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Objective: To comprehensively evaluate the effectiveness of preventive measures for acute kidney injury (AKI) in children and identify the effective strategies. Methods: Databases were systematically searched including CNKI, Wanfang, VIP, China Biology Medicine National Knowledge Infrastructure, PubMed, Embase, Cochrane Library databases, and the reference lists of relevant papers for randomized controlled trials on preventing pediatric AKI up to December 2023. Literature screening was conducted based on the inclusion and exclusion criteria, followed by data extraction and quality assessment of included studies. Traditional and network meta-analyses were performed, along with trial sequential analysis (TSA). Results: A total of 21 studies involving 3 483 children were included. Traditional and network meta-analysis showed that dexmedetomidine was effective in preventing AKI in children undergoing cardiac surgery or cardiac angiography ( OR= 0.26, 0.27; 95% CI 0.11-0.64, 0.13-0.58). Remote ischemic preconditioning (RIPC) was effective in preventing AKI in children after cardiac surgery ( OR= 0.43, 0.44; 95% CI 0.24-0.79, 0.23-0.83). Traditional and network meta-analysis specific to children with sepsis or septic shock showed that balanced solution was effective in preventing pediatric AKI ( OR= 0.58, 0.52; 95% CI 0.42-0.79, 0.37-0.73). TSA indicated that the total sample sizes of dexmedetomidine (348 cases) and RIPC (666 cases) both reached the required information size (320 and 534 cases); additionally, the Z -curve for balanced solution (cumulative Z= 3.38) crossed the TSA monitoring boundary ( Z= 3.29). Conclusion: Dexmedetomidine reduces the risk of AKI in children undergoing cardiac surgery or cardiac angiography, RIPC decreases the risk of AKI in children after cardiac surgery, and balanced solution lowers the risk of AKI in children with sepsis or septic shock.

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus ( S. aureus ), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus , there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB 138-147 ), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD + treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD + administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD + administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD + blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential., Competing Interests: JI, RE, YN, AG, SE, HC, AV, AE No competing interests declared, (© 2023, Iske, El Fatimy, Nian et al.)

Staphylococcus aureus is a human pathogen with many infections originating on mucosal surfaces. One common group of S. aureus is the USA200 (CC30) clonal group, which produces toxic shock syndrome toxin-1 (TSST-1). Many USA200 infections occur on mucosal surfaces, particularly in the vagina and gastrointestinal tract. This allows these organisms to cause cases of menstrual TSS and enterocolitis. The current study examined the ability of two lactobacilli, Lactobacillus acidophilus strain LA-14 and Lacticaseibacillus rhamnosus strain HN001, for their ability to inhibit the growth of TSST-1 positive S. aureus, the production of TSST-1, and the ability of TSST-1 to induce pro-inflammatory chemokines from human vaginal epithelial cells (HVECs). In competition growth experiments, L. rhamnosus did not affect the growth of TSS S. aureus but did inhibit the production of TSST-1; this effect was partially due to acidification of the growth medium. L. acidophilus was both bactericidal and prevented the production of TSST-1 by S. aureus. This effect appeared to be partially due to acidification of the growth medium, production of H 2 O 2 , and production of other antibacterial molecules. When both organisms were incubated with S. aureus, the effect of L. acidophilus LA-14 dominated. In in vitro experiments with HVECs, neither lactobacillus induced significant production of the chemokine interleukin-8, whereas TSST-1 did induce production of the chemokine. When the lactobacilli were incubated with HVECs in the presence of TSST-1, the lactobacilli reduced chemokine production. These data suggest that these two bacteria in probiotics could reduce the incidence of menstrual and enterocolitis-associated TSS. IMPORTANCE Toxic shock syndrome (TSS) Staphylococcus aureus commonly colonize mucosal surfaces, giving them the ability to cause TSS through the action of TSS toxin-1 (TSST-1). This study examined the ability of two probiotic lactobacilli to inhibit S. aureus growth and TSST-1 production, and the reduction of pro-inflammatory chemokine production by TSST-1. Lacticaseibacillus rhamnosus strain HN001 inhibited TSST-1 production due to acid production but did not affect S. aureus growth. Lactobacillus acidophilus strain LA-14 was bactericidal against S. aureus, partially due to acid and H 2 O 2 production, and consequently also inhibited TSST-1 production. Neither lactobacillus induced the production of pro-inflammatory chemokines by human vaginal epithelial cells, and both inhibited chemokine production by TSST-1. These data suggest that the two probiotics could reduce the incidence of mucosa-associated TSS, including menstrual TSS and cases originating as enterocolitis., Competing Interests: The authors declare a conflict of interest. A.V.G., A.L.R., and D.S.M. are employees of The Procter & Gamble Company. J.M. and L.H. are employed by IFF Health & Biosciences. The other authors report no conflicts of interest.

