Mechanistic consideration of the effect of perioperative volatile anesthetics on phagocytes.

A growing literature has shown that volatile anesthetics are promiscuous molecules targeting multiple molecules, some of which are critical for immunological functions. We focused on studies that delineated target molecules of volatile anesthetics on immune cells and summarized the effects of volatile anesthetics on immune functions. We also presented the perspectives of studying volatile anesthetics-mediated immunomodulation.

Anesthetics isoflurane and sevoflurane attenuate flagellin-mediated inflammation in the lung.

Isoflurane and sevoflurane are volatile anesthetics (VA) widely used in clinical practice to provide general anesthesia. We and others have previously shown that VAs have immunomodulatory effects and may have a significant impact on the progression of disease states. Flagellin is a component of Gram negative bacteria and plays a significant role in the pathophysiology of bacterial pneumonia through its binding to Toll-like Receptor 5 (TLR5). Our results showed that VAs, not an intravenous anesthetic, significantly attenuated the activation of TLR5 and the release of the neutrophil chemoattractant IL-8 from lung epithelial cells. Furthermore, flagellin-induced lung injury was significantly attenuated by VAs by inhibiting neutrophil migration to the bronchoalveolar space. The lungs of cystic fibrosis (CF) patients are highly colonized by Pseudomonas aeruginosa, which causes inflammation. The retrospective study of oxygenation in patients with CF who had received VA versus intravenous anesthesia suggested that VAs might have the protective effect for gas exchange. To understand the interaction between VAs and TLR5, a docking simulation was performed, which indicated that isoflurane and sevoflurane docked into the binding interphase between TLR5 and flagellin.

The effect of anesthetics on toll like receptor 9.

Toll like receptors (TLRs) are critical receptors to respond to danger signals, and their functions are relevant in the perioperative period. We previously reported that volatile anesthetics directly bound to TLR2 and TLR4 and attenuated their functions. Given that TLR9 can respond to mitochondrial DNA, a danger signal that is released upon tissue injury, we examined the role of anesthetics on TLR9 function. Our reporter assay showed that volatile anesthetics isoflurane and sevoflurane increased the activation of TLR9, while propofol attenuated it. TLR9 activation occurs via its dimerization. The dimerization is facilitated by unmethylated cytosine-phosphate-guanine (CpG) DNA as well as DNA containing cytosine at the second position from 5'-end (5'-xCx DNA). Our structural analysis using photoactivable anesthetics and rigid docking simulation showed that isoflurane and sevoflurane bound to both TLR9 dimer interface and 5'-xCx DNA binding site. Propofol bound to the TLR9 antagonist binding site. This is the first illustration that anesthetics can affect the binding of nucleic acids to their receptor. This study sets the foundation for the effect of anesthetics on TLR9 and will pave the way for future studies to determine the significance of such interactions in the clinical setting.

The Role of Anesthetic Management in Surgical Site Infections After Pediatric Intestinal Surgery.

BACKGROUND: Although surgical site infections (SSIs) remain a significant health care issue, a limited number of studies have analyzed risk factors for SSIs in children, particularly the role of intraoperative anesthetic management. Pediatric patients are less likely to have major adult risk factors for SSIs such as smoking and diabetes. Thus children may be more suitable as a cohort for examining the role of intraoperative anesthetics in SSIs. AIM: We examined an association between SSI incidence and anesthetic management in children who underwent elective intestinal surgery in a single institution. METHODS: We performed a retrospective study of 621 patients who underwent elective intestinal surgery under general anesthesia between January 2017 and September 2019, with primary outcome as the incidence of SSIs. We compared patients who were dichotomized in accordance with the median of the sevoflurane dose. We used propensity score (PS) pairwise matching of these patients to avoid selection biases. PS matching yielded 204 pairs of patients. RESULTS: We found that higher doses of sevoflurane were associated with a higher incidence of SSIs (9.8% versus 3.9%, P = 0.019). We adjusted for intraoperative factors that were not included in the PS adjustment factors, and multivariate regression analysis after PS matching showed compatible results (odds ratio: 2.58, 95% confidence interval: 1.11-6.04, P = 0.028). CONCLUSIONS: Higher doses of sevoflurane are associated with increased odds of SSIs after pediatric elective intestinal surgery. A randomized controlled study of volatile anesthetic-based versus intravenous anesthetic-based anesthesia will be needed to further determine the role of anesthetic drugs in SSI risk.

