Viral-vectored respiratory mucosal vaccine strategies.

Increasing global concerns of pandemic respiratory viruses highlight the importance of developing optimal vaccination strategies that encompass vaccine platform, delivery route, and regimens. The decades-long effort to develop vaccines to combat respiratory infections such as influenza, respiratory syncytial virus, and tuberculosis has met with challenges, including the inability of systemically administered vaccines to induce respiratory mucosal (RM) immunity. In this regard, ample preclinical and available clinical studies have demonstrated the superiority of RM vaccination to induce RM immunity over parenteral route of vaccination. A great stride has been made in developing vaccines for RM delivery against respiratory pathogens, including M. tuberculosis and SARS-CoV-2. In particular, inhaled aerosol delivery of adenoviral-vectored vaccines has shown significant promise.

Adenoviral-vectored next-generation respiratory mucosal vaccines against COVID-19.

The world is in need of next-generation COVID-19 vaccines. Although first-generation injectable COVID-19 vaccines continue to be critical tools in controlling the current global health crisis, continuous emergence of SARS-CoV-2 variants of concern has eroded the efficacy of these vaccines, leading to staggering breakthrough infections and posing threats to poor vaccine responders. This is partly because the humoral and T-cell responses generated following intramuscular injection of spike-centric monovalent vaccines are mostly confined to the periphery, failing to either access or be maintained at the portal of infection, the respiratory mucosa (RM). In contrast, respiratory mucosal-delivered vaccine can induce immunity encompassing humoral, cellular, and trained innate immunity positioned at the respiratory mucosa that may act quickly to prevent the establishment of an infection. Viral vectors, especially adenoviruses, represent the most promising platform for RM delivery that can be designed to express both structural and nonstructural antigens of SARS-CoV-2. Boosting RM immunity via the respiratory route using multivalent adenoviral-vectored vaccines would be a viable next-generation vaccine strategy.

Vedolizumab subcutaneous formulation maintenance therapy for patients with IBD: a systematic review and meta-analysis.

Background: The application of vedolizumab (VDZ) subcutaneous (SC) formulation has brought more convenience and hope to patients with moderate-to-severe inflammatory bowel diseases (IBDs) in the coronavirus disease 2019 context. Objective: This study aimed to systematically evaluate all previous studies that used VDZ SC formulation for maintenance therapy in patients with IBD. Design: Systematic review and meta-analysis. Data Sources and Methods: The search was conducted using the subject and free terms related to 'Vedolizumab', 'Subcutaneous', and 'IBD', in Embase, PubMed, Web of Science, Cochrane, and at ClinicalTrials.gov databases between 2008 and 2022. The methodological quality of randomized controlled trials (RCTs) and cohort studies was assessed using the Cochrane Handbook of Systematic Reviews and the Newcastle-Ottawa Scale, respectively. The endpoints included efficacy, safety, and immunogenicity. Results: A total of 60 studies and 2 completed clinical registry trials were retrieved, of which 3 RCTs with high methodological quality, and 3 cohort studies with large heterogeneity were included in the meta-analysis. In the RCT study design, patients with ulcerative colitis (UC) under different conditions after treated with VDZ SC were significantly distinct than those for placebo (PBO) in clinical remission, endoscopic remission, and biochemical remission. In Crohn's disease (CD), the aforementioned parameters were slightly higher than those for PBO, but there was not statistically significant in endoscopic remission and the efficacy of anti-tumor necrosis factor-naive patients. The clinical remission, endoscopic remission, and biochemical remission in patients with UC after VDZ SC treatment were similar to those after intravenous (IV) treatment. The risk ratios in patients experiencing adverse events (AEs) and serious AEs after VDZ SC and PBO treatments were 86% and 89% in UC, and 96% and 80% in CD, respectively. Compared with IV, safety was not statistically different. The risk of developing anti-VDZ antibody after VDZ SC treatment was only 20% of that after PBO in patients with UC, but it was 9.38 times in CD. Conclusion: VDZ SC treatment maintained the clinical efficacy of IV induction in patients with IBD without increasing the safety risk, and the efficacy was more pronounced in patients with UC. Immunogenicity might be a potential factor for the decrease in efficacy rate in patients with IBD. Registration: INPLASY 2022120115.

