Substantial Protection Research Articles

Measures of Population Immunity Can Predict the Dominant Clade of Influenza A (H3N2) in the 2017-2018 Season and Reveal Age-Associated Differences in Susceptibility and Antibody-Binding Specificity.

For antigenically variable pathogens such as influenza, strain fitness is partly determined by the relative availability of hosts susceptible to infection with that strain compared with others. Antibodies to the hemagglutinin (HA) and neuraminidase (NA) confer substantial protection against influenza infection. We asked if a cross-sectional antibody-derived estimate of population susceptibility to different clades of influenza A (H3N2) could predict the success of clades in the following season. We collected sera from 483 healthy individuals aged 1 to 90 years in the summer of 2017 and analyzed neutralizing responses to the HA and NA of representative strains using focus reduction neutralization tests (FNRT) and enzyme-linked lectin assays (ELLA). We estimated relative population-average and age-specific susceptibilities to circulating viral clades and compared those estimates to changes in clade frequencies in the following 2017-2018 season. The clade to which neutralizing antibody titers were lowest, indicating greater population susceptibility, dominated the next season. Titer correlations between viral strains varied by age, suggesting age-associated differences in epitope targeting driven by shared past exposures. Yet substantial unexplained variation remains within age groups. This study indicates how representative measures of population immunity might improve evolutionary forecasts and inform selective pressures on influenza.

Measures of population immunity can predict the dominant clade of influenza A (H3N2) in the 2017-2018 season and reveal age-associated differences in susceptibility and antibody-binding specificity.

For antigenically variable pathogens such as influenza, strain fitness is partly determined by the relative availability of hosts susceptible to infection with that strain compared to others. Antibodies to the hemagglutinin (HA) and neuraminidase (NA) confer substantial protection against influenza infection. We asked if a cross-sectional antibody-derived estimate of population susceptibility to different clades of influenza A (H3N2) could predict the success of clades in the following season. We collected sera from 483 healthy individuals aged 1 to 90 years in the summer of 2017 and analyzed neutralizing responses to the HA and NA of representative strains using Focus Reduction Neutralization Tests (FNRT) and Enzyme-Linked Lectin Assays (ELLA). We estimated relative population-average and age-specific susceptibilities to circulating viral clades and compared those estimates to changes in clade frequencies in the following 2017-18 season. The clade to which neutralizing antibody titers were lowest, indicating greater population susceptibility, dominated the next season. Titer correlations between viral strains varied by age, suggesting age-associated differences in epitope targeting driven by shared past exposures. Yet substantial unexplained variation remains within age groups. This study indicates how representative measures of population immunity might improve evolutionary forecasts and inform selective pressures on influenza.

Prospects of universal influenza virus vaccine and the current challenges of new antiviral drugs

The profound impact of influenza viruses on human health persists as a significant burden, given their potent capacity to cause morbidity and mortality. Despite efforts to mitigate the annual burden of influenza, the effectiveness of current seasonal vaccines in providing substantial protection falls short, leaving undesirable pandemic of influenza viruses. The challenges posed by the influenza pandemic lies from the constant changes inherent in the virus itself, as well as the limitations of current immunization approaches in achieving sufficient immunogenicity. Influenza viruses exhibit antigenic drift and shift, undergoing antigenic evolution by altering the surface glycoproteins. These changes contribute to the persistent and dynamic nature of the influenza virus, posing formidable challenges to effective prevention and control strategies. Currently, there is growing recognition of unique viral targets that hold promise development of broad-protective vaccines against influenza. These targets are distinct from traditional vaccine targets and offer the potential for more comprehension protection against diverse strains of the virus. Here, we present a review about the novel drugs and vaccines that target the influenza virus would signify the unique immune correlates of protection that need to be initiated to accelerate the vaccine efficacy.

