A Dual-Adjuvanted Parenteral-Intranasal Subunit Nanovaccine generates Robust Systemic and Mucosal Immunity Against SARS-CoV-2 in Mice.

Existing parenteral SARS-CoV-2 vaccines produce only limited mucosal responses, essential for reducing transmission and achieving sterilizing immunity. Appropriately designed mucosal boosters can overcome the shortcomings of parenteral vaccines and enhance pre-existing systemic immunity. Here, a new protein subunit nanovaccine is developed by utilizing dual-adjuvanted (RIG-I: PUUC RNA and TLR-9: CpG DNA) polysaccharide-amino acid-lipid nanoparticles (PAL-NPs) along with SARS-CoV-2 S1 trimer protein, that can be delivered both intramuscularly (IM) and intranasally (IN) to generate balanced mucosal-systemic SARS-CoV-2 immunity. Mice receiving IM-Prime PUUC+CpG PAL subunit nanovaccine, followed by an IN-Boost, developed high levels of IgA, IgG, and cellular immunity in the lungs and showed robust systemic humoral immunity. Interestingly, as a purely intranasal subunit vaccine (IN-Prime/IN-Boost), PUUC+CpG PAL-NPs induced stronger lung-specific T cell immunity than IM-Prime/IN-Boost, and a comparable IgA and neutralizing antibodies, although with a lower systemic antibody response, indicating that a fully mucosal delivery route for SARS-CoV-2 vaccination may also be feasible. The data suggest that PUUC+CpG PAL subunit nanovaccine is a promising candidate for generating SARS-CoV-2 specific mucosal immunity.

Safety and efficacy of toll-like receptor agonists as therapeutic agents and vaccine adjuvants for infectious diseases in animals: a systematic review.

Introduction: Strengthening global health security relies on adequate protection against infectious diseases through vaccination and treatment. Toll-like receptor (TLR) agonists exhibit properties that can enhance immune responses, making them potential therapeutic agents or vaccine adjuvants. Methods: We conducted an extensive systematic review to assess the efficacy of TLR agonists as therapeutic agents or vaccine adjuvants for infectious diseases and their safety profile in animals, excluding rodents and cold-blooded animals. We collected qualitative and available quantitative data on the efficacy and safety outcomes of TLR agonists and employed descriptive analysis to summarize the outcomes. Results: Among 653 screened studies, 51 met the inclusion criteria. In this review, 82% (42/51) of the studies used TLR agonists as adjuvants, while 18% (9/51) applied TLR agonist as therapeutic agents. The predominant TLR agonists utilized in animals against infectious diseases was CpG ODN, acting as a TLR9 agonist in mammals, and TLR21 agonists in chickens. In 90% (46/51) of the studies, TLR agonists were found effective in stimulating specific and robust humoral and cellular immune responses, thereby enhancing the efficacy of vaccines or therapeutics against infectious diseases in animals. Safety outcomes were assessed in 8% (4/51) of the studies, with one reporting adverse effects. Discussion: Although TLR agonists are efficacious in enhancing immune responses and the protective efficacy of vaccines or therapeutic agents against infectious diseases in animals, a thorough evaluation of their safety is imperative to in-form future clinical applications in animal studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=323122.

Efficacy of nonopioid analgesics and adjuvants in multimodal analgesia for reducing postoperative opioid consumption and complications in obesity: a systematic review and network meta-analysis.