Risk factors for pediatric surgical site infection following neurosurgical procedures for hydrocephalus: a retrospective single-center cohort study.

BACKGROUND: Infection is a major complication following cerebral spinal fluid (CSF) diversion procedures for hydrocephalus. However, pediatric risk factors for surgical site infection (SSI) are currently not well defined. Because a SSI prevention bundle is increasingly introduced, the purpose of this study was to evaluate risk factors associated with SSIs following CSF diversion surgeries following a SSI bundle at a single quaternary care pediatric hospital. METHODS: We performed a retrospective cohort study of patients undergoing CSF diversion procedures from 2017 to 2019. SSIs were identified prospectively through continuous surveillance. We performed unadjusted logistic regression analyses and univariate analyses to determine an association between SSIs and patient demographics, comorbidities and perioperative factors to identify independent risk factors for SSI. RESULTS: We identified a total of 558 CSF diversion procedures with an overall SSI rate of 3.4%. The SSI rates for shunt, external ventricular drain (EVD) placement, and endoscopic third ventriculostomy (ETV) were 4.3, 6.9 and 0%, respectively. Among 323 shunt operations, receipt of clindamycin as perioperative prophylaxis and presence of cardiac disease were significantly associated with SSI (O.R. 4.99, 95% C.I. 1.27-19.70, p = 0.02 for the former, and O.R. 7.19, 95% C.I. 1.35-38.35, p = 0.02 for the latter). No risk factors for SSI were identified among 72 EVD procedures. CONCLUSION: We identified receipt of clindamycin as perioperative prophylaxis and the presence of cardiac disease as risk factors for SSI in shunt procedures. Cefazolin is recommended as a standard antibiotic for perioperative prophylaxis. Knowing that unsubstantiated beta-lactam allergy label is a significant medical problem, efforts should be made to clarify beta-lactam allergy status to maximize the number of patients who can receive cefazolin for prophylaxis before shunt placement. Further research is needed to elucidate the mechanism by which cardiac disease may increase SSI risk after shunt procedures.

CD11c regulates neutrophil maturation.

Sepsis continues to be associated with high morbidity and mortality. Currently, sepsis is managed only conservatively. In sepsis, a substantial number of neutrophils is required, leading to accelerated neutrophil production. Immature neutrophils are released into the circulation to meet a demand, despite their less effective functioning in microbial eradication. Although an intervention to provide more mature neutrophils may serve as a potential sepsis treatment, the mechanism of neutrophil differentiation and maturation remains poorly understood. We discovered that CD11c, traditionally known as a dendritic cell marker, was expressed in neutrophils and regulated neutrophil maturation and effector functions. In the absence of CD11c, neutrophil maturation was impaired in the bone marrow, concomitant with a significant increase in the proliferation and apoptosis of preneutrophils, associated with less effector functions. Under lipopolysaccharide challenge, inducing an emergent neutrophil production in the bone marrow, CD11c deficiency exaggerated the release of immature neutrophils into the circulation, associated with a significant proliferation and apoptosis of preneutrophils. In contrast, constitutively active CD11c knock-in mice showed accelerated neutrophil maturation associated with enhanced effector functions, which further supports the notion that CD11c regulates neutrophil maturation. Furthermore, the constitutively active CD11c knock-in mice offered enhanced bacterial eradication. Taken together, we discovered that CD11c was critical for the regulation of neutrophil maturation, and CD11c activation could serve as a potential target for sepsis treatment.

Protection of the third-dose and fourth-dose mRNA vaccines against SARS-CoV-2 Omicron subvariant: a systematic review and meta-analysis.

