) and the role of family factors in it. However, few studies have treated IA as a multidimensional mechanism and explored the underlying linkage of online learning, IA, and parental marital status with a cross-lagged network approach. The study aimed to examine the relationship between online learning during the COVID-19 pandemic, Internet addiction (IA), and parental marital status among Chinese adolescents. METHODS: The sample consisted of 2356 adolescents who completed the Internet Addiction Test twice over a four-month period. Four symptom networks and two cross-lagged panel networks were performed. RESULTS: The results showed that adolescents from divorced families had a higher prevalence of IA (27 %) compared to those from non-divorced families (17 %). The strongest cross-lagged association was found between "spending more time online" and "preferring the excitement online". In the divorced group, "school grades suffering" had the highest influence, while in the non-divorced group, "anticipation" had the highest influence. CONCLUSION: This study highlights the relationship between online learning, IA, and parental divorce and suggests that long-term online learning may contribute to IA, and parental divorce may exacerbate problematic Internet use and increase IA levels.

Effects of awake prone position vs. usual care on acute hypoxemic respiratory failure in patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

Background: Previous studies have shown that an awake prone position may be beneficial for the treatment of acute respiratory distress syndrome (ARDS) or acute hypoxic respiratory failure (AHRF) in patients with COVID-19, but the results are not consistent, especially in terms of oxygenation outcomes and intubation rate. This systematic review and meta-analysis assessed the effects of the awake prone position on AHRF in patients with COVID-19 with all randomized controlled trials (RCTs). Methods: An extensive search of online databases, including MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials from 1 December 2019 to 30 October 2022, with no language restrictions was performed. This systematic review and meta-analysis are based on the PRISMA statement. We only included RCTs and used the Cochrane risk assessment tool for quality assessment. Results: Fourteen RCTs fulfilled the selection criteria, and 3,290 patients were included. A meta-analysis found that patients in the awake prone position group had more significant improvement in the SpO2/FiO2 ratio [mean difference (MD): 29.76; 95% confidence interval (CI): 1.39-48.13; P = 0.001] compared with the usual care. The prone position also reduced the need for intubation [odd ratio (OR): 0.72; 95% CI: 0.61 to 0.84; P < 0.0001; I 2 = 0%]. There was no significant difference in mortality, hospital length of stay, incidence of intensive care unit (ICU) admission, and adverse events between the two groups. Conclusion: The awake prone position was a promising intervention method, which is beneficial to improve the oxygenation of patients with ARDS or AHRF caused by COVID-19 and reduce the need for intubation. However, the awake prone position showed no obvious advantage in mortality, hospital length of stay, incidence of ICU admission, and adverse events. Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42022367885.

Hopelessness during and after the COVID-19 pandemic lockdown among Chinese college students: A longitudinal network analysis.

INTRODUCTION: In China, recurrent pandemics require frequent city-wide lockdowns and quarantine actions to contain the impact of COVID-19, exposing college students to psychological problems, including hopelessness. Hence, the purpose of helping problematic college students alleviate hopelessness symptoms motivates us to carry out the present study to explore their interrelationship. METHODS: Hopelessness (i.e., a complex phenomenon with important clinical consequences, such as depression and suicidality) was investigated in a large longitudinal sample of college students (N = 2787; 58.59% female; age mean ± SD = 18.34 ± 0.92) who were recruited during and after the COVID-19 lockdown using the Beck Hopelessness Scale (BHS). RESULTS: Applying the novel approach (i.e., symptom network analysis), the results indicated that the edge of #BHS1 (i.e., [NOT] hope-enthusiasm)-#BHS15 (i.e., [NOT] faith-in-the-future) showed the strongest association both in Wave 1 and Wave 2. Similarly, #BHS20 (i.e., not-trying) had the highest node expectedinfluence (centrality) in the hopelessness symptoms network both among Wave 1 and Wave 2. The Network Comparison Test indicated that the global network strength significantly differed between the two time points. As expected, college students' hopelessness will gradually dissipate with the end of segregation control. The stability and accuracy indicated that the network analysis results were trustworthy. CONCLUSIONS: The study findings provide evidence that central nodes and edges connecting symptoms should be addressed. Further interventions and treatments that may target these symptoms are essential to effectively alleviate the overall hopelessness level among college students. Theoretical and clinical potential consequences were discussed in detail.