Internal microstructure of spray dried particles affects viral vector activity in dry vaccines.

To maintain the activity of sensitive biologics during encapsulation by spray drying, a better understanding of deactivation pathways in dried particles is necessary. The effect of solid-air interfaces within dried particles on viral deactivation was examined with three binary excipient blends, mannitol/dextran (MD), xylitol/dextran (XD), and lactose/trehalose (LT). Particles encapsulating human serotype 5 adenovirus viral vector (AdHu5) were produced via both spray drying and acoustic levitation. The particles' internal microstructure was directly visualized, and the location of a viral vector analogue was spatially mapped within the particles by volume imaging using focused ion beam sectioning and scanning electron microscopy. The majority of the viral vector analogue was found at, or near, the solid-air interfaces. Peclet number and crystallization kinetics governed the internal microstructure of the particles: XD particles with minimal internal voids retained the highest viral activity, followed by MD particles with a few large voids, and finally LT particles with numerous internal voids exhibited the lowest viral activity. Overall, AdHu5 activity decreased as the total solid-air interfacial area increased (as quantified by nitrogen sorption). Along with processing losses, this work highlights the importance of surface area within particles as an indicator of activity losses for dried biologics.

Design Considerations for Intratracheal Delivery Devices to Achieve Proof-of-Concept Dry Powder Biopharmaceutical Delivery in Mice.

PURPOSE: Intratracheal delivery and consistent dosing of dry powder vaccines is especially challenging in mice. To address this issue, device design of positive pressure dosators and actuation parameters were assessed for their impacts on powder flowability and in vivo dry powder delivery. METHODS: A chamber-loading dosator assembled with stainless-steel, polypropylene or polytetrafluoroethylene needle-tips was used to determine optimal actuation parameters. Powder loading methods including tamp-loading, chamber-loading and pipette tip-loading were compared to assess performance of the dosator delivery device in mice. RESULTS: Available dose was highest (45%) with a stainless-steel tip loaded with an optimal mass and syringe air volume, primarily due to the ability of this configuration to dissipate static charge. However, this tip encouraged more agglomeration along its flow path in the presence of humidity and was too rigid for intubation of mice compared to a more flexible polypropylene tip. Using optimized actuation parameters, the polypropylene pipette tip-loading dosator achieved an acceptable in vivo emitted dose of 50% in mice. After administering two doses of a spray dried adenovirus encapsulated in mannitol-dextran, high bioactivity was observed in excised mouse lung tissue three days post-infection. CONCLUSIONS: This proof-of-concept study demonstrates for the first time that intratracheal delivery of a thermally stable, viral-vectored dry powder can achieve equivalent bioactivity to the same powder, reconstituted and delivered intratracheally. This work may guide the design and device selection process for murine intratracheal delivery of dry powder vaccines to help progress this promising area of inhalable therapeutics.

Bow-and-arrow sign on point-of-care ultrasound for diagnosis of pacemaker lead-induced heart perforation: A case report and literature review.

BACKGROUND: Pacemaker lead-induced heart perforation is a rare but life-threatening complication of pacemaker implantation, and timely diagnosis remains a challenge for clinicians. Here, we report a case of pacemaker lead-induced cardiac perforation rapidly diagnosed by a "bow-and-arrow" sign on point-of-care ultrasound (POCUS). CASE SUMMARY: A 74-year-old Chinese woman who had undergone permanent pacemaker implantation 26 d before suddenly developed severe dyspnea, chest pain, and hypotension. The patient had received emergency laparotomy for an incarcerated groin hernia and was transferred to the intensive care unit 6 d before. Computed tomography was not available due to unstable hemodynamic status, so POCUS was performed at the bedside and revealed severe pericardial effusion and cardiac tamponade. Subsequent pericardiocentesis yielded a large volume of bloody pericardial fluid. Further POCUS by an ultrasonographist revealed a unique "bow-and-arrow" sign indicating right ventricular (RV) apex perforation by the pacemaker lead, which facilitated the rapid diagnosis of lead perforation. Given the persistent drainage of pericardial bleeding, urgent off-pump open chest surgery was performed to repair the perforation. However, the patient died of shock and multiple organ dysfunction syndrome within 24 h post-surgery. In addition, we also performed a literature review on the sonographic features of RV apex perforation by lead. CONCLUSION: POCUS enables the early diagnosis of pacemaker lead perforation at the bedside. A step-wise ultrasonographic approach and the "bow-and-arrow" sign on POCUS are helpful for rapid diagnosis of lead perforation.