BACKGROUND: Managing postoperative pain in patients with obesity is challenging. Although multimodal analgesia has proved effective for pain relief, the specific impacts of different nonopioid i.v. analgesics and adjuvants on these patients are not well-defined. This study aims to assess the effectiveness of nonsteroidal antiinflammatory drugs, paracetamol, ketamine, α-2 adrenergic receptor agonists, lidocaine, magnesium, and oral gabapentinoids in reducing perioperative opioid consumption and, secondarily, in mitigating the occurrence of general and postoperative pulmonary complications (POPCs), nausea, vomiting, PACU length of stay (LOS), and hospital LOS among surgical patients with obesity. METHODS: A systematic review and network meta-analysis was performed. PubMed, Scopus, Web of Science, CINAHL, and EMBASE were searched. Only English-language RCTs investigating the use of nonopioid analgesics and adjuvants in adult surgical patients with obesity were included. The quality of evidence and certainty were assessed using the RoB 2 tool and GRADE framework, respectively. RESULTS: In total, 37 RCTs involving 3602 patients were included in the quantitative analysis. Compared with placebo/no intervention or a comparator, dexmedetomidine, ketamine, lidocaine, magnesium, and gabapentin significantly reduced postoperative opioid consumption after surgery. Ketamine/esketamine also significantly reduced POPCs. Ibuprofen, dexmedetomidine, and lidocaine significantly reduced postoperative nausea, whereas dexmedetomidine, either alone or combined with pregabalin, and lidocaine reduced postoperative vomiting. Dexmedetomidine significantly reduced PACU LOS, whereas both paracetamol and lidocaine reduced hospital LOS. CONCLUSIONS: Intravenous nonopioid analgesics and adjuvants are crucial in multimodal anaesthesia, reducing opioid consumption and enhancing postoperative care in adult surgical patients with obesity. SYSTEMATIC REVIEW PROTOCOL: CRD42023399373 (PROSPERO).

Adjuvant Use of the Invariant-Natural-Killer-T-Cell Agonist α-Galactosylceramide Leads to Vaccine-Associated Enhanced Respiratory Disease in Influenza-Vaccinated Pigs.

Invariant natural killer T (iNKT) cells are glycolipid-reactive T cells with potent immunoregulatory properties. iNKT cells activated with the marine-sponge-derived glycolipid, α-galactosylceramide (αGC), provide a universal source of T-cell help that has shown considerable promise for a wide array of therapeutic applications. This includes harnessing iNKT-cell-mediated immune responses to adjuvant whole inactivated influenza virus (WIV) vaccines. An important concern with WIV vaccines is that under certain circumstances, they are capable of triggering vaccine-associated enhanced respiratory disease (VAERD). This immunopathological phenomenon can arise after immunization with an oil-in-water (OIW) adjuvanted WIV vaccine, followed by infection with a hemagglutinin and neuraminidase mismatched challenge virus. This elicits antibodies (Abs) that bind immunodominant epitopes in the HA2 region of the heterologous virus, which purportedly causes enhanced virus fusion activity to the host cell and increased infection. Here, we show that αGC can induce severe VAERD in pigs. However, instead of stimulating high concentrations of HA2 Abs, αGC elicits high concentrations of interferon (IFN)-γ-secreting cells both in the lungs and systemically. Additionally, we found that VAERD mediated by iNKT cells results in distinct cytokine profiles and altered adaptation of the challenge virus following infection compared to an OIW adjuvant. Overall, these results provide a cautionary note about considering the formulation of WIV vaccines with iNKT-cell agonists as a potential strategy to modulate antigen-specific immunity.

Characterization of the Immune-Modulating Properties of Different ß-Glucans on Myeloid Dendritic Cells.

In allergen-specific immunotherapy, adjuvants are explored for modulating allergen-specific Th2 immune responses to re-establish clinical tolerance. One promising class of adjuvants are ß-glucans, which are naturally derived sugar structures and components of dietary fibers that activate C-type lectin (CLR)-, "Toll"-like receptors (TLRs), and complement receptors (CRs). We characterized the immune-modulating properties of six commercially available ß-glucans, using immunological (receptor activation, cytokine secretion, and T cell modulating potential) as well as metabolic parameters (metabolic state) in mouse bone marrow-derived myeloid dendritic cells (mDCs). All tested ß-glucans activated the CLR Dectin-1a, whereas TLR2 was predominantly activated by Zymosan. Further, the tested ß-glucans differentially induced mDC-derived cytokine secretion and activation of mDC metabolism. Subsequent analyses focusing on Zymosan, Zymosan depleted, ß-1,3 glucan, and ß-1,3 1,6 glucan revealed robust mDC activation with the upregulation of the cluster of differentiation 40 (CD40), CD80, CD86, and MHCII to different extents. ß-glucan-induced cytokine secretion was shown to be, in part, dependent on the activation of the intracellular Dectin-1 adapter molecule Syk. In co-cultures of mDCs with Th2-biased CD4+ T cells isolated from birch allergen Bet v 1 plus aluminum hydroxide (Alum)-sensitized mice, these four ß-glucans suppressed allergen-induced IL-5 secretion, while only Zymosan and ß-1,3 glucan significantly suppressed allergen-induced interferon gamma (IFNγ) secretion, suggesting the tested ß-glucans to have distinct effects on mDC T cell priming capacity. Our experiments indicate that ß-glucans have distinct immune-modulating properties, making them interesting adjuvants for future allergy treatment.