LazySampling and LinearSampling: fast stochastic sampling of RNA secondary structure with applications to SARS-CoV-2.

Many RNAs fold into multiple structures at equilibrium, and there is a need to sample these structures according to their probabilities in the ensemble. The conventional sampling algorithm suffers from two limitations: (i) the sampling phase is slow due to many repeated calculations; and (ii) the end-to-end runtime scales cubically with the sequence length. These issues make it difficult to be applied to long RNAs, such as the full genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To address these problems, we devise a new sampling algorithm, LazySampling, which eliminates redundant work via on-demand caching. Based on LazySampling, we further derive LinearSampling, an end-to-end linear time sampling algorithm. Benchmarking on nine diverse RNA families, the sampled structures from LinearSampling correlate better with the well-established secondary structures than Vienna RNAsubopt and RNAplfold. More importantly, LinearSampling is orders of magnitude faster than standard tools, being 428× faster (72 s versus 8.6 h) than RNAsubopt on the full genome of SARS-CoV-2 (29 903 nt). The resulting sample landscape correlates well with the experimentally guided secondary structure models, and is closer to the alternative conformations revealed by experimentally driven analysis. Finally, LinearSampling finds 23 regions of 15 nt with high accessibilities in the SARS-CoV-2 genome, which are potential targets for COVID-19 diagnostics and therapeutics.

Comparing the centrality symptoms of major depressive disorder samples across junior high school students, senior high school students, college students and elderly adults during city lockdown of COVID-19 pandemic-A network analysis.

INTRODUCTION: Recently, in the view of network analysis, depression has been conceptualized as a complex and dynamic network model combining individual symptoms. To date, no studies have systematically examined and compared depressive symptom networks across different populations. METHODS: A total of 36,105 participants were recruited and asked to complete the Patient Health Questionnaire-9 among junior high school students, senior high school students, college students, and elderly adults who were more susceptible to depression during the COVID-19 lockdown in China. In the analysis, we applied the optimal cutoff score ≥ 8 for students and a score ≥ 6 for elderly adults to identify 5830 participants who were likely to be depressed. The index of "strength" was used to identify central symptoms in the network structure. RESULTS: The results showed that Sad Mood was the most central symptom among junior high school students, senior high school students, and college students, but the most central symptom in the elderly was Guilt. Among the top three central symptoms, Suicide Ideation was unique to senior high school students, while Anhedonia was most prevalent among college students. Guilt - Suicide Ideation, Anhedonia - Energy, Anhedonia - Sad Mood, and Sleep - Energy showed the strongest association among junior and senior high school students, college students, and elderly adults, respectively. NCT (i.e., Network Comparison Test) suggested that the network's global connectivity was ultimately inconsistent, but the network structure remained roughly intact. CONCLUSION: In treatment, targeting central symptoms may be critical to alleviating depression.

Immunogenicity, durability, and safety of an mRNA and three platform-based COVID-19 vaccines as a third dose following two doses of CoronaVac in China: A randomised, double-blinded, placebo-controlled, phase 2 trial.