Abstract: The orphan receptor, G protein-coupled receptor (GPR) 75, which has been shown to mediate various effects of 20-hydroxyeicosatetraenoic acid (20-HETE), is considered as a therapeutic target in the treatment of cardiovascular diseases in which changes in the production of 20-HETE play a key role in their pathogenesis. Our previous studies showed that 20-HETE mimetic, N -(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), protects against vascular hyporeactivity, hypotension, tachycardia, and arterial inflammation induced by lipopolysaccharide (LPS) in rats. This study tested the hypothesis that the GPR75 signaling pathway mediates these effects of 5,14-HEDGE in response to systemic exposure to LPS. Mean arterial pressure reduced by 33 mm Hg, and heart rate increased by 102 beats/min at 4 hours following LPS injection. Coimmunoprecipitation studies demonstrated that (1) the dissociation of GPR75/Gα q/11 and GPR kinase interactor 1 (GIT1)/protein kinase C (PKC) α, the association of GPR75/GIT1, large conductance voltage and calcium-activated potassium subunit β (MaxiKβ)/PKCα, MaxiKβ/proto-oncogene tyrosine-protein kinase (c-Src), and epidermal growth factor receptor (EGFR)/c-Src, MaxiKβ, and EGFR tyrosine phosphorylation were decreased, and (2) the association of GIT1/c-Src was increased in the arterial tissues of rats treated with LPS. The LPS-induced changes were prevented by 5,14-HEDGE. N -[20-Hydroxyeicosa-6( Z ),15( Z )-dienoyl]glycine, a 20-HETE antagonist, reversed the effects of 5,14-HEDGE in the arterial tissues of LPS-treated rats. Thus, similar to 20-HETE, by binding to GPR75 and activating the Gα q/11 /PKCα/MaxiKβ, GIT1/PKCα/MaxiKβ, GIT1/c-Src/MaxiKβ, and GIT1/c-Src/EGFR signaling pathways, 5,14-HEDGE may exert its protective effects against LPS-induced hypotension and tachycardia associated with vascular hyporeactivity and arterial inflammation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Nonabsorbable nasal packing is often placed for the treatment of epistaxis or after sinonasal or skull base surgery. Antibiotics are often prescribed to prevent toxic shock syndrome (TSS), a rare, potentially fatal occurrence. However, the risk of TSS must be balanced against the major risk of antibiotic use, specifically Clostridium difficile colitis (CDC). The purpose of this study is to evaluate in terms of cost-effectiveness whether antibiotics should be prescribed when nasal packing is placed., Study Design: A clinical decision analysis was performed using a Markov model to evaluate whether antibiotics should be given., Setting: Patients with nonabsorbable nasal packing placed., Methods: Utility scores, probabilities, and costs were obtained from the literature. We assess the cost-effectiveness of antibiotic use when the risk of community-acquired CDC is balanced against the risk of TSS from nasal packing. Sensitivity analysis was performed for assumptions used in the model., Results: The incremental cost-effectiveness ratio for antibiotic use was 334,493 US dollars (USD)/quality-adjusted life year (QALY). Probabilistic sensitivity analysis showed that not prescribing antibiotics was cost-effective in 98.0% of iterations at a willingness to pay of 50,000 USD/QALY. Sensitivity analysis showed that when the risk of CDC from antibiotics was greater than 910/100,000 or when the incidence of TSS after nasal packing was less than 49/100,000 cases, the decision to withhold antibiotics was cost-effective., Conclusions: Routine antibiotic prophylaxis in the setting of nasal packing is not cost-effective and should be reconsidered. Even if antibiotics are assumed to prevent TSS, the risk of complications from antibiotic use is of greater consequence., Level of Evidence: 3a.