A chimeric strain of porcine reproductive and respiratory syndrome virus 2 derived from HP-PRRSV and NADC30-like PRRSV confers cross-protection against both strains

Porcine reproductive and respiratory syndrome (PRRS) is one of the most significant swine viral infectious diseases worldwide. Vaccination is a key strategy for the control and prevention of PRRS. At present, the NADC30-like PRRSV strain has become the predominant epidemic strain in China, superseding the HP-PRRSV strain. The existing commercial vaccines offer substantial protection against HP-PRRSV, but their efficacy against NADC30-like PRRSV is limited. The development of a novel vaccine that can provide valuable cross-protection against both NADC30-like PRRSV and HP-PRRSV is highly important. In this study, an infectious clone of a commercial MLV vaccine strain, GD (HP-PRRSV), was first generated (named rGD). A recombinant chimeric PRRSV strain, rGD-SX-5U2, was subsequently constructed by using rGD as a backbone and embedding several dominant immune genes, including the NSP2, ORF5, ORF6, and ORF7 genes, from an NADC30-like PRRSV isolate. In vitro experiments demonstrated that chimeric PRRSV rGD-SX-5U2 exhibited high tropism for MARC-145 cells, which is of paramount importance in the production of PRRSV vaccines. Moreover, subsequent in vivo inoculation and challenge experiments demonstrated that rGD-SX-5U2 confers cross-protection against both HP-PRRSV and NADC30-like PRRSV, including an improvement in ADG levels and a reduction in viremia and lung tissue lesions. In conclusion, our research demonstrated that the chimeric PRRSV strain rGD-SX-5U2 is a novel approach that can provide broad-spectrum protection against both HP-PRRSV and NADC30-like PRRSV. This may be a significant improvement over previous MLV vaccinations.

Prevention of Sunlight-Induced Cell Damage by Selective Blue-Violet-Light-Filtering Lenses in A2E-Loaded Retinal Pigment Epithelial Cells.

Blue light accelerates retinal aging. Previous studies have indicated that wavelengths between 400 and 455 nm are most harmful to aging retinal pigment epithelia (RPE). This study explored whether filtering these wavelengths can protect cells exposed to broad sunlight. Primary porcine RPE cells loaded with 20 µM A2E were exposed to emulated sunlight filtered through eye media at 1.8 mW/cm2 for 18 h. Filters selectively filtering out light over 400-455 nm and a dark-yellow filter were interposed. Cell damage was measured by apoptosis, hydrogen peroxide (H2O2) production, and mitochondrial membrane potential (MMP). Sunlight exposure increased apoptosis by 2.7-fold and H2O2 by 4.8-fold, and halved MMP compared to darkness. Eye Protect SystemTM (EPS) technology, filtering out 25% of wavelengths over 400-455 nm, reduced apoptosis by 44% and H2O2 by 29%. The Multilayer Optical Film (MOF), at 80% of light filtered, reduced apoptosis by 91% and H2O2 by 69%, and increased MMP by 73%, overpassing the dark-yellow filter. Photoprotection increased almost linearly with blue-violet light filtering (400-455 nm) but not with total blue filtering (400-500 nm). Selective filters filtering out 25% (EPS) to 80% (MOF) of blue-violet light offer substantial protection without affecting perception or non-visual functions, making them promising for preventing light-induced retinal damage with aesthetic acceptance for permanent wear.

The Potential of Clove (Syzygium aromaticum) Essential Oil as Sunscreen and Anti-Aging Agents: An In Vitro and In Silico Study

The earth thermal conditions increase exposure to sunlight, triggering skin damage. The skin has defense mechanisms but needs additional protection to prevent photoaging. Using sunscreen is an effort to reduce the harmful effects of sun exposure. Natural ingredients with antioxidant activity can be developed into sunscreen and antiaging products, including cloves. This study aims to assess the antioxidant, sun protection, and anti-aging properties of essential oils derived from clove leaves and buds. The antioxidant activity was assessed by the DPPH system and then formulated into 5 and 10 % clove leaves cream, as well as 5 and 10 % clove bud cream. The SPF values were assessed using a spectrophotometer and the Mansur formula. The antiaging potential was assessed using the in silico method with MMP-1 protein employing the Auto Dock Vina software, followed by analysis and visualization using BIOVIA Discovery Studio. The essential oils from clove leaves and buds have DPPH IC50 values of 23.09 and 30.31 ppm. The SPF values of clove leaves essential oil, 5 % leaves cream, and 10 % leaves cream are 38.61, 14.32, and 22.15. Meanwhile, the SPF values of clove bud essential oil, 5 % bud cream, and 10 % bud cream are 38.19, 9.32, and 18.16. The in silico test revealed that caryophyllene, eugenol, humulene, and phenol, 2-methoxy-4-(2-propenyl), acetate) have strong interactions because they can interact with the active site of proteins using hydrogen, hydrophobic, and van der Waals bonds. The essential oils from clove leaves and buds exhibit very strong antioxidant activity and offer ultra-protection as a sunscreen. The cream formulations still exhibit sunscreen activity, albeit at a lower level compared to pure essential oil. Caryophyllene, eugenol, humulene, and phenol, 2-methoxy-4-(2-propenyl)-, acetate), have potential as antiaging agents, as indicated by their binding affinity and chemical bond interactions observed in the in silico test. HIGHLIGHTS Clove buds and leaves exhibit antioxidant properties. Essential oil from clove buds and leaves demonstrates a substantial Sun Protection Factor (SPF). The compounds contained in clove essential oil exhibit promise as prospective agents in anti-aging applications. GRAPHICAL ABSTRACT