Background: More effective vaccine candidates against variants of concern as a booster dose are needed in people primed with two-dose inactivated COVID-19 vaccines. Methods: This randomised, double-blinded, investigator-initiated phase 2 trial aims to evaluate immunogenicity, durability, and safety of an mRNA vaccine candidate (RQ3013) and three other platform vaccines (an adenovirus-vectored vaccine candidate [ChAdTS-S], a recombinant protein vaccine candidate [ZR202-CoV], and an inactivated vaccine [CoronaVac]) as a booster. 250 eligible volunteers, who had received a prime two-dose CoronaVac (3 to 5 weeks apart) vaccination 100-270 days before, were randomly assigned in a 1:1:1:1:1 ratio to receive a third dose of RQ3013 (30 µg mRNA per 0.15 mL), ChAdTS-S (5×1010 viral particles per 0.5 mL), ZR202-CoV (25 µg prefusion-stabilized Spike ectodomain trimer per 0.5 mL), CoronaVac (3 µg inactivated CN02 strain of SARS-CoV-2 per 0.5 mL) or placebo (0.5 mL of 0.9% sodium chloride solution) via intramuscular injection into the upper arm at a single clinical site in Kunming, China. Participants, investigators, and immunogenicity laboratory were masked to group assignment. The primary immunogenicity outcomes were geometric mean titres (GMTs) of neutralising antibodies against live SARS-CoV-2 (wild-type, delta and omicron) virus at day 0 (before vaccination), day 7, day 14 and day 28 after vaccination, as analysed in a modified intention-to-treat (mITT) population (all participants who completed their booster doses and had at least one post-dose immunogenicity data). Secondary outcomes include T cell responses against the wild-type and omicron SARS-CoV-2 Spike protein. The primary safety outcome was incidence of adverse events within 14 days after the booster vaccination. This trial is registered with ChiCTR.org.cn, ChiCTR2200057758. Findings: Between January 1, 2022, and February 28, 2022, 235 eligible participants were enrolled and vaccinated, and the primary analysis included 234 participants. At baseline, neutralising antibodies against wild-type virus, the delta, or omicron variants were low or undetectable in all groups. After the booster vaccination, GMTs of neutralising antibodies ranged from 75.4 (95% confidence interval [CI] 61.4-92.5) in CoronaVac to 950.1 (95% CI 785.4-1149.3) in RQ3013 against live wild-type SARS-CoV-2, and from 8.1 (95% CI: 6.1-10.7) in CoronaVac to 247.0 (95% CI 194.1-314.3) in RQ3013 against the omicron variant at day 14. Immunogenicities of all heterologous regimens were superior to that of homologous regimen in neutralisation against all tested SARS-CoV-2 strains, with RQ3013 showing the highest geometric mean ratios (GMRs) of 12.6, 14.7, and 31.3 against the wild-type, the delta variant and the omicron variant compared to CoronaVac at day 14 post-vaccination, respectively. Durability analysis at day 90 showed that >90% of participants in RQ3013 and ZR202-CoV were seropositive for the omicron variant while ZR202-CoV with adjuvants containing CpG showed a slightly better durability than RQ3013. T cell responses specific to the omicron variant were similar to that of the wild-type, with RQ3013 showing the highest boosting effect. Any solicited injection site or systemic adverse events reported within 14 days after vaccination were most commonly observed in RQ3013 (47/47, 100%), followed by ZR202-CoV (46/47, 97.9%) and ChAdTS-S (43/48, 89.6%), and then CoronaVac (37/46, 80.4%) and placebo (21/47, 44.7%). More than 90% of the adverse events were grade 1 (mild) or 2 (moderate) with a typical resolution time of 3 days. No grade 4 adverse events or serious adverse events were reported by study vaccines. Interpretation: Although all study vaccines boosted neutralising antibodies with no safety concerns, RQ3013 showed much stronger cross-neutralisation and cellular responses, adding more effective vaccine candidates against the omicron variant. Funding: Yunnan Provincial Science and Technology Department China (202102AA100051 and 202003AC100010), the Double First-class University funding to Yunnan University, National Natural Science Foundation of China (81960116, 82060368 and 82170711), Yunnan Natural Science Foundation (202001AT070085), High-level Health Technical Personnel Project of Yunnan Province (H-2018102) and Spring City Plan: The High-level Talent Promotion and Training Project of Kunming.