Background: Preoperative steroid use has been associated with worse surgical outcomes. The purpose of this study was to determine whether laparoscopic surgery reduces the risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use., Methods: Patients with ulcerative colitis undergoing a total abdominal colectomy were identified from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database (2005-2019). Patients were stratified based on preoperative chronic steroid use and operative approach (open versus laparoscopic). The primary outcome was septic shock/sepsis. Multivariable regression models were used to assess the association between laparoscopic surgery and rates of septic shock/sepsis among steroid users and non-steroid users in both the elective and emergent settings., Results: Among 8,644 patients undergoing a total abdominal colectomy, 67.1% were steroid users and 32.9% were non-steroid users. Compared with an open approach, elective laparoscopic surgery was associated with lower rates of septic shock/sepsis, albeit with higher readmission rates for both steroid users (15.1% [laparoscopic] vs 12.0% [open], P = .005) and non-steroid users (12.6% [laparoscopic] vs 9.4% [open], P = .019). On adjusted analysis, ulcerative colitis patients with chronic steroid use undergoing an elective laparoscopic total abdominal colectomy demonstrated a reduced risk of septic shock/sepsis compared to open surgery (odds ratio 0.61, 95% confidence interval 0.49-0.76, P < .001). Similar findings were seen among chronic steroid users undergoing emergent laparoscopic procedures (odds ratio 0.54, 95% confidence interval 0.31-0.95, P = .031)., Conclusion: Laparoscopic surgery was associated with a reduced risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use, suggesting that minimally invasive surgery may be a promising option among this unique patient population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Short chain fatty acids readily crosses the gut-blood and blood-brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Stevioside, a diterpenoid glycoside, is widely used as a natural sweetener; meanwhile, it has been proven to possess various pharmacological properties as well. However, until now there were no comprehensive evaluations focused on the anti-inflammatory activity of stevioside. Thus, the anti-inflammatory activities of stevioside, both in macrophages (RAW 264.7 cells, THP-1 cells, and mouse peritoneal macrophages) and in mice, were extensively investigated for the potential application of stevioside as a novel anti-inflammatory agent. The results showed that stevioside was capable of down-regulating lipopolysaccharide (LPS)-induced expression and production of pro-inflammatory cytokines and mediators in macrophages from different sources, such as IL-6, TNF-α, IL-1β, iNOS/NO, COX2, and HMGB1, whereas it up-regulated the anti-inflammatory cytokines IL-10 and TGF-β1. Further investigation showed that stevioside could activate the AMPK -mediated inhibition of IRF5 and NF-κB pathways. Similarly, in mice with LPS-induced lethal shock, stevioside inhibited release of pro-inflammatory factors, enhanced production of IL-10, and increased the survival rate of mice. More importantly, stevioside was also shown to activate AMPK in the periphery blood mononuclear cells of mice. Together, these results indicated that stevioside could significantly attenuate LPS-induced inflammatory responses both in vitro and in vivo through regulating several signaling pathways. These findings further strengthened the evidence that stevioside may be developed into a therapeutic agent against inflammatory diseases.

Aberrant activation of NLRP3 inflammasome has been implicated in a variety of human inflammatory diseases, but currently, no pharmacological NLRP3 inhibitor has been approved. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and dextran sodium sulfate-induced (DSS-induced) colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis (NASH). Collectively, our study identifies echinatin as a potentially novel inhibitor of NLRP3 inflammasome, and its use may be developed as a therapeutic approach for the treatment of NLRP3-driven diseases.

More than 15 million people have been affected by coronavirus disease 2019 (COVID-19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID-19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin-angiotensin-aldosterone system (RAAS) is focused in COVID-19 and a vicious circle consisting of the Adrenergic system-RAAS-Angiotensin converting enzyme 2 (ACE2)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (which is referred to as the "ARAS loop") is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID-19, and beta-adrenergic blockers are proposed as a potential treatment option. Beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta-adrenergic blockers may decrease the morbidity and mortality in COVID-19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo., (© 2020 Wiley Periodicals LLC.)

Staphylococcal superantigen toxins lead to a devastating cytokine storm resulting in shock and multi-organ failure. We have previously assessed the safety and immunogenicity of a recombinant toxic shock syndrome toxin 1 variant vaccine (rTSST-1v) in clinical trials (NCT02971670 and NCT02340338). The current study assessed neutralizing antibody titers after repeated vaccination with escalating doses of rTSST-1v. At study entry, 23 out of 34 subjects (67.6%) had neutralizing antibody titers inhibiting T cell activation as determined by 3 H-thymidine incorporation at a serum dilution of ≤1:100 with similar figures for inhibition of IL-2 activation (19 of 34 subjects, 55.9%) as assessed by quantitative PCR. After the first vaccination, numbers of subjects with neutralization titers inhibiting T cell activation (61.7% ≥ 1:1000) and inhibiting IL-2 gene induction (88.2% ≥ 1:1000) increased. The immune response was augmented after the second vaccination (inhibiting T cell activation: 78.8% ≥ 1:1000; inhibiting IL-2 induction: 93.9% ≥ 1:1000) corroborated with a third immunization months later in a small subgroup of subjects. Assessment of IFNγ, TNFα and IL-6 inhibition revealed similar results, whereas neutralization titers did not change in placebo participants. Antibody titer studies show that vaccination with rTSST-1v in subjects with no/low neutralizing antibodies can rapidly induce high titer neutralizing antibodies persisting over months.