Corrigendum: Differential biodistribution of adenoviral-vectored vaccine following intranasal and endotracheal deliveries leads to different immune outcomes.

[This corrects the article DOI: 10.3389/fimmu.2022.860399.].

Intranasal multivalent adenoviral-vectored vaccine protects against replicating and dormant M.tb in conventional and humanized mice.

Viral-vectored vaccines are highly amenable for respiratory mucosal delivery as a means of inducing much-needed mucosal immunity at the point of pathogen entry. Unfortunately, current monovalent viral-vectored tuberculosis (TB) vaccine candidates have failed to demonstrate satisfactory clinical protective efficacy. As such, there is a need to develop next-generation viral-vectored TB vaccine strategies which incorporate both vaccine antigen design and delivery route. In this study, we have developed a trivalent chimpanzee adenoviral-vectored vaccine to provide protective immunity against pulmonary TB through targeting antigens linked to the three different growth phases (acute/chronic/dormancy) of Mycobacterium tuberculosis (M.tb) by expressing an acute replication-associated antigen, Ag85A, a chronically expressed virulence-associated antigen, TB10.4, and a dormancy/resuscitation-associated antigen, RpfB. Single-dose respiratory mucosal immunization with our trivalent vaccine induced robust, sustained tissue-resident multifunctional CD4+ and CD8+ T-cell responses within the lung tissues and airways, which were further quantitatively and qualitatively improved following boosting of subcutaneously BCG-primed hosts. Prophylactic and therapeutic immunization with this multivalent trivalent vaccine in conventional BALB/c mice provided significant protection against not only actively replicating M.tb bacilli but also dormant, non-replicating persisters. Importantly, when used as a booster, it also provided marked protection in the highly susceptible C3HeB/FeJ mice, and a single respiratory mucosal inoculation was capable of significant protection in a humanized mouse model. Our findings indicate the great potential of this next-generation TB vaccine strategy and support its further clinical development for both prophylactic and therapeutic applications.

Differentially Expressed Genes and Signalling Pathways Regulated by High Selenium Involved in Antioxidant and Immune Functions of Goats Based on Transcriptome Sequencing.

The objective of this study is to observe the effect of high selenium on the antioxidant and immune functions of growing goats based on transcriptome sequencing. Eighteen goats were randomly divided into three groups: (1) the control (CON) group was fed a basal diet, and (2) the treatment 1 group (LS) and treatment 2 group (HS) were fed a basal diet with 2.4 and 4.8 mg/kg selenium-yeast (SY), respectively. The results indicate that HS treatment significantly (p < 0.05) increased the apparent digestibility of either extract and significantly increased (p < 0.05) total antioxidant capacity, whereas it significantly (p < 0.05) decreased plasma aspartate aminotransferase and malondialdehyde relative to the control group. The LS treatment had significantly (p < 0.05) increased glutathione S-transferase and catalase compared to CON. A total of 532 differentially expressed genes (DEGs) between the CON and HS were obtained using transcriptome sequencing. Kyoto Encyclopedia of Genes and Genomes analysis identified upregulated (p < 0.05) DEGs mainly related to vascular smooth muscle contraction, alpha-linolenic acid metabolism, biosynthesis of unsaturated fatty acids, the VEGF signalling pathway, and proteoglycans in cancer; downregulated (p < 0.05) DEGs mainly related to the NOD-like receptor signalling pathway, influenza A, cytokine-cytokine receptor interaction, haematopoietic cell lineage, and African trypanosomiasis. Ontology analyses of the top genes show that the identified DEGs are mainly involved in the regulation of granulocyte macrophage colony-stimulating factor production for biological processes, the external side of the plasma membrane for cellular components, and carbohydrate derivative binding for molecular functions. Seven genes are considered potential candidate genes for regulating antioxidant activity, including selenoprotein W, 1, glutathione peroxidase 1, glutathione S-transferase A1, tumour necrosis factor, tumour necrosis factor superfamily member 10, tumour necrosis factor superfamily member 8, and tumour necrosis factor superfamily member 13b. The experimental observations indicate that dietary supplementation with 4.8 mg/kg SY can enhance antioxidant and immune functions by improving muscle immunity, reducing the concentrations of inflammatory molecules, and modulating antioxidant and inflammatory signalling pathways in growing goats.