Use of Haemophilus influenzae Type b-Containing Vaccines Among American Indian and Alaska Native Infants: Updated Recommendations of the Advisory Committee on Immunization Practices - United States, 2024.

Invasive Haemophilus influenzae type b (Hib) disease is a serious bacterial infection that disproportionally affects American Indian and Alaska Native (AI/AN) populations. Hib vaccination with a monovalent Hib conjugate vaccine consisting of Hib capsular polysaccharide (polyribosylribitol phosphate [PRP]) conjugated to outer membrane protein complex of Neisseria meningitidis serogroup B, PRP-OMP (PedvaxHIB, Merck and Co., Inc.) has historically been preferred for AI/AN infants, who are at increased risk for invasive Hib disease, because it provides substantial protection after the first dose. On June 26, 2024, CDC's Advisory Committee on Immunization Practices (ACIP) recommended that a hexavalent, combined diphtheria and tetanus toxoids and acellular pertussis (DTaP), inactivated poliovirus (IPV), Hib conjugate, and hepatitis B (HepB) vaccine, DTaP-IPV-Hib-HepB (Vaxelis, MSP Vaccine Company) should be included with monovalent PRP-OMP in the preferential recommendation for AI/AN infants because of the PRP-OMP Hib component. A primary Hib vaccination series consisting of either 1) monovalent PRP-OMP (2-dose series at ages 2 and 4 months) or 2) DTaP-IPV-Hib-HepB (3-dose series at ages 2, 4, and 6 months) is preferred for AI/AN infants. DTaP-IPV-Hib-HepB is only indicated for use in infants at ages 2, 4, and 6 months and should not be used for the booster doses of Hib, DTaP, or IPV vaccines. For the booster dose of Hib vaccine, no vaccine formulation is preferred for AI/AN children; any Hib vaccine (except DTaP-IPV-Hib-HepB) should be used. This report summarizes evidence considered for these recommendations and provides clinical guidance for the use of Hib-containing vaccines among AI/AN infants and children.

Real-World Effectiveness of Nirsevimab Against Respiratory Syncytial Virus: A Test-Negative Case-Control Study.