Objective: Streptococcus pyogenes (Group A Streptococcus; GAS) causes a variety of infections that include life-threatening, severe invasive GAS infections, such as streptococcal toxic shock syndrome (STSS), with > 30% mortality rate, despite effective antibiotics and treatment options. STSS clinical isolates highly express streptolysin O (SLO), a member of a large family of pore-forming toxins called cholesterol-dependent cytolysins (CDCs). SLO is an important toxic factor for GAS and may be an effective therapeutic target for the treatment of STSS. Our aim was to identify a monoclonal antibody (mAb) that reacts with SLO and has therapeutic potential for STSS treatment., Results: We focused on mAbs that had originally been established as neutralizing reagents to perfringolysin O (PFO), another member of the CDC family, as some cross-reactivity with SLO had been reported. Here, we confirmed cross-reactivity of an anti-PFO mAb named HS1 with SLO. In vitro analysis revealed that HS1 mAb sufficiently prevented human neutrophils from being killed by STSS clinical isolates. Furthermore, prophylactic and therapeutic injection of HS1 mAb into C57BL/6 mice significantly improved the survival rate following lethal infection with an STSS clinical isolate. These results highlight the therapeutic potential of HS1 mAb for STSS treatment.

Tofacitinib, a janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Septic arthritis (SA) and sepsis caused by Staphylococcus aureus (S. aureus), for which RA patients are at risk, are infections with high mortality. The aim of this study was to investigate the effect of tofacitinib on S. aureus infections using mouse models. In vitro tofacitinib treated mouse splenocytes were stimulated with S. aureus derived stimuli. Mice pre-treated with tofacitinib were inoculated intravenously with either arthritogenic- or septic doses of S. aureus. Arthritis severity and mortality were compared between groups. Additionally, pre-treated mice were challenged with staphylococcal toxin TSST-1 to induce shock. Tofacitinib inhibited splenocyte proliferation and IFN-γ production in response to TSST-1 and dead S. aureus. In SA, tofacitinib treatment aggravated arthritis with more severe bone erosions. However, in sepsis, treated mice displayed significantly prolonged survival compared to controls. Similarly, in staphylococcal enterotoxin-induced shock tofacitinib pre-treatment, but not late treatment dramatically reduced mortality, which was accompanied by decreased levels of TNF-α and IFN-γ. Our findings show that tofacitinib treatment increase susceptibility of SA in mice, but has a positive effect on survival in S. aureus-induced sepsis and a strong protective effect in toxin-induced shock.

Objective: To assess the effects of a single dose of vitamin D on 25-hydroxyvitamin D (25OHD) levels and clinical outcomes in children with vitamin D deficiency (VDD) and sepsis., Methods: In this randomized, controlled trial, eligible children with VDD and sepsis were assigned to receive one dose of 150,000 IU of cholecalciferol or placebo. Serum concentrations of 25OHD, angiotensin-II (Ang-II), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed at baseline and 8 days after treatment. The cardiovascular Sequential Organ Failure Assessment (cv-SOFA) score, septic shock incidence, duration of ventilation, and mortality were also examined., Results: One hundred nine participants fulfilled the study requirements. The two groups had comparable baseline characteristics. Ang-II, IL-6, and TNF-α concentrations were all reduced after vitamin D supplementation. Furthermore, the cv-SOFA score (1.76 ± 0.8 vs. 2.3 ± 1.1) and incidence of septic shock (7% vs. 20%) were lower in the treatment group than in the control group. The duration of ventilation and mortality rates did not differ between two groups., Conclusions: A single dose of vitamin D improved 25OHD levels and the incidence of septic shock in children with VDD and sepsis.