Comparing Current and Next-Generation Humanized Mouse Models for Advancing HIV and HIV/Mtb Co-Infection Studies.

In people living with HIV, Mycobacterium tuberculosis (Mtb) is the major cause of death. Due to the increased morbidity/mortality in co-infection, further research is urgently required. A limiting factor to research in HIV and HIV/Mtb co-infection is the lack of accessible in vivo models. Next-generation humanized mice expressing HLA transgenes report improved human immune reconstitution and functionality, which may better recapitulate human disease. This study compares well-established huNRG mice and next-generation HLA I/II-transgenic (huDRAG-A2) mice for immune reconstitution, disease course, and pathology in HIV and TB. HuDRAG-A2 mice have improved engraftment of key immune cell types involved in HIV and TB disease. Upon intravaginal HIV-1 infection, both models developed significant HIV target cell depletion in the blood and tissues. Upon intranasal Mtb infection, both models sustained high bacterial load within the lungs and tissue dissemination. Some huDRAG-A2 granulomas appeared more classically organized, characterized by focal central necrosis, multinucleated giant cells, and foamy macrophages surrounded by a halo of CD4+ T cells. HIV/Mtb co-infection in huNRG mice trended towards worsened TB pathology and showed potential for modeling co-infection. Both huNRG and huDRAG-A2 mice are viable options for investigating HIV and TB, but the huDRAG-A2 model may offer advantages.

Dextran Mass Ratio Controls Particle Drying Dynamics in a Thermally Stable Dry Powder Vaccine for Pulmonary Delivery.

PURPOSE: Thermally stable, spray dried vaccines targeting respiratory diseases are promising candidates for pulmonary delivery, requiring careful excipient formulation to effectively encapsulate and protect labile biologics. This study investigates the impact of dextran mass ratio and molecular weight on activity retention, thermal stability and aerosol behaviour of a labile adenoviral vector (AdHu5) encapsulated within a spray dried mannitol-dextran blend. METHODS: Comparing formulations using 40 kDa or 500 kDa dextran at mass ratios of 1:3 and 3:1 mannitol to dextran, in vitro quantification of activity losses and powder flowability was used to assess suitability for inhalation. RESULTS: Incorporating mannitol in a 1:3 ratio with 500 kDa dextran reduced viral titre processing losses below 0.5 log and displayed strong thermal stability under accelerated aging conditions. Moisture absorption and agglomeration was higher in dextran-rich formulations, but under low humidity the 1:3 ratio with 500 kDa dextran powder had the lowest mass median aerodynamic diameter (4.4 µm) and 84% emitted dose from an intratracheal dosator, indicating strong aerosol performance. CONCLUSIONS: Overall, dextran-rich formulations increased viscosity during drying which slowed self-diffusion and favorably hindered viral partitioning at the particle surface. Reducing mannitol content also minimized AdHu5 exclusion from crystalline regions that can force the vector to air-solid interfaces where deactivation occurs. Although increased dextran molecular weight improved activity retention at the 1:3 ratio, it was less influential than the ratio parameter. Improving encapsulation ultimately allows inhalable vaccines to be prepared at higher potency, requiring less powder mass per inhaled dose and higher delivery efficiency.

Differential Biodistribution of Adenoviral-Vectored Vaccine Following Intranasal and Endotracheal Deliveries Leads to Different Immune Outcomes.