Unravelling psychiatric heterogeneity and predicting suicide attempts in women with trauma-related dissociation using artificial intelligence Desentrañando la Heterogeneidad Psiquiátrica y Prediciendo los Intentos Suicidas en Mujeres con Disociación Relacionada con el Trauma Usando Inteligencia Artificial 使用人工智能揭示具有创伤相关解离女性的精神病学异质性和预测其自杀意图

Background: Suicide is a leading cause of death, and rates of attempted suicide have increased during the COVID-19 pandemic. The under-diagnosed psychiatric phenotype of dissociation is associated with elevated suicidal self-injury;however, it has largely been left out of attempts to predict and prevent suicide. Objective: We designed an artificial intelligence approach to identify dissociative patients and predict prior suicide attempts in an unbiased, data-driven manner. Method: Participants were 30 controls and 93 treatment-seeking female patients with posttraumatic stress disorder (PTSD) and various levels of dissociation, including some with the PTSD dissociative subtype and some with dissociative identity disorder (DID). Results: Unsupervised learning models identified patients along a spectrum of dissociation. Moreover, supervised learning models accurately predicted prior suicide attempts with an score up to 0.83. DID had the highest risk of prior suicide attempts, and distinct subtypes of dissociation predicted suicide attempts in PTSD and DID. Conclusions: These findings expand our understanding of the dissociative phenotype and underscore the urgent need to assess for dissociation to identify individuals at high-risk of suicidal self-injury. HIGHLIGHTS Dissociation, feelings of detachment and disruption in one's sense of self and surroundings, is associated with an elevated risk of suicidal self-injury;however, it has largely been left out of attempts to predict and prevent suicide. Using machine learning techniques, we found dissociative identity disorder had the highest risk of prior suicide attempts, and distinct subtypes of dissociation predicted suicide attempts in posttraumatic stress disorder and dissociative identity disorder. These findings underscore the urgent need to assess for dissociation to identify individuals at high-risk of suicidal self-injury.

Risk of adverse outcomes in inflammatory bowel disease patients infected with SARS-CoV-2: a systematic review and meta-analysis.

BACKGROUND: Between people with and without inflammatory bowel disease (IBD), there was no statistically significant difference in the probability of contracting the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the risk of adverse outcomes in IBD patients after virus infection remains unclear. METHODS: Eligible studies conducted from January 1, 2020 to March 17, 2022 were obtained by searching PubMed, Embase, and Web of Science. Information was collected in tables from the included studies. Random-effects and fixed-effects models were used as measures for the pooled estimates. All data were estimated by R version 4.1.3. RESULTS: Twenty-four studies were included. The risk ratio (RR) of adverse outcomes in COVID-19 patients with IBD increased by 32% (RR 1.32; 95% CI 1.06-1.66) relative to COVID-19 patients without IBD. The RR of mortality was higher in COVID-19 patients with IBD from Europe (RR 1.72; 95% CI 1.11-2.67) than in those that were not from Europe (RR 1.00; 95% CI 0.79-1.26; χ2 = 4.67; P = 0.03). Patients with ulcerative colitis were at higher risk of adverse outcomes after SARS-CoV-2 infection than patients with Crohn's disease patients (RR1.38; 95% CI 1.27-1.50). The IBD drugs treatment was associated with the risk of adverse outcomes, the pooled odds ratio (OR) of mesalazine (1.79; 95% CI 1.59-2.02), immunomodulators (1.30; 95% CI 1.10-1.53), and anti-TNF (0.47; 95% CI 0.41-0.53) were assessed. CONCLUSION: COVID-19 patients with IBD had an increased risk of adverse outcomes than those without IBD, whereas anti-TNF treatment might reduce the risk.

Seeking bridge symptoms of anxiety, depression, and sleep disturbance among the elderly during the lockdown of the COVID-19 pandemic-A network approach.