Aim: Melatonin is an indolamine secreted by the pineal gland, as well as most of the organs and tissues. In addition to regulating circadian biology, studies have confirmed the multiple pharmacological effects of melatonin. Melatonin provides a strong defense against septic myocardial injury. However, the underlying mechanism has not been fully described. In this study, we investigated the protective effects of melatonin against lipopolysaccharide (LPS)-induced myocardial injury as well as the mechanisms involved. Methods: Mice were intraperitoneally injected with LPS to induce a septic myocardial injury model or an LPS shock model, depending on the dose of LPS. Melatonin was given (20 mg/kg/day, via intraperitoneal injection) for a week prior to LPS insult. 6 h after LPS injection, echocardiographic analysis, TUNEL staining, transmission electron microscopy (TEM), western blot, quantitative real-time PCR and ELISA were used to investigate the protective effects of melatonin against LPS induced myocardial injury. AMPK inhibitor, autophagy activator and inhibitor, siRNAs were used for further validation. Results: Survival test showed that melatonin significantly increased the survival rate after LPS-induced shock. In the sepsis model, melatonin markedly ameliorated myocardial dysfunction, decreased the release of inflammatory cytokines, activated AMP-activated protein kinase (AMPK), improved mitochondrial function, and activated autophagy. To confirm whether the protection of melatonin was mediated by AMPK and autophagy, Compound C, an AMPK inhibitor; 3-MA, an autophagy inhibitor; and Rapamycin (Rapa), an autophagy activator, were used in this study. AMPK inhibition down-regulated autophagy, abolished protection of melatonin, as indicated by significantly decreased cardiac function, increased inflammation and damaged mitochondrial function. Furthermore, autophagy inhibition by 3-MA significantly impaired the protective effects of melatonin, whereas autophagy activation by Rapa reversed LPS + Compound C induced myocardial injury. In addition, in vitro studies further confirmed the protection of melatonin against LPS-induced myocardial injury and the mechanisms involving AMPK-mediated autophagy signaling. Conclusions: In summary, our results demonstrated that melatonin protects against LPS-induced septic myocardial injury by activating AMPK mediated autophagy pathway., (Copyright © 2020 Di, Wang, Hu, Yan, Ma, Li, Li and Gao.)

Purpose: Identification of patients for epidemiologic research through administrative coding has important limitations. We investigated the feasibility of a search based on natural language processing (NLP) on the text sections of electronic health records for identification of patients with septic shock., Materials and Methods: Results of an explicit search strategy (using explicit concept retrieval) and a combined search strategy (using both explicit and implicit concept retrieval) were compared to hospital ICD-9 based administrative coding and to our department's own prospectively compiled infection database., Results: Of 8911 patients admitted to the medical or surgical ICU, 1023 (11.5%) suffered from septic shock according to the combined search strategy. This was significantly more than those identified by the explicit strategy (518, 5.8%), by hospital administrative coding (549, 5.8%) or by our own prospectively compiled database (609, 6.8%) (p < .001). Sensitivity and specificity of the automated combined search strategy were 72.7% (95%CI 69.0%-76.2%) and 93.0% (95%CI 92.4%-93.6%), compared to 56.0% (95%CI 52.0%-60.0%) and 97.5% (95%CI 97.1%-97.8%) for hospital administrative coding., Conclusions: An automated search strategy based on a combination of explicit and implicit concept retrieval is feasible to screen electronic health records for septic shock and outperforms an administrative coding based explicit approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ellipticine, a natural product from Ochrosia elliptica, has been broadly investigated for its anticancer effects. Although inflammation has been clearly identified as a key factor in the onset and progression of cancer, the relationship between ellipticine and inflammation remains unknown. Hence, the aims of the present study were to assess the effects of ellipticine on the inflammatory responses to lipopolysaccharide (LPS)-induced macrophages and to potentially identify the underlying mechanisms involved. Viability testing showed that ellipticine was not significantly toxic to Raw264.7 cells and actually conveyed protective effects to LPS-stimulated Raw264.7 cells and human peripheral blood monocytes by decreasing the secretion of inflammatory factors (TNF-α and IL-6). The results of western blot analysis and electrophoretic mobility shift assays showed that ellipticine markedly suppressed LPS-induced activation of the JNK/AP-1 (c-Fos and c-Jun) signaling pathway, but not ERK/p38/NF-κB pathway (p65 and p50) activation. Furthermore, ellipticine reduced the inflammatory response and mortality in a mouse model of LPS-induced endotoxic shock. Collectively, these data indicate that ellipticine may be a potential therapeutic agent for the treatment of inflammation-associated diseases.

Fraxin, the effective component isolated from Cortex Fraxini, has been reported to have anti-inflammation effects. The aim of this study was to explore the effect of fraxin on lipopolysaccharide (LPS)-induced endotoxic shock in mice. We used Kunming male mice to establish the model, and we found that fraxin could improve the survival rate of the LPS-induced mice. Histopathological study showed that fraxin could mitigate the injuries in LPS-induced lung and liver tissues. The levels of tumour necrosis factor-α and interleukin-6 both in serum and lung, liver tissues, and the productions of nitric oxide (NO), aspartate transaminase and alanine transaminase in serum were decreased by fraxin. Western blot assay demonstrated that the pretreatment with fraxin could downregulate LPS-induced protein expressions of nuclear factor-kappa B (NF-κB) and NLRP3 inflammatory corpuscle signalling pathways. Overall, fraxin had protective effects on LPS-induced endotoxic shock mice and the possible mechanisms might activate through NF-κB and NLRP3 inflammatory corpuscle signalling pathways., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