Infectious diseases of the respiratory tract are one of the top causes of global morbidity and mortality with lower respiratory tract infections being the fourth leading cause of death. The respiratory mucosal (RM) route of vaccine delivery represents a promising strategy against respiratory infections. Although both intranasal and inhaled aerosol methods have been established for human application, there is a considerable knowledge gap in the relationship of vaccine biodistribution to immune efficacy in the lung. Here, by using a murine model and an adenovirus-vectored model vaccine, we have compared the intranasal and endotracheal delivery methods in their biodistribution, immunogenicity and protective efficacy. We find that compared to intranasal delivery, the deepened and widened biodistribution in the lung following endotracheal delivery is associated with much improved vaccine-mediated immunogenicity and protection against the target pathogen. Our findings thus support further development of inhaled aerosol delivery of vaccines over intranasal delivery for human application.

Effect of Purple Corn Anthocyanin on Antioxidant Activity, Volatile Compound and Sensory Property in Milk During Storage and Light Prevention.

The aim of this study was to observe the effect of purple corn anthocyanin on the light-induced antioxidant activity, free radicals, volatile compounds, color parameters, and sensory properties of milk during storage. There were four groups: (1) negative control, no addition of anthocyanins + exposure to fluorescent light (NC); (2) positive control 1, no addition of anthocyanins + protected from fluorescent light (PC1); (3) positive control 2, the addition of 0.3% (w/v) anthocyanins + exposure to fluorescent light (PC2); and (4) the addition of 0.3% anthocyanins + protected from fluorescent light (AC). The results indicated that the concentration of antioxidant activity parameters in the NC group decreased during the entire storage period, whereas antioxidant activity parameters were unchanged except for the glutathione peroxidase (GSH-Px) in the AC group. Moreover, the NC group showed lower levels of 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity and higher levels of superoxide anion and hydrogen peroxide than the other groups after 1 d of storage period. The extent of malondialdehyde accumulation and lipid peroxidation in the control groups were greater than that of the AC group. Twenty-two volatile compounds were determined in milk, which consisted of eight alcohols, three ketones, five aldehydes, two esters, and four hydrocarbons by headspace gas chromatography mass spectrometer analysis. Specifically, individual aldehydes, esters and hydrocarbons in the AC group remained at relatively stable values during storage relative to the other three groups. Stronger positive correlations were detected between several antioxidant activities (superoxide dismutase, GSH-Px) and DPPH scavenging activity as well as total ketones in milk. Adding of anthocyanin did not impact on the color values of L*, a* and b* in light-protected milk during the entire storage period. Some sensory evaluation parameters (flat, garlic/onion/weedy, oxidized-light, oxidized-metal, rancid) in AC group were significantly higher than that of the control group at the end of the period. In conclusion, the current study revealed that the addition of purple corn anthocyanin pigment to light-protected milk had the potential to prevent lipid oxidation, enhance antioxidant activity, maintain volatile compounds and increase the sensory scores.

3BDO inhibits the proliferation, epithelial-mesenchymal transition (EMT), and stemness via suppressing survivin in human glioblastoma cells.

Background: Glioblastoma (GBM) is a tumor of the central nervous system with an extremely poor prognosis. Stemness and EMT play important roles in GBM progression. 3-benzyl-5-((2-nitrophenoxy) methyl) dihydrofuran-2(3H)-one (3BDO), an autophagy inhibitor, has been reported to exert anti-cancer activities on lung carcinoma. However, the effects of 3BDO on GBM remain unknown. Therefore, the purpose of this study was to explore the effects of 3BDO on GBM and to investigate the underlying molecular mechanisms. Method: CCK-8 experiments and clone formation assays were conducted to determine the level of cell proliferation. Transwell assay was conducted to examine cell migration and invasion abilities. Western blotting and immunofluorescence staining were used to analyze protein expression levels. A xenograft mouse model was used to evaluate the effect of 3BDO in vivo. Results: We found that 3BDO inhibited U87 and U251 cell proliferation in a dose-dependent manner. Additionally, 3BDO decreased the degree of sphere formation and levels of stemness markers (sox2, nestin, and CD133) in GSCs. 3BDO also inhibited migration and invasion abilities and suppressed EMT markers (N-cadherin, vimentin, and snail) in GBM cells. Moreover, we found that 3BDO downregulated the expression of survivin in both GBM cells (U87, U251) and GSCs. Furthermore, overexpression of survivin decreased the therapeutic effect of 3BDO on EMT, invasion, migration, and proliferation of GBM cells, as well as decreased the stemness of GSCs. Finally, we demonstrated that 3BDO could inhibit tumor growth in a tumor xenograft mouse model constructed using U87 cells. Similar to the in vitro findings, 3BDO decreased the expression of survivin, EMT makers, and the degree of stemness in vivo. Conclusions: Our results demonstrate that 3BDO can repress GBM both in vitro and in vivo via downregulating survivin-mediated stemness and EMT.