OBJECTIVES: The rapid spread of the SARS-CoV-2 Omicron variant has raised concerns regarding waning vaccine-induced immunity and durability. We evaluated protection of the third-dose and fourth-dose mRNA vaccines against SARS-CoV-2 Omicron subvariant and its sublineages. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases and other resources (PubMed, Embase, CENTRAL, MEDLINE, CINAHL PLUS, APA PsycINFO, Web of Science, Scopus, ScienceDirect, MedRxiv and bioRxiv) were searched until December 2022. STUDY ELIGIBILITY CRITERIA: We included studies that assessed the effectiveness of mRNA vaccine booster doses against SARS-CoV-2 infection and severe COVID-19 outcomes caused by the subvariant. DATA EXTRACTION AND SYNTHESIS: Estimates of vaccine effectiveness (VE) at different time points after the third-dose and fourth-dose vaccination were extracted. Random-effects meta-analysis was used to compare VE of the third dose versus the primary series, no vaccination and the fourth dose at different time points. The certainty of the evidence was assessed by Grading of Recommendations, Assessments, Development and Evaluation approach. RESULTS: This review included 50 studies. The third-dose VE, compared with the primary series, against SARS-CoV-2 infection was 48.86% (95% CI 44.90% to 52.82%, low certainty) at ≥14 days, and gradually decreased to 38.01% (95% CI 13.90% to 62.13%, very low certainty) at ≥90 days after the third-dose vaccination. The fourth-dose VE peaked at 14-30 days (56.70% (95% CI 50.36% to 63.04%), moderate certainty), then quickly declined at 61-90 days (22% (95% CI 6.40% to 37.60%), low certainty). Compared with no vaccination, the third-dose VE was 75.84% (95% CI 40.56% to 111.12%, low certainty) against BA.1 infection, and 70.41% (95% CI 49.94% to 90.88%, low certainty) against BA.2 infection at ≥7 days after the third-dose vaccination. The third-dose VE against hospitalisation remained stable over time and maintained 79.30% (95% CI 58.65% to 99.94%, moderate certainty) at 91-120 days. The fourth-dose VE up to 60 days was 67.54% (95% CI 59.76% to 75.33%, moderate certainty) for hospitalisation and 77.88% (95% CI 72.55% to 83.21%, moderate certainty) for death. CONCLUSION: The boosters provided substantial protection against severe COVID-19 outcomes for at least 6 months, although the duration of protection remains uncertain, suggesting the need for a booster dose within 6 months of the third-dose or fourth-dose vaccination. However, the certainty of evidence in our VE estimates varied from very low to moderate, indicating significant heterogeneity among studies that should be considered when interpreting the findings for public health policies. PROSPERO REGISTRATION NUMBER: CRD42023376698.

αDß2 as a novel target of experimental polymicrobial sepsis.

Since sepsis was defined three decades ago, it has been a target of intensive study. However, there is no specific sepsis treatment available, with its high mortality and morbidity. αDß2 (CD11d/CD18) is one of the four ß2 integrin members. Its role in sepsis has been limitedly studied. Using an experimental polymicrobial sepsis model, we found that the deficiency of αDß2 was associated with less lung injury and better outcome, which was in sharp contrast to other ß2 integrin member αLß2 (CD11a/CD18), and αMß2 (CD11b/CD18). This phenotype was supported by a reduction of bacterial loads in αDß2 knockout mice. Further analysis showed that the deficiency of αDß2 led to a reduction of neutrophil cell death as well as an increase in neutrophil phagocytosis in both murine and human systems. Our data showed a unique role of αDß2 among the ß2 integrin members, which would serve as a potential target to improve the outcome of sepsis.

GltS regulates biofilm formation in methicillin-resistant Staphylococcus aureus.

Biofilm-based infection is a major healthcare burden. Methicillin-resistant Staphylococcus aureus (MRSA) is one of major organisms responsible for biofilm infection. Although biofilm is induced by a number of environmental signals, the molecule responsible for environmental sensing is not well delineated. Here we examined the role of ion transporters in biofilm formation and found that the sodium-glutamate transporter gltS played an important role in biofilm formation in MRSA. This was shown by gltS transposon mutant as well as its complementation. The lack of exogenous glutamate also enhanced biofilm formation in JE2 strain. The deficiency of exogenous glutamate intake accelerated endogenous glutamate/glutamine production, which led to the activation of the urea cycle. We also showed that urea cycle activation was critical for biofilm formation. In conclusion, we showed that gltS was a critical regulator of biofilm formation by controlling the intake of exogenous glutamate. An intervention to target glutamate intake may be a potential useful approach against biofilm.