Interim safety and immunogenicity analysis of the EuCorVac-19 COVID-19 vaccine in a Phase 3 randomized, observer-blind, immunobridging trial in the Philippines.

EuCorVac-19 (ECV-19) is a recombinant receptor binding domain (RBD) COVID-19 vaccine that displays the RBD (derived from the SARS-CoV-2 Wuhan strain) on immunogenic liposomes. This study compares the safety and immunogenicity of ECV-19 to the COVISHIELDTM (CS) adenoviral-vectored vaccine. Interim analysis is presented of a randomized, observer-blind, immunobridging Phase 3 trial in the Philippines in 2600 subjects, with treatment and biospecimen collection between October 2022 and January 2023. Healthy male and female adults who received investigational vaccines were 18 years and older, and randomly assigned to ECV-19 (n = 2004) or CS (n = 596) groups. Immunization followed a two-injection, intramuscular regimen with 4 weeks between prime and boost vaccination. Safety endpoints were assessed in all participants and immunogenicity analysis was carried out in a subset (n = 585 in ECV-19 and n = 290 in CS groups). The primary immunological endpoints were superiority of neutralizing antibody response, as well as noninferiority in seroresponse rate (defined as a 4-fold increase in RBD antibody titers from baseline). After prime vaccination, ECV-19 had a lower incidence of local solicited adverse events (AEs) (12.0% vs. 15.8%, p < 0.01), and solicited systemic AEs (13.1 vs. 17.4%, p < 0.01) relative to CS. After the second injection, both ECV-19 and CS had lower overall solicited AEs (7.8% vs. 7.6%). For immunological assessment, 98% of participants had prior COVID-19 exposure (based on the presence of anti-nucleocapsid antibodies) at the time of the initial immunization, without differing baseline antibody levels or microneutralization (MN) titers against the Wuhan strain in the two groups. After prime vaccination, ECV-19 induced higher anti-RBD IgG relative to CS (1,464 vs. 355 BAU/mL, p < 0.001) and higher neutralizing antibody response (1,303 vs. 494 MN titer, p < 0.001). After boost vaccination, ECV-19 and CS maintained those levels of anti-RBD IgG (1367 vs. 344 BAU/mL, p < 0.001) and neutralizing antibodies (1128 vs. 469 MN titer, p < 0.001). ECV-19 also elicited antibodies that better neutralized the Omicron variant, compared to CS (763 vs. 373 MN titer, p < 0.001). Women displayed higher responses to both vaccines than men. The ECV-19 group had a greater seroresponse rate compared to CS (83% vs. 30%, p < 0.001). In summary, both ECV-19 and CS had favorable safety profiles, with ECV-19 showing diminished local and systemic solicited AE after prime immunization. ECV-19 had significantly greater immunogenicity in terms of anti-RBD IgG, neutralizing antibodies, and seroresponse rate. These data establish a relatively favorable safety and immunogenicity profile for ECV-19. The trial is registered on ClinicalTrials.gov (NCT05572879).

The adjuvant BcfA activates antigen presenting cells through TLR4 and supports TFH and TH1 while attenuating TH2 gene programming.

