Comparison of volume-controlled ventilation, pressure-controlled ventilation and pressure-controlled ventilation-volume guaranteed in infants and young children in the prone position: A prospective randomized study.

STUDY OBJECTIVE: To explore if the pressure-controlled ventilation (PCV) and pressure-controlled ventilation-volume guaranteed (PCV-VG) modes are superior to volume-controlled ventilation (VCV) in optimizing intraoperative respiratory mechanics in infants and young children in the prone position. DESIGN: A single-center prospective randomized study. SETTING: Children's Hospital, Zhejiang University School of Medicine. PATIENTS: Pediatric patients aged 1 month to 3 years undergoing elective spinal cord detethering surgery. INTERVENTIONS: Patients were randomly allocated to the VCV group, PCV group and PCV-VG group. The target tidal volume (VT) was 8 mL/kg and the respiratory rate (RR) was adjusted to maintain a constant end tidal CO2. MEASUREMENTS: The primary outcome was intraoperative peak airway pressure (Ppeak). Secondary outcomes included other respiratory and ventilation variables, gas exchange values, serum lung injury biomarkers concentration, hemodynamic parameters and postoperative respiratory complications. MAIN RESULTS: A total of 120 patients were included in the final analysis (40 in each group). The VCV group showed higher Ppeak at T2 (10 min after prone positioning) and T3 (30 min after prone positioning) than the PCV and PCV-VG groups (T2: P = 0.015 and P = 0.002, respectively; T3: P = 0.007 and P = 0.009, respectively). The prone-related decrease in dynamic compliance was prevented by PCV and PCV-VG ventilation modalities at T2 and T3 than by VCV (T2: P = 0.008 and P = 0.015, respectively; T3: P = 0.015 and P = 0.014, respectively). Additionally, there were no significant differences in other secondary outcomes among the three groups. CONCLUSION: In infants and young children undergoing spinal cord detethering surgery in the prone position, PCV-VG may be a better ventilation mode due to its ability to mitigate the increase in Ppeak and decrease in Cdyn while maintaining consistent VT.

Function and mechanism of TREM2 in bacterial infection.

Triggering receptor expressed on myeloid cells 2 (TREM2), which is a lipid sensing and phagocytosis receptor, plays a key role in immunity and inflammation in response to pathogens. Here, we review the function and signaling of TREM2 in microbial binding, engulfment and removal, and describe TREM2-mediated inhibition of inflammation by negatively regulating the Toll-like receptor (TLR) response. We further illustrate the role of TREM2 in restoring organ homeostasis in sepsis and soluble TREM2 (sTREM2) as a diagnostic marker for sepsis-associated encephalopathy (SAE). Finally, we discuss the prospect of TREM2 as an interesting therapeutic target for sepsis.

Impact of intravenous administration of nalbuphine at different time points for postoperative analgesia and sedation in adenotonsillectomized children: a prospective, randomized controlled trial.

Objective: To compare the efficacy of intravenous administration of nalbuphine at different time points for postoperative analgesia and sedation in adenotonsillectomized children. Methods: Patients with obstructive sleep apnea syndrome scheduled for adenotonsillectomy were randomly divided into group A (patients received intravenous nalbuphine 0.2 mg/kg before anesthesia induction), group B (patients received intravenous nalbuphine 0.2 mg/kg 10 min before the end of surgery), and group C (patients did not receive nalbuphine injection). The time points for measuring outcomes were before anesthesia induction (T0), extubation (T1), and 0, 15, 30, or 45 min in the postanesthesia care unit (PACU) (T2-T5, respectively). Results: There were 40 patients in group A, 41 patients in group B and 39 patients in group C. Patients in group B had significantly lower FLACC (Face, Legs, Activity, Cry, Consolability) pain scores at T2-T5 than those in group C (all p<0.05). Patients in group B had higher Ramsay Sedation Score at T2-T4 than those in group C (all p<0.05). The proportion of patients who received remedial analgesia in the PACU in group A (17.5%, p=0.008) and group B (9.8%, p<0.001) was significantly lower than that in group C (46.2%). Conclusion: Intravenous administration of nalbuphine 10 min before the end of adenotonsillectomy in children could decrease pain intensity and increase sedation levels during the recovery period with the reduction of remedial analgesia in the PACU.Trial registration number ChiCTR2200060118.