Surgical Site Infections and Perioperative Optimization of Host Immunity by Selection of Anesthetics.

Surgical site infections are significant health care issues, and efforts to mitigate their occurrence have been ongoing worldwide, mainly focusing to reduce the spillage of microbes to the otherwise sterile tissues. Optimization of host immunity has been also recognized including temperature regulation (normothermia), adequate oxygenation, and glucose management. A number of papers have described the role of anesthetics in host immunity. The role of anesthetics in postoperative outcomes including surgical site infections has been also studied. We will review the current literature and propose the importance of anesthetic selection to potentially mitigate surgical site infections.

Cathepsin L regulates pathogenicCD4 T cells in experimental autoimmune encephalomyelitis.

Previously we reported that IL-17-producing CD4 T cells (Th17) were increased in mice lacking the protease inhibitor SerpinB1 and several SerpinB1-inhibitable cysteine cathepsins were induced in the Th17 cells, most prominently cathepsin L (CtsL). Since CtsL also mediates invariant chain processing in thymic epithelial cells, deficiency of CtsL leads to impaired CD4 T cell thymic selection, which hinders the direct investigation of CD4 T cells in CtsL -/- mouse. In the current study, through transplanting the CtsL -/- bone marrow into lethally irradiated CtsL-sufficient Rag/- mice (bone marrow chimeras), we reconstituted the immune system of CtsL -/- chimeric mice, which possessed normal CD4 T cell development and allowed us to study the intrinsic role of CtsL in CD4 T cells in Th17 cell-driven autoimmune diseases. Surprisingly, we found that CtsL -/- CD4 T cells had no defects in differentiation of naïve CD4 T cells into Th1, Treg and Th17 cells in vitro. However, in vivo, in experimental autoimmune encephalomyelitis (EAE) model, deficiency of CtsL significantly decreased the activation of IL-17, GM-CSF and IFN-γ producing pathogenic CD4 T cells. Compared with wild type (wt) controls, CtsL -/- CD4 T cells were also less accumulated in the spinal cord in EAE. Thus, for the first time, our study provided the direct in vivo evidence that CtsL was involved in CD4 T cells acquiring pathogenicity in the autoimmune disease.

The Microbial Flora in an Experimental Polymicrobial Abdominal Sepsis Model Probed by 16S rRNA Sequencing.

BACKGROUND: Cecal ligation and puncture (CLP) surgery is a widely used preclinical model to induce and study sepsis because it is considered to recapitulate the course of human sepsis the most. This model is highly dependent on the polymicrobial gut flora and represents polymicrobial abdominal sepsis. While the majority of studies using CLP model have focused on the delineation of host immune responses, a limited number of reports have described the composition of microbial strains in this model, although microbial composition can significantly affect the outcome of sepsis in general. METHODS: CLP surgery was performed in mice on C57BL6/J from the Jackson laboratory. We examined the composition of microbes at the peritoneal cavity using 16S rRNA sequencing after CLP surgery at 12 and 24 hours. Baseline cecal microbial flora was also analyzed. RESULTS: The bacteria strains from the initial cecum flora consisted of mixed aerobic and anaerobic flora. There was a significant change of bacteria flora from the peritoneal cavity between 12 and 24 hours following CLP surgery. Particularly a significantly increased proportion of anaerobic microbes were noted at 24 hours after CLP surgery. We also tested bacterial composition of cecal flora of mice on the same background from the same vendor 6 months later. Baseline cecal microbial flora was different from earlier mice, showing that baseline cecal flora could be different depending on the batch of mice. CONCLUSION: There was a dynamical chance of peritoneal microbes during CLP sepsis. Potential difference in baseline cecal flora should be kept in mind upon CLP surgery even when using mice from the same vendor.