Nirsevimab, a long-acting monoclonal antibody, has demonstrated efficacy against RSV-related lower respiratory tract infections (LRTIs) in clinical trials. Post-licensure monitoring is essential to confirm these benefits in real-world settings. To evaluate the real-world effectiveness of nirsevimab against medically attended RSV infections in infants and to assess how effectiveness varies by disease severity, dosage, and time since immunization. This test-negative case-control study used inpatient, outpatient, and emergency room data from the Yale New Haven Health System. Nirsevimab-eligible infants who were tested for RSV using polymerase chain reaction between October 1, 2023 and May 9, 2024 were included. Cases were infants with confirmed RSV infections; controls were those who tested negative. Nirsevimab immunization, verified through state immunization registries. Effectiveness was estimated using multivariable logistic regression, adjusting for age, calendar month, and individual risk factors. Separate models examined effectiveness by clinical setting, disease severity, dose, and time since immunization. Broader outcomes, including all-cause LRTI and LRTI-related hospitalization, were also analyzed, with stratification by early and late respiratory seasons. The analytic sample included 3,090 infants (median age 6.7 months, IQR 3.6-9.7), with 680 (22.0%) RSV-positive and 2,410 (78.0%) RSV-negative. 21 (3.1%) RSV-positive and 309 (12.8%) RSV-negative infants received nirsevimab. Effectiveness against RSV infection was 68.4% (95% CI, 50.3%-80.8%). Effectiveness was 61.6% (95% CI, 35.6%-78.6%) for outpatient visits and 80.5% (95% CI, 52.0%-93.5%) for hospitalizations. The highest effectiveness, 84.6% (95% CI, 58.7%-95.6%), was observed against severe RSV outcomes requiring ICU admission or high-flow oxygen. Although effectiveness against RSV infections declined over time, it remained significant at 55% (95% credible interval, 16%-75%) at 14 weeks post-immunization. Protective effectiveness was also observed against all-cause LRTI and LRTI-related hospitalizations during peak RSV season (49.4% [95% CI, 10.7%-72.9%] and 79.1% [95% CI, 27.6%-94.9%], respectively). However, from February to May, when RSV positivity was low, effectiveness against these broader outcomes was negligible. Nirsevimab provided substantial protection against RSV-related outcomes for at least three months. These findings support the continued use of nirsevimab and provide evidence that may help build public confidence in the immunization program. Question: What is the effectiveness of nirsevimab against medically attended respiratory syncytial virus (RSV) infections in infants?Findings: 680 RSV test-positive cases and 2,410 RSV test-negative controls were included in this test-negative case-control study. Nirsevimab's effectiveness was 69% against RSV infections, 81% against RSV-associated hospitalization, and 85% against severe RSV disease. Effectiveness against RSV infection declined from 79% at 2 weeks post-immunization to 55% at 14 weeks post-immunization.Meaning: Nirsevimab provides strong protection against a wide range of RSV outcomes, but its effectiveness diminishes over time. These data can be utilized to optimize nirsevimab's implementation and sustain its uptake.

Suppression of Thrips palmi population by spray-on application of dsRNA targeting V-ATPase-B

The RNA interference (RNAi)-based gene silencing technique has enormous potential as a non-chemical and eco-friendly alternative to hazardous pesticides. This study reports a spray-induced gene silencing (SIGS) approach for managing Thrips palmi by lowering survival and offspring development. Vacuolar ATP synthases (V-ATPases) are responsible for survival, egg-laying, and viability of eggs in insects. In the current study, T. palmi V-ATPase-B was targeted to suppress the pest population by spray-on application of double-stranded RNA (dsRNA). Silencing of V-ATPase-B was first validated by oral administration of dsV-ATPase-B. The expression of V-ATPase-B was reduced by 5.40-fold post-dsRNA feeding leading to increased mortality (57.03 %) and reduced reproductive fitness (67.73 %). Spray-on application of naked dsV-ATPase-B at concentrations of 3.0 μg/mL and 5.0 μg/mL effectively suppressed the population by 30.00 % and 43.33 %, respectively. The expression of the target gene was downregulated by up to 4.24-fold. Two consecutive sprays at a concentration of 5.0 μg/mL provided substantial protection against the fresh release of T. palmi for up to 10 days. The spray-on application of dsV-ATPase-B would be an eco-friendly alternative for managing T. palmi populations thereby reducing crop damage and limiting the spread of orthotospoviruses.

Impact of SARS-CoV-2 infection and vaccination on cesarean section outcomes: a retrospective analysis.

Pregnant individuals have faced unique challenges during the COVID-19 pandemic, necessitating a closer examination of maternal and fetal health outcomes. Investigate the morbidity and mortality associated with SARS-CoV-2 infection among pregnant individuals, considering vaccination status and variant strains. Retrospective cohort. Tertiary state hospital. Patients who underwent cesarean sections were categorized into three periods: pre-vaccination (before 31 August 2021), early post-vaccination (from September 2021), and late post-vaccination (aligned with 70% immunization coverage by 2 September 2021). Data collected included demographic information (age, gravidity, parity count, gestational age, newborn APGAR scores), cesarean section indications, chronic diseases, vaccination status, vaccine type and doses, SARS-CoV-2 variant status, ICU admission, and mortality due to COVID-19. ICU admission and mortality rates, focusing on the impact of SARS-CoV-2 infection and vaccination status. 297 COVID PCR-positive symptomatic patients who underwent cesarean sections. In the pre-vaccination group, there were 13 mortalities (8.1%) compared to 9 (6.6%) post-vaccination (P=.610). Maternal ARDS was seen in 46.2% of pre-vaccination mortalities versus 11.1% post-vaccination (P=.045). COVID-19 delta variant patients had higher ICU admission (80%) and mortality rates (40%). Rates of COVID-19 PCR-positive cesarean sections, ICU admissions, and mortality declined significantly in early (P=.021, P=.004, P=.009), respectively and late post-vaccination periods (P<.001, P<.001, P=.0019), respectively. Vaccinated patients had no ICU admissions or mortality. Vaccination against COVID-19 is crucial for pregnant individuals as it significantly reduces the risk of severe illness. While vaccines offer substantial protection, the pandemic's acute phase might be waning, yet COVID-19 remains a global threat, particularly in regions with limited vaccine access. Continued vigilance and proactive measures are essential to mitigate ongoing risks and the emergence of new variant strains. Retrospective observational design and the single-center setting, which may affect the generalizability of the findings.