Introduction: Adjuvants added to subunit vaccines augment antigen-specific immune responses. One mechanism of adjuvant action is activation of pattern recognition receptors (PRRs) on innate immune cells. Bordetella colonization factor A (BcfA); an outer membrane protein with adjuvant function, activates TH1/TH17-polarized immune responses to protein antigens from Bordetella pertussis and SARS CoV-2. Unlike other adjuvants, BcfA does not elicit a TH2 response. Methods: To understand the mechanism of BcfA-driven TH1/TH17 vs. TH2 activation, we screened PRRs to identify pathways activated by BcfA. We then tested the role of this receptor in the BcfA-mediated activation of bone marrow-derived dendritic cells (BMDCs) using mice with germline deletion of TLR4 to quantify upregulation of costimulatory molecule expression and cytokine production in vitro and in vivo. Activity was also tested on human PBMCs. Results: PRR screening showed that BcfA activates antigen presenting cells through murine TLR4. BcfA-treated WT BMDCs upregulated expression of the costimulatory molecules CD40, CD80, and CD86 and produced IL-6, IL-12/23 p40, and TNF-α while TLR4 KO BMDCs were not activated. Furthermore, human PBMCs stimulated with BcfA produced IL-6. BcfA-stimulated murine BMDCs also exhibited increased uptake of the antigen DQ-OVA, supporting a role for BcfA in improving antigen presentation to T cells. BcfA further activated APCs in murine lungs. Using an in vitro TH cell polarization system, we found that BcfA-stimulated BMDC supernatant supported TFH and TH1 while suppressing TH2 gene programming. Conclusions: Overall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses.

Anti-cancer agent 5-fluorouracil reverses meropenem resistance in carbapenem-resistant Gram-negative pathogens.

The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens demands urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. Herein, we identified the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimal inhibitory concentration of meropenem against blaNDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited the potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-ß-lactamases (MBLs), such as NDM and IMP, or serine ß-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., with 32 of them obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcriptional and expressional level of the blaNDM-5 gene. Additionally, the 5-FU combined with meropenem can enhance bacterial metabolism, and stimulate the production of Reactive Oxygen Species (ROS), thereby rendering bacteria more susceptible to meropenem. This drug combination could effectively elevate the survival rate from 16.7% to 83.3% compared to meropenem monotherapy, and reduce bacteria loads in tissues in a mouse systemic infection model. Collectively, these findings reveal that the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against carbapenem-resistant bacteria infections.

Vaccines and allergy: Back to the right places.

Hypersensitivity reactions represent one of the most common causes of hesitancy for adherence to national vaccination programs. The majority of hypersensitivity reactions after vaccination are mild, and anaphylaxis is reported to be rare, although it remains challenging to estimate the frequency attributed to each single vaccine, either because of the lower number of administered doses of less common vaccines, or the administration of simultaneous vaccine in most of the vaccination programs. Although literature remains scattered, international consensus guides clinicians in identifying patients who might need the administration of vaccines in protected environments due to demonstrated hypersensitivity to vaccine components or adjuvants. Here we provide the current guidance on hypersensitivity reactions to vaccines and on vaccination of children with allergy disorders.

Protection against influenza hospitalizations from enhanced influenza vaccines among older adults: A systematic review and network meta-analysis.

BACKGROUND: Influenza vaccines are available to help protect persons aged ≥65 years, who experience thousands of influenza hospitalizations annually. Because some influenza vaccines may work better than others, we sought to assess benefit of high-dose (HD), adjuvanted (ADJ), and recombinant (RIV) influenza vaccines ("enhanced influenza vaccines") compared with standard-dose unadjuvanted influenza vaccines (SD) and with one another for prevention of influenza-associated hospitalizations among persons aged ≥65 years. METHODS: We searched MEDLINE, Embase, CINAHL, Scopus, and Cochrane Library to identify randomized or observational studies published between January 1990 and October 2023 and reporting relative vaccine effectiveness (rVE) of HD, ADJ, or RIV for prevention of influenza-associated hospitalizations among adults aged ≥65 years. We extracted study data, assessed risk of bias, and conducted random-effects network meta-analysis and meta-regression. RESULTS: We identified 32 studies with 90 rVE estimates from five randomized and 27 observational studies (71,459,918 vaccinated participants). rVE estimates varied across studies and influenza seasons. Pooled rVE from randomized studies was 20% (95% CI -54 to 59) and 25% (95% CI -19 to 53) for ADJ and HD compared with SD, respectively; rVE was 6% (95% CI -109 to 58) for HD compared with ADJ; these differences were not statistically significant. In observational studies, ADJ, HD, and RIV conferred modestly increased protection compared with SD (rVE ranging from 10% to 19%), with no significant differences between HD, ADJ, and RIV. With enhanced vaccines combined, rVE versus SD was 18% (95% CI 3 to 32) from randomized and 11% (95% CI 8 to 14) from observational evidence. Meta-regression of observational studies suggested that those requiring laboratory confirmation of influenza reported greater benefit of enhanced vaccines. CONCLUSIONS: HD, ADJ, and RIV provided stronger protection than SD against influenza hospitalizations among older adults. No differences in benefit were observed in comparisons of enhanced influenza vaccines with one another.