Background: Besides physical changes, elderly adults are prone to have mental disorders such as anxiety, depression, and sleep disturbance, and the pandemic of COVID-19 worsened the situation. However, internal relationships and co-occurrence of psychopathologies were scarcely examined. Therefore, in the current study, through network analysis, we inspected relationships among symptoms of depression, anxiety, and sleep disturbance and identified key symptoms that espoused the disease. Methods: We asked 1,302 elderly adults to fill in Patient Health Questionnaire-2 (depressive symptoms), the Generalized Anxiety Disorder-2 (anxiety symptoms), and the Youth Self-rating Insomnia Scale (sleep disturbance) and then constructed three networks for elderly adults, male elderly, and female elderly. Via network analysis, we accomplished four goals. First, we identified symptom with the highest centrality (i.e., strength) index for each network; then, we found the strongest correlation (i.e., edges) in each network; thirdly, we confirmed specific nodes that could bridge anxiety, depression, and sleep disturbance; the last was to compare networks based on genders. Network stability and accuracy tests were performed. Results: Networks of elderly adults, male elderly, and female elderly were stable, accurate, and intelligible. Among all networks, "Nervousness"- "Excessive worry" (GAD-1- GAD-2) had the strongest correlation, and "Nervousness" (GAD-1) had the highest strength and bridge strength value. When we made a comparison between female elderly's and male elderly's networks, except for the significant difference in the mean value of "Difficulty initiating sleep" (YSIS-3), the findings showed that the two networks were similar. Network stability and accuracy proved to be reliable. Conclusions: In networks of anxiety, depression, and sleep disturbance, anxiety played a conspicuous role in comorbidity, which could be a target for practical intervention and prevention.

Centrality and bridge symptoms of anxiety, depression, and sleep disturbance among college students during the COVID-19 pandemic-a network analysis.

Symptoms of depression and anxiety usually co-occur and are inextricably linked to sleep disturbance. However, little is known about the symptom-to-symptom relationships among these three mental disorders. Hence, to improve our understanding of concurrent depression, anxiety, and sleep disturbance, we used the network analysis approach to construct an interplay relationship among the above three mental disorders and identify which specific symptoms bridge these aggregations. We collected data from a large sample (N = 6710, male = 3074, female = 3636; mean age = 19.28) at a university. We estimated the symptom network structure of depression, anxiety, and sleep disturbance as assessed by the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and Youth Self-Rating Insomnia Scale during the COVID-19 lockdown. We further investigated four goals: first, identifying the individual core symptoms in the network by the index of "expected influence"; second, determining the bridge symptoms that play roles in linking different mental disorders by the index of bridge expected influence (1-step); third, examining the robustness of all results; and fourth, providing an overall structure that may or may not differ by sex. The network structure was stable, accurate, and predictable. Items referring to sleep dissatisfaction, poor sleep quality, and uncontrollable worry were potentially core symptoms in the interplay among depression, anxiety, and sleep disturbance. Sleep, guilt, restlessness, irritability, and feeling afraid can function as bridges among depression, anxiety, and sleep disturbance, which is clinically relevant and theoretically important. The results suggested that the network structures significantly differed between the female and male networks. Robustness tests also revealed that the results were reliable.

The Pharmacological Mechanism of Xiyanping Injection for the Treatment of Novel Coronavirus Pneumonia (COVID-19): Based on Network Pharmacology Strategy.

Purpose: The possible mechanism of Xiyanping injection treatment COVID-19 is discussed through the network pharmacology. Methods: Obtaining the chemical structure of Xiyanping injection through the patent application and obtaining control compounds I, II, III, IV, V, Yanhuning injection (VI, VII), Chuanhuning injection (VIII, IX), 10 compounds were analyzed by D3Targets-2019-nCoV. The human anti-COVID-19 gene in COVID-19 DisGeNET was intersected with the CTD Andrographolide target gene and then combined with D3Targets-2019-nCoV, resulting in 93 genes, using the Venny 2.1 platform. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. The GO, KEGG, and tissue of the target were analyzed using the Metascape platform and DAVID platform. The gene expression in the respiratory system was analyzed using the ePlant platform. The CB-Dock is used for the docking verification and degree values of the first 20 genes. Results: Finally, 1599 GO and 291 KEGG results were obtained. GO is mostly associated with the cell stress response to chemicals, the cell response to oxidative stress, and the cell response to reactive oxygen species. In total, 218 KEGG pathway concentrations were related to infection and other diseases and 73 signaling pathways mostly related to inflammation and immune pathways, such as TNF signaling pathway and MAPK signaling pathway. The molecular docking results show that Xiyanping injection, compound III, has a good docking relationship with 20 target proteins such as HSP90AA1. Tissue has 22 genes that are pooled in the lungs. Conclusion: Xiyanping injection may inhibit the release of various inflammatory factors by inhibiting intracellular pathways such as MAPK and TNF. It acts on protein targets such as HSP90AA1 and plays a potential therapeutic role in COVID-19. Thus, compound III may be treated as a potential new drug for the treatment of COVID-19 and the Xiyanping injection may treat patients with COVID-19 infection.

Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials.

BACKGROUND: All currently available SARS-CoV-2 vaccines are administered by intramuscular injection. We aimed to evaluate the safety and immunogenicity of a live-attenuated influenza virus vector-based SARS-CoV-2 vaccine (dNS1-RBD) administered by intranasal spray in healthy adults. METHODS: We did double-blind, randomised, placebo-controlled phase 1 and 2 trials, followed by a phase 2 extension trial, at a single centre in Jiangsu, China. Healthy adults (≥18 years) who had negative serum or fingertip blood total antibody tests for SARS-CoV-2 (in phases 1 and 2), with no prevalent SARS-CoV-2 infection or history of infection and no SARS-CoV-2 vaccination history (in all three trials reported here), were enrolled. Participants were randomly allocated (4:1 in phase 1, 2:1 in phase 2, and 1:1 in the extension trial) to receive two intranasal doses of the dNS1-RBD vaccine or placebo on days 0 and 14 or, for half of the participants in phase 2, on days 0 and 21. To avoid cross-contamination during administration, vaccine and placebo recipients were vaccinated in separate rooms in the extension trial. The phase 1 primary outcome was safety (adverse events recorded on days 0-44; serious adverse events recorded from day 0 until 12 months after the second dose). In the phase 2 and extension trials, the primary immunogenicity outcomes were SARS-CoV-2-specific T-cell response in peripheral blood (measured by IFN-γ ELISpot), proportion of participants with positive conversion for SARS-CoV-2 receptor-binding domain (RBD)-specific IgG and secretory IgA (s-IgA) antibodies, and concentration of SARS-CoV-2 RBD IgG in serum and SARS-CoV-2 RBD s-IgA in the nasopharynx (measured by ELISA) at 1 month after the second dose in the per-protocol set for immunogenicity. χ2 test and Fisher's exact test were used to analyse categorical data, and t test and Wilcoxon rank sum test to compare the measurement data between groups. These trials were registered with the Chinese Clinical Trial Registry (ChiCTR2000037782, ChiCTR2000039715, and ChiCTR2100048316). FINDINGS: Between Sept 1, 2020, and July 4, 2021, 63, 724, and 297 participants without a history of SARS-CoV-2 vaccination were enrolled in the phase 1, phase 2, and extension trials, respectively. At least one adverse reaction after vaccination was reported in 133 (19%) of 684 participants in the vaccine groups. Most adverse reactions were mild. No vaccine-related serious adverse event was noted. Specific T-cell immune responses were observed in 211 (46% [95% CI 42-51]) of 455 vaccine recipients in the phase 2 trial, and in 48 (40% [31-49]) of 120 vaccine recipients compared with one (1% [0-5]) of 111 placebo recipients (p<0·0001) in the extension trial. Seroconversion for RBD-specific IgG was observed in 48 (10% [95% CI 8-13]) of 466 vaccine recipients in the phase 2 trial (geometric mean titre [GMT] 3·8 [95% CI 3·4-4·3] in responders), and in 31 (22% [15-29]) of 143 vaccine recipients (GMT 4·4 [3·3-5·8]) and zero (0% [0-2]) of 147 placebo recipients (p<0·0001) in the extension trial. 57 (12% [95% CI 9-16]) of 466 vaccine recipients had positive conversion for RBD-specific s-IgA (GMT 3·8 [95% CI 3·5-4·1] in responders) in the phase 2 trial, as did 18 (13% [8-19]) of 143 vaccine recipients (GMT 5·2 [4·0-6·8]) and zero (0% [0-2]) of 147 placebo recipients (p<0·0001) in the extension trial. INTERPRETATION: dNS1-RBD was well tolerated in adults. Weak T-cell immunity in peripheral blood, as well as weak humoral and mucosal immune responses against SARS-CoV-2, were detected in vaccine recipients. Further studies are warranted to verify the safety and efficacy of intranasal vaccines as a potential supplement to current intramuscular SARS-CoV-2 vaccine pools. Steps should be taken in future studies to reduce the potential for cross-contamination caused by the vaccine strain aerosol during administration. FUNDING: National Key Research and Development Program of China, National Science, Fujian Provincial Science, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai Biological Pharmacy Enterprise.