Tracking vaccine effectiveness in an evolving pandemic, countering misleading hot takes and epidemiological fallacies.

With the emergence of Omicron and establishment of antibody waning over time, vaccine effectiveness, especially against infection, declined sharply from the original levels seen after the initial rollout. However, studies have demonstrated that they still provided substantial protection vs. severe/fatal disease even with Omicron and after waning. Social media has been rife with reports claiming vaccines provided no benefit and some even claiming they made things worse, often driven by simple presentations of raw observational data using erroneous arguments involving epidemiological fallacies including the base rate fallacy, Simpson's paradox, and the ecological fallacy and ignoring the extensive bias especially from confounding that are inherent features of these data. Similar fallacious arguments have been made by some in promoting vaccination policies as well. Generally, vaccine effectiveness cannot be accurately estimated from raw population summaries, but instead require rigorous, careful studies using epidemiological designs and statistical analysis tools attempting to adjust for key confounders and sources of bias. This article summarizes what aggregated evidence across studies reveals about effectiveness of the mRNA vaccines as the pandemic has evolved, chronologically summarized with emerging variants, and highlighting some of the fallacies and flawed arguments feeding social media-based claims that have obscured society's collective understanding.

Enhancing Sustainability through Weather Derivative Option Contracts: A Risk Management Tool in Greek Agriculture

This paper investigates the efficacy of weather derivatives as a risk management tool in the agricultural sector of Naousa, Greece, focusing on tree crops sensitive to temperature variations. The specific purpose is to assess how effectively weather derivative options can mitigate financial risks for farmers by providing strategic solutions. The study assesses the strategic application of Heating Degree Days (HDD) index options and their potential to alleviate economic vulnerabilities faced by farmers due to temperatures fluctuations. Employing different strike prices in Long Call and Straddle options strategies on the HDD index, the research offers tailored risk management solutions that cater to varying risk aversions among farmers. Moreover, the study applies the Value at Risk (VaR) methodology to quantify the financial security that weather derivatives can furnish, revealing a significantly reduced probability of severe financial losses in hedged scenarios compared to no-hedge conditions. Results show that all implemented strategies effectively enhance financial outcomes compared to scenarios without hedging, highlighting the exceptional utility of weather derivatives as risk management tools in the agricultural sector. Strategy 4, which exhibits the lowest VaR, emerges as the most effective, providing substantial protection against adverse weather conditions. This research supports the notion that weather derivatives can substantially contribute to the economic sustainability of rural economies, influencing policy decisions toward enhancing financial instruments for risk management in agriculture.

Protective Effects of Small Molecular Inhibitors on Steel Corrosion: The Generation of a Multi-Electric Layer on Passivation Films

The durability of reinforced concrete structures is significantly influenced by the effectiveness of small molecular inhibitors in preventing the corrosion of steel reinforcements. In a concrete environment, the passive film on steel bars serves as a critical protective component. In this study, a molecular dynamics (MD) simulation is used to study the inhibition mechanism of chloride ions by common corrosion inhibitors (2-Amino-2-thiazoline) in concrete in an excess chloride solution. The results reveal that inhibitors adsorb onto the steel surface primarily through van der Waals forces, with more than 90% of the adsorption occurring vertically. Despite this strong adsorption, inhibitors alone do not form a protective film. In the presence of chloride ions, which frequently penetrate concrete, the coverage rate of inhibitors on the steel surface decreases from 74% to 64%. Nevertheless, inhibitor molecules still provide substantial protection in chloride-rich concrete environments. Further analysis indicates that inhibitor molecules inhibit chloride ions in two ways. Corrosion inhibitor molecules actively desorb from the steel surface to capture chloride ions and prevent them from approaching. Additionally, inhibitors form a multi-electron layer on the steel surface to enhance passive film protection and hinder chloride ion diffusion through Coulombic interactions.