Comparison of staged LLIF combined with posterior instrumented fusion with posterior instrumented fusion alone for the treatment of adult degenerative lumbar scoliosis with sagittal imbalance.

BACKGROUND: To retrospectively compare the clinical and radiological outcomes of staged lateral lumbar interbody fusion (LLIF) combined with posterior instrumented fusion(PIF)with PIF alone for the treatment of adult degenerative lumbar scoliosis (ADLS) with sagittal imbalance. METHODS: ADLS patients with sagittal imbalance underwent corrective surgery were included and divided into staged group (underwent multilevel LLIF in the first-stage and PIF in the second-stage) and control group (PIF alone). The clinical and radiological outcomes were evaluated and compared between the two groups. RESULTS: Forty-five patients with an average age of 69.7±6.3 years were enrolled, including 25 in the staged group and 20 in the control group. Compared with preoperative values, patients in both groups achieved significant improvement in terms of ODI, VAS back, VAS leg and spinopelvic parameters after surgery, which were maintained well during the follow-up period. Compared with control group, total operative time in the staged group was longer, but the amounts of blood loss and blood transfusion were reduced. The average posterior fixation segments were 6.20±1.78 in the staged group and 8.25±1.16 in the control group (P<0.01), respectively. Posterior column osteotomy (PCO) was performed in 9 patients (36%) in the staged group, while PCO and/or pedicle subtraction osteotomy were performed in 15 patients (75%) in the control group (P<0.01). There was no difference in complications between the two groups. CONCLUSION: Both surgical strategies were effective for the treatment of ADLS with sagittal imbalance. However, staged treatment was less invasive, which reduced the number of posterior fixation segments and osteotomy requirement.

TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis.

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi). TREM2hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.

Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage in various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, acute kidney injury and hemorrhagic shock. I/R damage is often irreversible, and current treatments for I/R injury are limited. Ferroptosis, a type of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, has been implicated in multiple diseases, including I/R injury. Emerging evidence suggests that ferroptosis can serve as a therapeutic target to alleviate I/R injury, and pharmacological strategies targeting ferroptosis have been developed in I/R models. Here, we systematically summarize recent advances in research on ferroptosis in I/R injury and provide a comprehensive analysis of ferroptosis-regulated genes investigated in the context of I/R, as well as the therapeutic applications of ferroptosis regulators, to provide insights into developing therapeutic strategies for this devastating disease.

Human Neutrophil Defensins Disrupt Liver Interendothelial Junctions and Aggravate Sepsis.

Human neutrophil peptides 1-3 (HNP1-3), also known as human α-defensins, are the most abundant neutrophil granule proteins. The genes that encode HNP1-3, DEFA1/DEFA3, exhibit extensive copy number variations, which correlate well with their protein levels. Human and mouse studies have shown that increased copy numbers of DEFA1/DEFA3 worsen sepsis outcomes. Additionally, high concentrations of HNP1-3 in body fluids have been reported in patients with sepsis. However, direct evidence for the pathogenic role of HNP1-3 proteins during sepsis progression is lacking. In current study, sepsis was induced by means of cecal puncture and ligation. Various doses of HNP-1 (low dose with 0.5 mg/kg body weight and high dose with 10 mg/kg body weight) or phosphate buffer saline were intraperitoneally administered to mice at six hours after sepsis onset. Survival rate was monitored, and vascular permeability, endothelial cell pyroptosis, and immunofluorescence of endothelial adherens junction protein vascular endothelial-cadherin were evaluated. The administration of a high dose of HNP-1 after sepsis onset led to increased mortality, more severe liver injury, and increased vascular permeability in the liver and mesentery. The injection of high dose of HNP-1 did not directly induce liver endothelial cell death but destroyed interendothelial junctions in the liver. Moreover, genetic deficiency of nucleotide-binding oligomerization domain-like receptor protein-3 or caspase-1 abrogated the high mortality and disrupted liver interendothelial junctions caused by high dose of HNP-1 during sepsis. This study directly demonstrates that neutrophil defensins play a key role in regulating endothelial stability during sepsis development.