Cryoprotective agents influence viral dosage and thermal stability of inhalable dry powder vaccines.

Increasing viral dosage within dry powder vaccines reduces the powder mass required to elicit an immune response through pulmonary delivery. This work analyzes how cryoprotective agents affect viral activity, particle properties and thermal stability of a spray dried, inhalable vaccine vector under high viral loading. Stock suspensions of a human serotype 5 adenovirus (AdHu5) vector in either neat phosphate buffered saline (PBS), 10% glycerol in PBS, or 5% trehalose in PBS were added to a mannitol-dextran formulation prior to spray drying. At high viral loading, spray dried powder containing glycerol had a viral titre log loss of 2.8 compared to 0.7 log loss using neat PBS. Powders containing glycerol had a lower glass transition temperature (Tg) compared to all other formulations, permitting greater viral mobility and exposure to heat damage. Inclusion of glycerol also promoted particle cohesion during spray drying and lower yields. Using 5% trehalose as a cryogenic alternative, viral powders had a viral log loss of 1.5 and the highest displayed thermal stability over time. Additionally, trehalose-containing powders had smaller particles with lower water moisture content and higher powder yield compared to glycerol-containing powders. These findings demonstrate the importance of cryoprotective agent selection when developing thermostable vaccine powders.

Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2.

The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Antidepressant effect of electroacupuncture on modulating the expression of c-Fos/AP-1 through the JNK signaling pathway.

The effectiveness and safety of electroacupuncture (EA) for depression have been identified by abundant clinical trials and experimental findings. The c-Jun-NH(2)-terminal kinase (JNK) signaling pathway is considered to be involved in the antidepressant mechanism of EA. However, the antidepressant effect of EA via modulating the expression of c-Fos/activator protein-1 (AP-1) under the condition of JNK inhibition remains unexplored. In this study, we investigated the antidepressant effect and possible mechanism of EA in regulating the expression of c-Fos/AP-1 under the condition of JNK inhibition by SP600125 in rats exposed to chronic unpredictable mild stress (CUMS). The depression-like behaviors were evaluated by the body weight, sucrose preference test (SPT), and open field test (OFT). The expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum of CUMS induced rat model of depression were detected by ELISA. The results indicated that treatment with EA and fluoxetine can reverse the CUMS-induced depression-like behaviors in rats and can up-regulate the expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum. Of note, the data demonstrated that SP600125, the inhibitor of JNK signaling pathway, can exert synergistic effect with EA in regulating CUMS-induced abnormal activation of the JNK signaling pathway. The antidepressant effect of EA might be mediated by modulating the expression of c-Fos/AP-1.

Validation of a diffusion-based single droplet drying model for encapsulation of a viral-vectored vaccine using an acoustic levitator.

Development of thermally stable spray dried viral-vectored vaccine powders is dependent on the selection of a proper excipient or excipient blend for encapsulation, which can be a time and resource intensive process. In this work, a diffusion-based droplet drying model was developed to compute droplet drying time, size, and component distribution. The model predictions were validated using an acoustic levitator to dry droplets containing protein-coated or fluorescently labelled silica nanoparticles (as adenoviral vector analogues) and a range of excipient blends. Surface morphology of the dried particles was characterized by atomic force microscopy and the distribution of silica nanoparticles was quantified by confocal microscopy. The modelled distributions of adenovirus agreed with the microscopy results for three mannitol/dextran excipient blends with varying molecular weight dextrans, verifying the equations and assumptions of the model. Viral vector activity data for adenovirus in a range of (poly)saccharide/sugar alcohol formulations were also compared to the model outputs, suggesting that viral activity decreases when the model predicts increasing adenovirus concentrations near the air-solid interface. Using a validated model with excipient property inputs that are readily available in the literature can facilitate the development of viral-vectored vaccines by identifying promising excipients without the need for experimentation.