A broad-spectrum multiepitope vaccine against seasonal influenza A and B viruses in mice

Influenza viruses pose a persistent threat to global public health, necessitating the development of innovative and broadly effective vaccines. This study focuses on a multiepitope vaccine (MEV) designed to provide broad-spectrum protection against different influenza viruses. The MEV, containing 19B-cell linear epitopes, 7 CD4+ T cells, and 11 CD8+ T cells epitopes identified through enzyme-linked immunospot assay (ELISPOT) in influenza viruses infected mice, was administered through a regimen of two doses of DNA vaccine followed by one dose of a protein vaccine in C57BL/6 female mice. Upon lethal challenge with both seasonal circulating strains (H1N1, H3N2, BV, and BY) and historical strains (H1N1-PR8 and H3N2-X31), MEV demonstrated substantial protection against different influenza seasonal strains, with partial efficacy against historical strains. Notably, the increased germinal centre B cells and antibody-secreting cells, along with robust T cell immune responses, highlighted the comprehensive immune defence elicited by MEV. Elevated hemagglutinin inhibition antibody was also observed against seasonal circulating and historical strains. Additionally, mice vaccinated with MEV exhibited significantly lower counts of inflammatory cells in the lungs compared to negative control groups. Our results demonstrated the efficacy of a broad-spectrum MEV against influenza viruses in mice. Conducting long-term studies to evaluate the durability of MEV-induced immune responses and explore its potential application in diverse populations will offer valuable insights for the continued advancement of this promising vaccine. Funding bodies are described in the Acknowledgments section.

Evaluation of different heterologous-homologous vaccine regimens against challenge with GI-23 lineage infectious bronchitis virus

This study assesses different IBV vaccination regimens in broiler chickens using commercially available live attenuated GI-23 (Egyptian-VAR2) and GI-1 (H120) vaccines. Vaccines were administered at 1, 14 days of age, or both. The ciliostasis test, following wild-type VAR2 challenge at 28 days of age, indicated that classic H120+VAR2 at one day old followed by the VAR2 vaccine at 14 days of age provided the highest level of protection (89.58%). Similarly, administering VAR2 at 1 day of age and classic H120 at 14 days of age demonstrated substantial protection (85.42%). Conversely, administering only classic H120 and VAR2 at one day old resulted in the lowest protection level (54.17%). Tracheal virus shedding quantification and assessment of trachea and kidney degenerative changes were significantly lower in vaccinated groups compared to the unvaccinated-challenged group. In conclusion, a carefully planned vaccination regimen based on homologous vaccination offers the most effective clinical protection in broiler chickens.

Baicalin attenuates PD-1/PD-L1 axis-induced immunosuppression in piglets challenged with Glaesserella parasuis by inhibiting the PI3K/Akt/mTOR and RAS/MEK/ERK signalling pathways

Infection of piglets with Glaesserella parasuis (G. parasuis) induces host immunosuppression. However, the mechanism underlying the immunosuppression of piglets remains unclear. Activation of the PD-1/PD-L1 axis has been shown to trigger host immunosuppression. Baicalin possesses anti-inflammatory and immunomodulatory functions. However, whether baicalin inhibits PD-1/PD-L1 activation and thus alleviates host immunosuppression has not been investigated. In this study, the effect of baicalin on the attenuation of piglet immunosuppression induced by G. parasuis was evaluated. Seventy piglets were randomly divided into the control group, infection group, levamisole group, BMS-1 group, 25 mg/kg baicalin group, 50 mg/kg baicalin group and 100 mg/kg baicalin group. Following pretreatment with levamisole, BMS-1 or baicalin, the piglets were challenged with 1 × 108 CFU of G. parasuis. Our results showed that baicalin, levamisole and BMS-1 modified routine blood indicators and biochemical parameters; downregulated IL-1β, IL-10, IL-18, TNF-α and IFN-γ mRNA expression; and upregulated IL-2 and IL-8 mRNA expression in blood. Baicalin, levamisole and BMS-1 increased the proportions of CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+ T cells and CD3–CD21+ B cells in the splenocyte population, increased the proportions of CD3+ T cells, CD3+CD4+ T cells and CD3+CD8+ T cells in the blood, and inhibited PD-1/PD-L1 and TIM-3 activation. Baicalin, levamisole and BMS-1 reduced p-PI3K, p-Akt, and p-mTOR expression, the p-MEK1/2/MEK1/2 and p-ERK1/2/ERK1/2 ratios and increased RAS expression. Baicalin, levamisole and BMS-1 provided substantial protection against G. parasuis challenge and relieved tissue histopathological damage. Our findings might provide new strategies for controlling G. parasuis infection and other immunosuppressive diseases.