Background: Colchicine binds to intracellular tubulin and prevents mitosis. Colchicine is also used as an anti-inflammatory drug. Meanwhile, excess administration of medication or accidental ingestion of colchicine-containing plants can cause acute colchicine poisoning, which initially results in gastrointestinal effects that may be followed by multiorgan dysfunction. However, the mechanism of colchicine poisoning remains unclear, and there are no standard therapeutic strategies., Aims: We focused on intestinal barrier function and attempted to reveal the underlying mechanism of colchicine poisoning using an animal model., Methods: Colchicine was orally administered to C57Bl/6 mice. Then, we performed histopathological analysis, serum endotoxin assays, and intestinal permeability testing. Additionally, the LPS-TLR4 signaling inhibitor TAK-242 was intraperitoneally injected after colchicine administration to analyze the therapeutic effect., Results: We observed villus height reduction and increased numbers of apoptotic cells in the gastrointestinal epithelium of colchicine-treated mice. Both intestinal permeability and serum endotoxin levels were higher in colchicine-treated mice than in control mice. Although colchicine-poisoned mice died within 25 h, those that also received TAK-242 treatment survived for more than 48 h., Conclusion: Colchicine disrupted intestinal barrier function and caused endotoxin shock. Therapeutic inhibition of LPS-TLR4 signaling might be beneficial for treating acute colchicine poisoning.

Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1β by proteolytic cleavage via caspase-1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome-dependent immune responses remain poorly defined. Here, we show that the thiol-specific peroxidase peroxiredoxin-4 (Prdx4) directly regulates IL-1β generation by interfering with caspase-1 activity. We demonstrate that caspase-1 and Prdx4 form a redox-sensitive regulatory complex via caspase-1 cysteine 397 that leads to caspase-1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS-induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4-ΔLysMCre). Strikingly, we demonstrate that Prdx4 co-localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome-activated macrophages. Purified EVs are able to transmit a robust IL-1β-dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro-inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell-to-cell communication function of inflammasomes via macrophage-derived EVs., (© 2019 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Staphylococcal enterotoxin B (SEB) and related superantigenic toxins produced by Staphylococcus aureus are potent activators of the immune system. These protein toxins bind to major histocompatibility complex (MHC) class II molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the activation of both monocytes/macrophages and T lymphocytes. The bridging of TCRs with MHC class II molecules by superantigens triggers an early "cytokine storm" and massive polyclonal T-cell proliferation. Proinflammatory cytokines, tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 elicit fever, inflammation, multiple organ injury, hypotension, and lethal shock. Upon MHC/TCR ligation, superantigens induce signaling pathways, including mitogen-activated protein kinase cascades and cytokine receptor signaling, which results in NFκB activation and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. In addition, gene profiling studies have revealed the essential roles of innate antimicrobial defense genes in the pathogenesis of SEB. The genes expressed in a murine model of SEB-induced shock include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, endoplasmic reticulum/mitochondrial stress responses, immunoproteasome components, and IFN-stimulated genes. This review focuses on the signaling pathways induced by superantigens that lead to the activation of inflammation and damage response genes. The induction of these damage response genes provides evidence that SEB induces danger signals in host cells, resulting in multiorgan injury and toxic shock. Therapeutics targeting both host inflammatory and cell death pathways can potentially mitigate the toxic effects of staphylococcal superantigens.

In April 2018, the Surviving Sepsis Campaign (SSC) released an updated sepsis bundle, which combines directives previously listed in the three-hour and six-hour bundles. The authors discussed the reasoning and evidence supporting these changes. However, there are data that suggest these recommendations may be contrary to the best available evidence. Our purpose here is to highlight the areas where evidence is only as strong as the methodological constructs of the research used. This article is a narrative review of the available, limited evidence on which the one-hour bundle was based., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Preterm infants have increased risk of neonatal sepsis, potentially inducing brain injury, and they may benefit from early initiation of enteral milk feeding. Using preterm pigs as models, we hypothesized that early provision of bovine colostrum to parentally nourished newborns protects against sepsis and neuroinflammation during bloodstream infection. Preterm newborn pigs were administered 10 CFU/kg of intra-arterial Staphylococcus epidermidis (SE, an opportunistic pathogen often causing sepsis in preterm infants), followed by administration of total parenteral nutrition (TPN, SE + TPN, n = 15) or oral provision of bovine colostrum with supplementary parenteral nutrition (SE + COL, n = 14), and compared with uninfected, TPN-nourished controls (CON + TPN, n = 11). SE-infected animals showed multiple signs of sepsis, including lethargy, hypotension, respiratory acidosis, internal organ hemorrhages, cellular responses (leukopenia, thrombocytopenia), brain barrier disruption, and neuroinflammation. At 24 h, colostrum supplementation reduced the SE abundance in blood and cerebrospinal fluid (CSF, both P < 0.05). Furthermore, colostrum feeding normalized arterial blood pressure (38.5 ± 1.20 vs. 30.6 ± 3.79 mmHg), pH (7.37 ± 0.02 vs. 7.10 ± 0.07), and lactate (1.01 ± 0.11 vs. 4.20 ± 1.20 mM, all P < 0.05), and increased motor activity, to levels in controls (P < 0.001). Finally, colostrum-fed animals showed reduced blood-CSF barrier permeability and CSF leukocyte levels, and this was accompanied by normalized gene expression of tight junction proteins (Occludin, Claudin-5, both P < 0.05) and reduced expression of leukocyte chemoattractants (CXCL9-11, all P < 0.01). Early oral supplementation with bovine colostrum prevents septic shock and ameliorates brain barrier disruption and neuroinflammation during bloodstream infection in preterm pigs. Bovine colostrum supplementation may improve resistance against systemic infection in immature, immune-compromised preterm infants.