Investigation on the Synergy between Membrane Permeabilizing Amphiphilic α-Hydrazido Acids and Commonly Used Antibiotics against Drug-Resistant Bacteria.

The growth of (multi)drug resistance in bacteria is among the most urgent global health issues. Monocationic amphiphilic α-hydrazido acid derivatives are structurally simple mimics of antimicrobial peptides (AMPs) with fewer drawbacks. Their mechanism of membrane permeabilization at subtoxic concentrations was found to begin with an initial electrostatic attraction of isolated amphiphile molecules to the phospholipid heads, followed by a rapid insertion of the apolar portions. As the accumulation into the bilayer proceeded, the membrane increased its fluidity and permeability without being subjected to major structural damage. After having ascertained that α-hydrazido acid amphiphiles do not interact with bacterial DNA, they were subjected to synergy evaluation for combinations with conventional antibiotics. Synergy was observed for combinations with tetracycline against sensitive S. aureus and E. coli, as well as with ciprofloxacin and colistin against resistant strains. Additivity with a remarkable recovery in activity of conventional antibiotics (from 2-fold to ≥32-fold) together with largely subtoxic concentrations of α-hydrazido acid derivatives was found for combinations with ciprofloxacin toward susceptible S. aureus and methicillin toward MRSa. However, no potentiation of conventional antibiotics was observed for combinations with linezolid and gentamicin against the corresponding resistant S. aureus and E. coli strains.

Complement C5a Receptor Signaling in Macrophages Enhances Trained Immunity Through mTOR Pathway Activation.

Complement C5a receptor (C5aR) signaling in immune cells has various functions, inducing inflammatory or anti-inflammatory responses based on the type of ligand present. The Co1 peptide (SFHQLPARSRPLP) has been reported to activate C5aR signaling in dendritic cells. We investigated the effect of C5aR signaling via the Co1 peptide on macrophages. In peritoneal macrophages, the interaction between C5aR and the Co1 peptide activated the mTOR pathway, resulting in the production of pro-inflammatory cytokines. Considering the close associations of mTOR signaling with IL-6 and TNF-α in macrophage training, our findings indicate that the Co1 peptide amplifies ß-glucan-induced trained immunity. Overall, this research highlights a previously underappreciated aspect of C5aR signaling in trained immunity, and posits that the Co1 peptide is a potentially effective immunomodulator for enhancing trained immunity.

Role of Dexmedetomidine and Clonidine With Hyperbaric Ropivacaine in Subarachnoid Block: A Comprehensive Review.

Subarachnoid block (SAB), a fundamental technique in regional anesthesia, offers efficient anesthesia for various surgical procedures with advantages including rapid onset, reliable anesthesia, and reduced systemic effects compared to general anesthesia. Hyperbaric ropivacaine, a long-acting local anesthetic, has gained popularity due to its favorable pharmacokinetic profile and safety profile. However, to extend the duration and enhance the quality of anesthesia provided by hyperbaric ropivacaine, adjuvants such as dexmedetomidine and clonidine are frequently employed. This comprehensive review explores the roles of dexmedetomidine and clonidine as adjuvants to hyperbaric ropivacaine in SAB. It examines their pharmacological mechanisms, clinical efficacy, safety profiles, and comparative effectiveness in prolonging analgesia and enhancing anesthesia. The review synthesizes evidence from clinical studies to delineate the synergistic effects of these adjuvants, their impact on patient outcomes, and their potential advantages over traditional anesthesia techniques. Through a detailed analysis of current literature and clinical practices, this review aims to provide insights into optimizing the use of dexmedetomidine and clonidine in SAB protocols. It discusses clinical implications, offers recommendations for practice, and identifies future research directions to further enhance the efficacy and safety of SAB using these adjuvants.