An Animation Model Generation Method Based on Gaussian Mutation Genetic Algorithm to Optimize Neural Network.

With the rapid development of computer graphics, 3D animation has been applied to all fields of people's lives, especially in the industries of film and television works, games, and entertainment. The wide application of animation technology makes it difficult for general 3D animation effects to impress increasingly discerning audiences. Group animation, as a new focus, has received more and more attention and has become a hot issue in computer graphics. Traditional animation production mainly relies on manual drawing and key frame technologies. The limitations of these technologies make the production of group animation consume a lot of manpower, financial resources, and time, and cannot guarantee the intelligence of characters and the authenticity of group behavior. Therefore, in order to end the above issues, this paper proposes an animation model generation method based on Gaussian mutation genetic algorithm to optimize neural network, including obtaining animation scene data, according to the animation scene data, and extracting animation model elements. The elements are input into the model network, the target animation model is generated, and the target animation model is displayed. The method proposed in this paper improves the animation model generation method in the prior art to a certain extent. The proposed animation model is constructed only through fixed rules, and the composition rules of the model cannot be changed according to the historical data of the animation model construction and other factors. Technical issues that reduce the flexibility and accuracy of the animation model generation.

Novel biomarkers for acute respiratory distress syndrome: genetics, epigenetics and transcriptomics.

Acute respiratory distress syndrome (ARDS) can be induced by multiple clinical factors, including sepsis, acute pancreatitis, trauma, intestinal ischemia/reperfusion and burns. However, these factors alone may poorly explain the risk and outcomes of ARDS. Emerging evidence suggests that genomic-based or transcriptomic-based biomarkers may hold the promise to establish predictive or prognostic stratification methods for ARDS, and also to help in the development of novel therapeutic targets for ARDS. Notably, genetic/epigenetic variations correlated with susceptibility and prognosis of ARDS and circulating microRNAs have emerged as potential biomarkers for diagnosis or prognosis of ARDS. Although limited by sample size, ethnicity and phenotypic heterogeneity, ongoing genetic/transcriptomic research contributes to the characterization of novel biomarkers and ultimately helps to develop innovative therapeutics for ARDS patients.

Plain language summary As the severe form of lung injury, acute respiratory distress syndrome (ARDS) affects about 10% of patients in intensive care units and causes 30­40% of deaths. ARDS can be induced by multiple clinical factors, including sepsis, severe pancreatitis, trauma, intestinal ischemia/reperfusion and burns. Early identification of those with high risk of ARDS would increase diagnostic efficiency and further improve outcomes of patients. Here, we review the most recent evidence that supports the roles of various biomarkers in predicting ARDS risk and outcome. Ongoing research contributes to the characterization of novel biomarkers and ultimately helps to develop innovative and more tailored therapeutics for ARDS patients.

Improved targeting of the 16S rDNA nanopore sequencing method enables rapid pathogen identification in bacterial pneumonia in children.

Objectives: To develop a rapid and low-cost method for 16S rDNA nanopore sequencing. Methods: This was a prospective study on a 16S rDNA nanopore sequencing method. We developed this nanopore barcoding 16S sequencing method by adding barcodes to the 16S primer to reduce the reagent cost and simplify the experimental procedure. Twenty-one common pulmonary bacteria (7 reference strains, 14 clinical isolates) and 94 samples of bronchoalveolar lavage fluid from children with severe pneumonia were tested. Results indicating low-abundance pathogenic bacteria were verified with the polymerase chain reaction (PCR). Further, the results were compared with those of culture or PCR. Results: The turnaround time was shortened to 6~8 hours and the reagent cost of DNA preparation was reduced by employing a single reaction adding barcodes to the 16S primer in advance. The accuracy rate for the 21 common pulmonary pathogens with an abundance ≥ 99% was 100%. Applying the culture or PCR results as the gold standard, 71 (75.5%) of the 94 patients were positive, including 25 positive cultures (26.6%) and 52 positive quantitative PCRs (55.3%). The median abundance in the positive culture and qPCR samples were 29.9% and 6.7%, respectively. With an abundance threshold increase of 1%, 5%, 10%, 15% and 20%, the test sensitivity decreased gradually to 98.6%, 84.9%, 72.6%, 67.1% and 64.4%, respectively, and the test specificity increased gradually to 33.3%, 71.4%, 81.0%, 90.5% and 100.0%, respectively. Conclusions: The nanopore barcoding 16S sequencing method can rapidly identify the pathogens causing bacterial pneumonia in children.

Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8.

BACKGROUND: Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8, and is poorly understood, as only dozens of cases have been reported previously. Based on a newborn screening program, we evaluated the incidence, phenotype and genotype of IBDD as well as the prognosis. Moreover, we reviewed the variant spectrum in ACAD8 associated with IBDD. METHODS: Forty unrelated patients with IBDD were retrospectively screened for newborns between Jan 2012 and Dec 2020. Tandem mass spectrometry (MS/MS) was used to determine the concentrations of C4-acylcarnitine, C4/C2 (acetylcarnitine), and C4/C3 (propionylcarnitine). All suspected cases were genetically tested by metabolic genes panel. RESULTS: The incidence of IBDD here was 1: 62,599. All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. Isobutyrylglycine occurred in only 8 patients. During follow-up, four patients had a transient motor delay, and two patients had growth delay. Notably, one case harbored both ACAD8 compound heterozygous variants and a KMT2A de novo variant (c.2739del, p.E914Rfs*35), with IBDD and Wiedemann-Steiner syndrome together, had exact severe global developmental delay. All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. After 3-108 months of follow-up, most individuals were healthy except the case harboring the KMT2A variant. A total of 16 novel variants in ACAD8, c.4_5delCT, c.109C > T, c.110-2A > T, c.236G > A, c.259G > A, c.381-14G > A, c.413delA, c.473A > G, c.500delG, c.758 T > G, c.842-1G > A, c.911A > T, c.989G > A, c.1150G > C, c.1157A > G and c.1165C > T, were identified. Along with a literature review on 51 ACAD8 variants in 81 IBDD patients, we found that the most common variant was c.286G > A (27.2%), which has been observed solely in the Chinese population to date, followed by c.1000C > T (8.6%), c.1176G > T (3.7%) and c.455 T > C (3.1%). CONCLUSION: The concentration of C4-acylcarnitine in NBS plus subsequent genetic testing is necessary for IBDD diagnosis. Both the genotypes and ACAD8 variants in IBDD are highly heterogeneous, and no significant correlations between genotype and phenotype are present here in patients with IBDD. Our IBDD cohort with detaied clinical characteristics, genotypes and long-term prognosis will be helpful for the diagnosis and management of patients with IBDD in the future.

TREM2 Dictates Antibacterial Defense and Viability of Bone Marrow-derived Macrophages during Bacterial Infection.