Exploring the anti-inflammatory and immunomodulatory potential of licochalcone B against psoralidin-induced liver injury

Ethnopharmacological relevanceHerb-induced liver injury (HILI) represents an exacerbated inflammatory response, with Psoraleae fructus (PF) and its preparations recently associated with hepatotoxicity. Licorice, historically recognized as a detoxifying herbal remedy, is considered to possess hepatoprotective properties. Our previous research identified bavachin, bakuchiol, and psoralidin (PSO) as potential toxic constituents in PF, while licochalcone B (LCB) and echinatin were identified as bioactive components in licorice. However, evidence regarding the interactions of active compounds in herbs and their underlying mechanisms remains limited. Aim of the studyThe objective of this study is to assess the potential mechanisms through which LCB modulates immunological and anti-inflammatory responses to treat PSO-induced liver injury by using human hepatocyte cells (L02) and LPS-primed mice. MethodsThe ameliorative effects of LCB and echinatin on bavachin, bakuchiol, and PSO-induced liver injury were demonstrated in L02 cells. Subsequently, the efficacy of LCB on PSO-induced idiosyncratic liver injury was further validated in C57BL/6 mice under moderate inflammatory stress induced by LPS priming. The mechanisms were preliminarily explored with an integrated strategy of molecular docking, RT-PCR verification, and untargeted metabolomics. ResultsThe study shows that LCB significantly reduced cell injury induced by the three chemicals in PF and provided substantial protection against PSO-induced hepatic damage, as indicated by the levels of ALT, AST, and LDH. LCB normalized liver function and remarkedly alleviated hepatic lesions and inflammation caused by PSO in mice under moderate inflammatory stress. The mRNA profiles of both L02 cells and mice liver tissue revealed that LCB mitigated PSO-induced hepatotoxicity by regulating the gene expression of pro-inflammatory cytokines IL1B and TNF, as well as immunoinflammatory genes PIK3CA, AKT1, NFKB1, and NLRP3. Furthermore, untargeted metabolomics of liver tissue indicated that LCB could reverse the abnormal expression of 11 discriminatory metabolites, with the interrelationship between differential metabolites and target genes primarily clustering in glycerophospholipid metabolism, arachidonic acid metabolism, and phosphatidylinositol signaling system. ConclusionLCB demonstrated a superior anti-inflammatory and immunomodulatory effect on PSO-induced hepatotoxicity by modulating the inflammatory response and metabolic signaling system. Key interactive targets included phosphatidylcholine, phosphatidic acid, and subunit isoforms of PI3K.

Can metformin prevent cancer relative to sulfonylureas? A target trial emulation accounting for competing risks and poor overlap via double/debiased machine learning estimators.

There is mounting interest in the possibility that metformin, indicated for glycemic control in type 2 diabetes, has a range of additional beneficial effects. Randomized trials have shown that metformin prevents adverse cardiovascular events, and metformin use has also been associated with reduced cognitive decline and cancer incidence. In this paper, we dig more deeply into whether metformin prevents cancer by emulating target randomized trials comparing metformin to sulfonylureas as first line diabetes therapy using data from Clinical Practice Research Datalink, a U.K. primary care database (1987-2018). We included individuals with diabetes, no prior cancer diagnosis, no chronic kidney disease, and no prior diabetes therapy who initiated metformin (N=93353) or a sulfonylurea (N=13864). In our cohort, the estimated overlap weighted additive separable direct effect of metformin compared to sulfonylureas on cancer risk at 6 years was -1% (.95 CI=-2.2%, 0.1%), which is consistent with metformin providing no direct protection against cancer incidence or substantial protection. The analysis faced two methodological challenges-poor overlap, and pre-cancer death as a competing risk. To address these issues while minimizing nuisance model misspecification, we develop and apply double/debiased machine learning estimators of overlap weighted separable effects in addition to more traditional effect estimates.