Background: Streptococcus suis is an encapsulated zoonotic pathogen. Increasing antimicrobial resistance invokes the need for effective vaccines. Despite many attempts to develop an effective vaccine, none is currently available., Methods: A capsular polysaccharide (CPS)-expressing attenuated mutant 2015033 was constructed by deleting 5 virulence-associated factors (sly, scpA, ssnA, fhb, and ssads) in an infective S. suis strain SC19. The safety and immune effect of 2015033 were determined both in vitro and in vivo., Results: Deletion of 5 genes did not impact the growth ability and CPS generation of 2015033, and the mutant exhibited no cytotoxicity in different cell models. 2015033 was more easily eliminated by innate immunity both in vitro and in vivo. In addition, 2015033 showed a diminished invasive ability in different mouse organs (brain, lung, and liver) and avirulent properties in mice associated with weak inflammation-inducing ability. Immunization with 2015033 triggered T cell-dependent immunity, suppressed streptococcal toxic shock-like syndrome, and conferred sequence type-independent protection to mice during infection., Conclusions: This study presents the feasibility of the strategy of multigene deletion for the development of promising live vaccines against invasive encapsulated pathogens.

Background/purpose: While the use of oral antibiotic (OA) for bowel preparation is gaining popularity, it is unknown whether it increases the risk of Clostridium difficile infection (CDI). This study aimed to evaluate the impact of OA on the development of CDI after colectomy., Methods: Patients who underwent colectomy from the ACS-NSQIP data (2015 and 2016) were included. Patients who received OA as bowel preparation were compared to those who did not with respect to demographics, comorbidities, primary diagnosis, procedure type and approach, and 30-day postoperative complications. Multivariable analysis was performed to characterize the association between OA and CD infection after colectomy. A sub-group analysis was also conducted for patients who did not develop any postoperative infectious complication., Results: Of 36,374 included patients, 18,177 (50%) received OA and 527 (1.4%) developed CDI for the whole cohort. OA group had more younger, functionally independent and obese patients with lower American Society of Anesthesiologists and wound class. Smoking, diabetes, hypertension, dyspnea or ventilator-dependence, congestive heart failure, disseminated cancer, bleeding disorder, and perioperative transfusion were significantly higher for non-OA group. Mechanical bowel preparation, minimally invasive surgery, conversion to open and operative duration ≥ 180 min were more prevalent in the OA group. The OA group had significantly reduced occurrence of CDI; superficial, deep, and organ space infections; wound disruption; anastomotic leak; reoperation; and infections including sepsis, septic shock, pneumonia, and urinary tract infection. On multivariable analysis, OA reduced the odds for CDI after colectomy (OR = 0.6, 95% CI = [0.5-0.8]). For patients who did not develop infectious postoperative complications, OA was associated with lower risk of CDI (OR = 0.7, CI = [0.5-0.9]). While complications, reoperation, and readmission rates were the same, postoperative ileus and hospital stay were significantly lower for those who developed CDI after receiving OA when compared to non-OA., Conclusion: The use of OA as bowel preparation may reduce, rather than increase, the risk of 30-day CDI after colectomy. This effect may partly be due to the other recovery advantages associated with oral antibiotics. These data further support current data recommending the use of oral antibiotics for bowel preparation before colectomy.