Macrophages undergo profound metabolic reprogramming to join key immunoregulatory functions, which can be initiated by pattern recognition receptors. TREM2 (triggering receptor expressed on myeloid cells 2), a macrophage phagocytic receptor, plays pivotal roles in sepsis by enhancing bacterial clearance, which is associated with regulation of reactive oxygen species (ROS) production. However, how intracellular ROS participate in TREM2-mediated bactericidal activity remains unclear. This study was designed to investigate the organelle source and biological activity of ROS in the context of TREM2-mediated immune defense during Escherichiacoli infection. Bone marrow-derived macrophages (BMDMs) were transfected with TREM2-overexpressing adenoviruses or control viruses and challenged with E. coli. The BMDMs were administered to mouse models with local E. coli infection. In addition, monocytic TREM2 expression, NOX2 concentrations, and pyroptosis were detected in patients with bacterial sepsis. General ROS production was found to be comparable between TREM2-overexpressing and control BMDMs upon E. coli challenge. The deficiency of Nox2 led to impaired phagosome degradation and lack of bactericidal ability and abolished TREM2-mediated protective activity against pulmonary E. coli infection. Overexpression of TREM2 suppressed mitochondrial ROS generation, inhibited NLRP3/caspase-1 inflammasome activation, and finally protected BMDMs from gasdermin D-mediated pyroptosis during pulmonary E. coli infection. The protective role of TREM2 was further confirmed in mice with abdominal E. coli infection. Moreover, monocytic TREM2 expression was positively correlated with NOX2 concentrations and negatively correlated with pyroptosis and disease severity in patients with bacterial sepsis. Collectively, TREM2 controls macrophage immune functions by fine-tuning ROS generation and enhances the host defense against bacterial infection. Our data suggest that TREM2 is a promising candidate target for sepsis therapy.

Triggering receptor expressed on myeloid Cells-2 (TREM2) inhibits steroidogenesis in adrenocortical cell by macrophage-derived exosomes in lipopolysaccharide-induced septic shock.

PURPOSE: Endogenously produced glucocorticoids exhibit immunomodulating properties and are of pivotal importance for sepsis outcome. Uncontrolled activation of the immune-adrenal crosstalk increases the risk of sepsis-related death. Triggering receptor expressed on myeloid cells-2 (TREM2) is richly expressed on macrophages and has been demonstrated to improve outcome of sepsis by enhancing elimination of pathogens. However, the role and mode of action of macrophage TREM2 on adrenocortical steroidogenesis remains unclear in septic shock. METHODS: The acute septic shock model was established by intraperitoneally challenging wild-type (WT) and TREM2 knock-out (Trem2-/-) mice with lipopolysaccharide (LPS, 30 mg/kg). The mice were assessed for TREM2 expression and local inflammation in adrenal gland and for synthesis of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in vivo. Bone marrow-derived macrophages or macrophage-derived exosomes were isolated from WT and Trem2-/- mice and were co-cultured with adrenocortical cells. The expression of steroidogenic enzymes and corticosterone production was assessed. RESULTS: Genetic deficiency of TREM2 caused significantly higher corticosterone levels at the early stage of LPS-induced septic shock; whereas TREM2 deficiency neither increased CRH and ACTH nor exacerbated the inflammation in adrenocortical tissue during septic shock. Ex vivo study revealed that Trem2-/- macrophages significantly promoted the expression of steroidogenic enzymes and increased production of corticosterone. Furthermore, Trem2-/- macrophage-derived exosomes were able to mimic Trem2-/- macrophages in enhancing adrenocortical steroidogenesis. CONCLUSIONS: At the early stage of LPS-induced septic shock, corticosterone biosynthesis can be inhibited by macrophage TREM2 in adrenocortical cells, which might partially associate with macrophage-derived exosomes.

Triggering Receptor Expressed on Myeloid Cells-2 Protects Aged Mice Against Sepsis by Mitigating the IL-23/IL-17A Response.

BACKGROUND: Advancing age is an independent predictor of mortality in septic patients. Recent animal studies were unable to reflect this clinical pathophysiological process, largely hampering the development of new efficacious therapies. Triggering receptor expressed on myeloid cells-2 (TREM-2) is a novel immune regulator with multiple activities. However, very little is known about the regulatory role of TREM-2 in sepsis upon aging. METHODS: Blood samples were collected from septic patients within 24 h after intensive care unit admission. The patients were preselected into two groups based on the age (age with ≥60 years old and age with <60 years old). Sepsis in aged mice was induced by cecal ligation and puncture. The expression of TREM-2 was evaluated in septic patients and aged septic mice. Aged macrophages overexpressing TREM-2 and green fluorescent protein (GFP) were administered to aged septic mice after cecal ligation and puncture. Survival rate was monitored, and bacterial load and inflammatory mediators levels were evaluated. In vivo IL-23 function was blocked using appropriate monoclonal antibodies. RESULTS: The expression levels of TREM-2 were downregulated in both aged septic patients and aged septic mice. The administration of TREM-2-overexpressing macrophages significantly prolonged survival and alleviated organ injury in the aged septic mice. The protective effect did not affect host bacterial burden, but markedly inhibited the host IL-17A response, as determined by a multiplex cytokine assay. Screening the expression of IL-17A-related activating factors revealed that the IL-23 level in TREM-2-overexpressing macrophages was significantly lower than that in GFP-expressing macrophages. Blocking IL-23 after the administration of GFP-expressing macrophages protected aged mice against sepsis. CONCLUSIONS: TREM-2 prolonged survival of aged mice from sepsis by finely modulating the IL-23/IL-17A immune pathway. These results provide previously unidentified mechanistic insight into immune regulation by TREM-2 and new therapeutic targets in sepsis upon aging.