Effectiveness of mRNA COVID-19 Vaccines as First Booster Doses in England: An Observational Study in OpenSAFELY-TPP.

The UK delivered its first "booster" COVID-19 vaccine doses in September 2021, initially to individuals at high risk of severe disease, then to all adults. The BNT162b2 Pfizer-BioNTech vaccine was used initially, then also Moderna mRNA-1273. With the approval of the National Health Service England, we used routine clinical data to estimate the effectiveness of boosting with BNT162b2 or mRNA-1273 compared with no boosting in eligible adults who had received two primary course vaccine doses. We matched each booster recipient with an unboosted control on factors relating to booster priority status and prior COVID-19 immunization. We adjusted for additional factors in Cox models, estimating hazard ratios up to 182 days (6 months) following booster dose. We estimated hazard ratios overall and within the following periods: 1-14, 15-42, 43-69, 70-97, 98-126, 127-152, and 155-182 days. Outcomes included a positive SARS-CoV-2 test, COVID-19 hospitalization, COVID-19 death, non-COVID-19 death, and fracture. We matched 8,198,643 booster recipients with unboosted controls. Adjusted hazard ratios over 6-month follow-up were: positive SARS-CoV-2 test 0.75 (0.74, 0.75); COVID-19 hospitalization 0.30 (0.29, 0.31); COVID-19 death 0.11 (0.10, 0.14); non-COVID-19 death 0.22 (0.21, 0.23); and fracture 0.77 (0.75, 0.78). Estimated effectiveness of booster vaccines against severe COVID-19-related outcomes peaked during the first 3 months following the booster dose. By 6 months, the cumulative incidence of positive SARS-CoV-2 test was higher in boosted than unboosted individuals. We estimate that COVID-19 booster vaccination, compared with no booster vaccination, provided substantial protection against COVID-19 hospitalization and COVID-19 death but only limited protection against positive SARS-CoV-2 test. Lower rates of fracture in boosted than unboosted individuals may suggest unmeasured confounding. Observational studies should report estimated vaccine effectiveness against nontarget and negative control outcomes.

Enzyme-glycosylated ovalbumin/chitosan oligosaccharide nanoparticles: Simulation of in vitro digestion for the targeted release of vitamin D3 and application for encapsulation in beverages

Vitamin D3 (VD3) was encapsulated in TGaseOVA–chitosan (COS) composite nanoparticles. Isothermal titration calorimetry was used to explain the hydrophobic interaction between TGaseOVA and VD3 at the molecular level. The 87.7 nm TGaseOVA–COS composite nanoparticles achieved an encapsulation efficiency of 96.34% and loading capacity of 4.68% for 9 μg/ml VD3. An in vitro digestion experiment revealed that TGaseOVA–COS–VD3 composite nanoparticles had good stability in simulated gastric fluid and only 32.67% of the composite nanoparticles were released in simulated intestinal fluid. Meanwhile, sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the composite nanoparticles had a release rate of 100% in simulated intestinal fluid. TGaseOVA–COS–VD3 composite nanoparticles had a VD3 concentration of 8.73 μg/ml after pasteurization, indicating that they provided substantial protection to VD3 during pasteurization. TGaseOVA–COS was subjected to a 1-month simulated shelf life test. High-performance liquid chromatography confirmed that it had a VD3 retention rate of 90%. The concentration-dependent toxicity of VD3 was detected by using Caco-2 cells. VD3 exhibited toxicity at the concentration of 11 μg/ml. Therefore, the embedding dose of 9 μg/ml used in this work was considered a safe dose. TGaseOVA–COS composite nanoparticles have excellent stability and good VD3 slow-release properties. They can be used in concentrated clear beverages and other food and beverage products. Therefore, they have potential for applications in the food and pharmaceutical industries.