A live attenuated virus-based intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2.

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 d after single-dose vaccination or 9 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants, especially for the latest Omicron variant. In addition, this vaccine also provides cross-protection against H1N1 and H5N1 influenza viruses. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to the fight against the ongoing coronavirus disease 2019 pandemic and influenza infection, compensating limitations of current intramuscular vaccines.

A Bibliometric Analysis of Personal Protective Equipment and COVID-19 Researches.

COVID-19, which occurred at the end of December 2019, has evolved into a global public health threat and affects every aspect of human life. COVID-19's high infectivity and mortality prompted governments and the scientific community to respond quickly to the pandemic outbreak. The application of personal protective equipment (PPE) is of great significance in overcoming the epidemic situation. Since the discovery of severe acute respiratory coronavirus 2 (SARS-CoV-2), bibliometric analysis has been widely used in many aspects of the COVID-19 epidemic. Although there are many reported studies about PPE and COVID-19, there is no study on the bibliometric analysis of these studies. The citation can be used as an indicator of the scientific influence of an article in its field. The aim of this study was to track the research trends and latest hotspots of COVID-19 in PPE by means of bibliometrics and visualization maps.

Both Baicalein and Gallocatechin Gallate Effectively Inhibit SARS-CoV-2 Replication by Targeting Mpro and Sepsis in Mice.

The emergence of severe acute syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has led to the global COVID-19 pandemic. Although the symptoms of most COVID-19 patients are mild or self-curable, most of severe patients have sepsis caused by cytokine storms, which greatly increases the case fatality rate. Moreover, there is no effective drug that can limit the novel coronavirus thus far, so it is more needed to develop antiviral drugs for the SARS-CoV-2. In our research, we employed the techniques of molecular docking to screen 35 flavonoid compounds among which 29 compounds have Z-scores lower than - 6. Then, ( -)-gallocatechin gallate, ( +)-gallocatechin and baicalein were identified to have potent inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 5.774 ± 0.805 µM, 13.14 ± 2.081 µM and 5.158 ± 0.928 µM respectively by FRET assay. Molecular docking results also showed that ( -)-gallocatechin gallate, ( +)-gallocatechin and baicalein can non-covalently bind to Mpro through π-π stacking and hydrogen bonds in the Cys145 catalytic site. We further evaluated the effect of ( -)-gallocatechin gallate and baicalein on cytokine storms using a mouse model of sepsis. ( -)-Gallocatechin gallate and baicalein significantly reduced sepsis of mouse models on weight, murine sepsis score, and survival rate and reduced the inflammatory factor levels, such as TNF-α, IL-1α, IL-4, and IL-10. Overall, ( -)-gallocatechin gallate and baicalein show certain potential of treatment against COVID-19.

Daratumumab for Refractory IgD Multiple Myeloma with Lung Cancer and Persistent Thrombocytopenia: a Case Report.

BACKGROUND: Immunoglobulin D multiple myeloma (IgD-MM) is a rare but aggressive disease. The safety and effectiveness of anti-CD38 monoclonal antibody (daratumumab) have not been known in either IgD-MM or MM complicated with secondary neoplasm. METHODS: A fragile IgD-MM patient had an aggressively relapsed disease concurrent with lung cancer and severe thrombocytopenia, which led to a dilemma for management. After a failure of ixazomib-based chemotherapy, a salvage therapy with daratumumab unexpectedly induced complete remission and platelet recovery, and the patient successfully proceeded to lung cancer surgery. CONCLUSIONS: Our case indicates daratumumab is both safe and effective for refractory IgD-MM with severe complications.