2D Differential Metallic Immunopotentiators Drive High Diversity and Capability of Antigen-specific Immunity Against Tumor.

The therapeutic efficacy of vaccines for treating cancers in clinics remains limited. Here, a rationally designed cancer vaccine by placing immunogenically differential and clinically approved aluminum (Al) or manganese (Mn) in a 2D nanosheet (NS) architecture together with antigens is reported. Structurally optimal NS with a high molar ratio of Mn to Al (MANS-H) features distinctive immune modulation, markedly promoting the influx of heterogeneous innate immune cells at the injection site. Stimulation of multiple subsets of dendritic cells (DCs) significantly increases the levels, subtypes, and functionalities of antigen-specific T cells. MANS-H demonstrates even greater effectiveness in the production of antigen-specific antibodies than the commercial adjuvant (Alhydrogel) by priming T helper (Th)2 cells rather than T follicular helper (Tfh) cells. Beyond humoral immunity, MANS-H evokes high frequencies of antigen-specific Th1 and CD8+ cell immunity, which are comparable with Quil-A that is widely used in veterinary vaccines. Immunized mice with MANS-H adjuvanted vaccines exert strong potency in tumor regression by promoting effector T cells infiltrating at tumor and overcoming tumor resistance in multiple highly aggressive tumor models. The engineered immunogen with an intriguing NS architecture and safe immunopotentiators offers the next clinical advance in cancer immunotherapy.

Advancements and Challenges in Peptide-Based Cancer Vaccination: A Multidisciplinary Perspective.

With the continuous advancements in tumor immunotherapy, researchers are actively exploring new treatment methods. Peptide therapeutic cancer vaccines have garnered significant attention for their potential in improving patient outcomes. Despite its potential, only a single peptide-based cancer vaccine has been approved by the U.S. Food and Drug Administration (FDA). A comprehensive understanding of the underlying mechanisms and current development status is crucial for advancing these vaccines. This review provides an in-depth analysis of the production principles and therapeutic mechanisms of peptide-based cancer vaccines, highlights the commonly used peptide-based cancer vaccines, and examines the synergistic effects of combining these vaccines with immunotherapy, targeted therapy, radiotherapy, and chemotherapy. While some studies have yielded suboptimal results, the potential of combination therapies remains substantial. Additionally, we addressed the management and adverse events associated with peptide-based cancer vaccines, noting their relatively higher safety profile compared to traditional radiotherapy and chemotherapy. Lastly, we also discussed the roles of adjuvants and targeted delivery systems in enhancing vaccine efficacy. In conclusion, this review comprehensively outlines the current landscape of peptide-based cancer vaccination and underscores its potential as a pivotal immunotherapy approach.

Advancement in the Antigenic Epitopes and Vaccine Adjuvants of African Swine Fever Virus.

African swine fever virus (ASFV), a highly virulent double-stranded DNA virus, poses a significant threat to global pig farming, with mortality rates in domestic pigs reaching up to 100%. Originating in Kenya in 1921, ASFV has since proliferated to Western Europe, Latin America, Eastern Europe, and most recently China in 2018, resulting in substantial global agricultural losses. Antigenic epitopes, recognized by the immune system's T cells and B cells, are pivotal in antiviral immune responses. The identification and characterization of these antigenic epitopes can offer invaluable insights into the immune response against ASFV and aid in the development of innovative immunotherapeutic strategies. Vaccine adjuvants, substances that amplify the body's specific immune response to antigens, also play a crucial role. This review provides an overview of the progress in studying T/B-cell epitopes in ASFV proteins and ASFV vaccine adjuvants, highlighting their role in the immune response and potential use in new vaccine development.

Addition of Dexmedetomidine to Propofol Anesthesia for Middle-Ear Surgeries: A Prospective Randomized Double-Blind Study.