Airway Epithelial Hepcidin Coordinates Lung Macrophages and Immunity Against Bacterial Pneumonia.

BACKGROUND: Hepcidin is a liver-derived master regulator of iron metabolism through its molecular target ferroportin, the only known mammalian iron exporter. Accumulated evidence has shown the important roles of hepatic hepcidin in host defense and infections. Hepcidin is also expressed by airway epithelial cells. However, the function of epithelial hepcidin during bacterial pneumonia remains unknown. METHODS: Pneumonia was induced in hepcidin-1-deficient and wild-type mice using the most common bacterial agents, and the effects of hepcidin on survival, bacterial burden, iron status, and macrophage phagocytosis after bacterial pneumonia were assessed. RESULTS: Hepcidin levels decreased in airway epithelium during common pneumonia, while lung macrophage-derived ferroportin levels and pulmonary iron concentrations increased. Lack of hepcidin in the airway epithelium worsened the outcomes of pneumonia. Manipulation of hepcidin level in the airway epithelium in mice with macrophage-specific ferroportin deletion did not affect the progress of pneumonia. Increased pulmonary iron concentration not only facilitated bacterial growth but also led to the defective phagocytic function of lung macrophages via activation of RhoA GTPase through oxidation of RhoGDI. Furthermore, enhancing the hepcidin level in the airway epithelium rescued mice from lethal bacterial pneumonia. CONCLUSIONS: These findings identify an uncharacterized important role of airway epithelial hepcidin in protection against bacterial pneumonia and provide the basis for novel alternative therapeutic strategies for combatting bacterial pneumonia in future translational research.

Increased gene copy number of DEFA1/DEFA3 worsens sepsis by inducing endothelial pyroptosis.

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1-3 (HNP1-3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.

Self-Assembling Myristoylated Human α-Defensin 5 as a Next-Generation Nanobiotics Potentiates Therapeutic Efficacy in Bacterial Infection.

The increasing prevalence of antibacterial resistance globally underscores the urgent need to the update of antibiotics. Here, we describe a strategy for inducing the self-assembly of a host-defense antimicrobial peptide (AMP) into nanoparticle antibiotics (termed nanobiotics) with significantly improved pharmacological properties. Our strategy involves the myristoylation of human α-defensin 5 (HD5) as a therapeutic target and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with its parent HD5, the C-terminally myristoylated HD5 (HD5-myr)-assembled nanobiotic exhibited significantly enhanced broad-spectrum bactericidal activity in vitro. Mechanistically, it selectively killed Escherichia coli ( E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) through disruption of the cell wall and/or membrane structure. The in vivo results further demonstrated that the HD5-myr nanobiotic protected against skin infection by MRSA and rescued mice from E. coli-induced sepsis by lowering the systemic bacterial burden and alleviating organ damage. The self-assembled HD5-myr nanobiotic also showed negligible hemolytic activity and substantially low toxicity in animals. Our findings validate this design rationale as a simple yet versatile strategy for generating AMP-derived nanobiotics with excellent in vivo tolerability. This advancement will likely have a broad impact on antibiotic discovery and development efforts aimed at combating antibacterial resistance.