Background Middle-ear surgery commonly performed under a microscope requires a bloodless field provided by hypotensive anesthesia. Our objective was to study the effects of dexmedetomidine on propofol consumption and intraoperative hemodynamic stability. Methods One hundred adults undergoing elective middle-ear surgery were randomized into two groups. The propofol+dexmedetomidine group (Group PD) received a loading dose of dexmedetomidine 1µg/kg in 10ml normal saline over 10min followed by infusion of the same at 0.5µg/kg/h. Propofol-only group (Group P) received 10ml normal saline over 10min followed by an infusion of the same. General anesthesia was induced with intravenous morphine, propofol, and vecuronium, and maintained with propofol, oxygen, and N2O. During microscope use, we aimed to maintain mean arterial pressure (MAP) within 60-69mmHg. Results There was no significant difference in the mean (SD) consumption of propofol [Group P 8.6 (2.1)mg/kg/h vs Group PD 8.1 (1.5)mg/kg/h, P=0.172]. The induction dose of propofol was significantly less in Group PD [1.8 (0.3) vs 2 (0.4)mg/kg, P<0.001]. Except for the baseline value, the heart rate was significantly lower in Group PD, P<0.001. The time duration during which MAP was within 60-69mmHg was higher in Group P [37.5 (36.8) vs 30.9 (38.3)min] though the difference was not statistically significant. The recovery was delayed in Group PD [25.4 (8.6) vs 17.6 (4.9)min, P<0.001]. Group PD had a significantly better operative field, P=0.0003. Conclusion The addition of dexmedetomidine did not reduce propofol consumption but reduced the induction dose of propofol. Propofol and dexmedetomidine combination provided comparable mean arterial pressure and better operative field but caused delayed recovery.

Extraction and immunomodulatory effects of acid Lagenaria siceraria (Molina) Standl. Polysaccharide on chickens.

Herbal polysaccharides are extensively studied as vaccine adjuvants due to their safety and potent immunoenhancing activity. This study aimed to analyze the structure of Lagenaria siceraria (Molina) Standl polysaccharide (LSP50) and investigate its adjuvant activity for the H9N2 vaccine in broiler chickens. Structural analysis revealed that LSP50 primarily consisted of rhamnose, arabinose, xylose, mannose, glucose, and galactose with molar ratios of 23.12: 12.28: 10.87: 8.26: 2.64: 22.82 respectively. The adjuvant activity of LSP50 was evaluated, which showing significant enhancements compared to the H9N2 group. Parameters including the immune organ index, H9N2 specific IgG level, cytokines contents (IFN-γ, IL-2, IL-4, and IL-5), and the proportion of CD3e+CD8aT+cells were significantly increased in the LSP50 group (P < 0.05). Additionally, sequencing results showed that LSP50 modulates the immune response by regulating PLA2G12B and PTGDS genes involved in the arachidonic acid pathway. These findings were further validated through qPCR analysis to affirm the reliability of the sequencing data. In conclusion, our results demonstrate that LSP50 exhibits potent adjuvant activity, enhancing both cellular and humoral immunity.

Immune thrombocytopenia (ITP) - could it be part of autoimmune/inflammatory syndrome induced by adjuvants (ASIA)?

Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by thrombocytopenia and an increased bleeding risk, arising from autoantibody-mediated platelet destruction and impaired megakaryocyte function. The pathogenesis of ITP involves a multifaceted interplay of genetic predispositions, immune dysregulation, and environmental triggers, though the precise mechanisms remain uncertain. Several infectious agents, mostly viruses, have been implicated in both acute and chronic ITP through mechanisms such as molecular mimicry, direct bone marrow suppression, and immune dysregulation. Vaccinations, particularly those containing adjuvants like aluminum and those capable of inducing molecular mimicry, have also been associated with ITP, either as a new onset or as a relapse in preexisting cases. The role of drugs, particularly quinine, quinidine and certain antibiotics, in inducing ITP through various immunological pathways further illustrates the diverse etiologies of this condition. The multiple triggers of the disease raise the question of whether ITP may be classified as an autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This condition encompasses a range of autoimmune and inflammatory symptoms triggered by adjuvants, such as silicones, polypropylene meshes, metal implants, and mineral oils present in various medical materials and medications. Similar to that observed in some cases of ITP, adjuvants can trigger autoimmune or autoinflammatory responses via molecular mimicry, epitope spreading, and polyclonal activation. This narrative review explores the underlying environmental factors related to ITP and examines ITP triggers that could potentially support an association between ITP and ASIA syndrome.