Plasma levels of alarmin HNPs 1-3 associate with lung dysfunction after cardiac surgery in children.

BACKGROUND: Early onset of lung injury is considerable common after cardiac surgery and is associated with increasing in morbidity and mortality, but current clinical predictors for the occurrence of this complication always have limited positive warning value. This study aimed to evaluate whether elevated plasma levels of human neutrophil peptides (HNPs) 1-3 herald impaired lung function in infants and young children after cardiac surgery necessitating cardiopulmonary bypass (CPB). METHODS: Consecutive children younger than 3 years old who underwent cardiac surgery were prospectively enrolled. Plasma concentrations of HNPs 1-3 and inflammatory cytokines were measured before, and immediately after CPB, as well as at 1 h, 12 h, and 24 h after CPB. RESULTS: Thirty patients were enrolled, 18 (60%) of whom were infants. Plasma levels of HNPs 1-3 and the pro-inflammatory cytokine interleukin-6 (IL-6) significantly increased immediately after CPB (P < 0.001), while IL-8 increased 1 h after the CPB operation (P = 0.002). The anti-inflammatory cytokine IL-10 levels were also significantly elevated immediately after CPB compared with the baseline (P < 0.001). The stepwise multiple linear regression analysis showed that the plasma HNPs 1-3 levels immediately after CPB was independent correlated with the declined lung function, as reflected by the PaO2/FiO2 ratio on the first 2 days after operation (for the first day: OR, -1.067, 95% CI, -0.548 to -1.574; P < 0.001; for the second day: OR, -0.667, 95% CI, -0.183 to -1.148; P = 0.009) and prolonged mechanical ventilation time (OR, 0.039, 95% CI, 0.005 to 0.056; P = 0.011). Plasma levels of HNPs 1-3 and IL-10 returned to the baseline values, while IL-6 and IL-8 levels remained significantly higher than baseline 24 h after CPB (P ≤ 0.01). CONCLUSIONS: Elevated HNPs 1-3 levels immediately after CPB correlate with impaired lung function, and HNPs 1-3 could serve as a quantifiable early alarmin biomarker for onset of lung injury in infants and young children undergoing cardiac surgery with CPB.

The role of increased body mass index in outcomes of sepsis: a systematic review and meta-analysis.

BACKGROUND: The role of increased body mass index (BMI) in sepsis is controversial. We aimed to evaluate the associations between overweight (25 kg/m2 < BMI ≤ 29.9 kg/m2), obese (30 kg/m2 < BMI ≤ 39.9 kg/m2) and morbidly obese (BMI > 40 kg/m2) BMIs and outcomes in septic patients. METHODS: We searched the PubMed, Embase, Web of Science, Cochrane Library and ClinicalTrials.gov databases for studies published by December 1, 2016. Electronic database searches yielded 3713 articles, eight of which were included in this meta-analysis. Data were independently extracted by two reviewers, and a third reviewer participated in making decisions as needed. We used Review Manager to conduct the analysis, and the outcomes were reported with odds ratios (ORs) or mean differences (MDs). The primary outcome was mortality, and the secondary outcome was length of stay (LOS) in the intensive care unit (ICU) or the hospital. RESULTS: Data from eight studies involving a total of 9696 patients were pooled in our final analysis. Compared with patients with normal BMI (18.5 kg/m2 < BMI ≤ 24.9 kg/m2), patients with BMI ≥ 25 kg/m2 exhibited decreased mortality (OR 0.81; 95% confidence interval (CI), 0.74-0.89, P < 0.0001). In subgroup analysis, compared with normal-weight patients, overweight patients had lower mortality (OR 0.87; 95% CI 0.77-0.97, P = 0.02), whereas obese (OR 0.89, 95% CI 0.72-1.10, P = 0.29) and morbidly obese (OR 0.64, 95% CI 0.38-1.08, P = 0.09) patients did not exhibit significantly reduced mortality. CONCLUSIONS: In sepsis cases, overweight, but not obesity or morbid obesity, was associated with lower mortality. Further prospective studies are needed to clarify this relationship.