Sepsis, a systemic inflammatory response caused by infection or injury, is still one of the most important causes of death in clinical patients. The ongoing search for the pathogenesis of sepsis and novel therapeutic methods are highly urgent. In this study, we hypothesized that KPT330, a potent and specific small molecule inhibitor of CRM1, could reduce inflammation and attenuate the severity of sepsis. In LPS-induced sepsis model in vivo, administration of KPT330 increased survival rate and ameliorated LPS-induced lung injury, with suppressed levels of TNF-α, IL-6 and HMGB1 in the circulation and decreased macrophage and PMN subpopulations in peritoneal cavity. In vitro investigations showed that KPT330 dose-dependently inhibited LPS-triggered proinflammatory cytokines production including TNF-α, IL-6 and HMGB1 in macrophages. Furthermore, KPT330 treatment significantly suppressed TNF-α and IL-6 mRNA expression and inhibited HMGB1 necleocytoplasmic translocation by inhibiting CRM1 distribution. Moreover, the mechanism analysis demonstrated that KPT330 exerted anti-inflammation effects by inhibiting the production of pro-inflammatory cytokines through suppressing activation of NF-κB and p38 signaling. Thus, pharmacologic stimulation of KPT330 may present a promising therapeutic strategy for sepsis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock., Design: A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations., Methods: Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science., Results: The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction?, Conclusions: While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.

Background: Mosquitoes are armed with physiologically active compounds to suppress the host immunity including host inflammatory reaction. However, the specific anti-inflammatory components in mosquitoes remain unknown., Results: By searching for the immunomodulatory molecules from the mosquito Aedes aegypti (Diptera: Culicidae) at NCBI for anti-inflammatory function, five cecropins (for short in this study: AeaeCec1, 2, 3, 4 and 5) were selected. AeaeCec1-5 efficiently inhibited the expression of inducible nitric oxide synthase (iNOS), nitrite, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages and human peripheral blood mononuclear cells (PBMCs) with low toxicity to mammalian cells. Among the five analogues, AeaeCec5 had the strongest anti-inflammatory activity, and generated an additive effect with other AeaeCec peptides. In a mouse model of endotoxin shock, AeaeCec1-5 effectively reduced TNF-α, IL-1β and IL-6 expression in lungs, serum and peritoneal lavage and correspondingly reduced lung damage and edema, with AeaeCec5 showing the best protection. In mice infected with Escherichia coli or Pseudomonas aeruginosa, administration of AeaeCec5 reduced the production of TNF-α, IL-1β and IL-6 and correspondingly reduced lung tissue damage. These effects of Ae. aegypti AeaeCec1-5 were attributed to an efficient inhibition of the activation of mitogen-activated protein kinases (MAPKs) and transcriptional nuclear factor-κB (NF-κB) signaling pathways, as well as partial neutralization of LPS., Conclusions: The current work characterized the specific anti-inflammatory agents in Ae. aegypti and provided AeaeCec5 as a potent anti-endotoxin peptide that could serve as the basis for the development of anti-inflammatory therapy.

Purpose: Low-dose steroids may reduce the mortality of severely ill patients with septic shock. We sought to determine whether exposure to stress-dose steroids during and/or after cardiopulmonary resuscitation is associated with reduced risk of death due to postresuscitation septic shock., Methods: We analyzed pooled, individual patient data from two prior, randomized clinical trials (RCTs). RCTs evaluated vasopressin, steroids, and epinephrine (VSE) during resuscitation and stress-dose steroids after resuscitation in vasopressor-requiring, in-hospital cardiac arrest. In the second RCT, 15 control group patients received open-label, stress-dose steroids. Patients with postresuscitation shock were assigned to a Steroids (n = 118) or No Steroids (n = 73) group according to an "as-treated" principle. We used cumulative incidence competing risks Cox regression to determine cause-specific hazard ratios (CSHRs) for pre-specified predictors of lethal septic shock (primary outcome). In sensitivity analyses, data were analyzed according to the intention-to-treat (ITT) principle (VSE group, n = 103; control group, n = 88)., Results: Lethal septic shock was less likely in Steroids versus No Steroids group, CSHR, 0.40, 95% confidence interval (CI), 0.20-0.82; p = 0.012. ITT analysis yielded similar results: VSE versus Control, CSHR, 0.44, 95% CI, 0.23-0.87; p = 0.019. Adjustment for significant, between-group baseline differences in composite cardiac arrest causes such as "hypotension and/or myocardial ischemia" did not appreciably affect the aforementioned CSHRs., Conclusions: In this reanalysis, exposure to stress-dose steroids (primarily in the context of a combined VSE intervention) was associated with lower risk of postresuscitation lethal septic shock.

Fifteen currently marketed intravaginal protection products (11 types of tampon and 4 types of menstrual cup) were tested by the modified tampon sac method to determine their effect on Staphylococcus aureus growth and toxic shock syndrome toxin 1 (TSST-1) production. Most tampons reduced S. aureus growth and TSST-1 production, with differences based on brand and composition, and the level of S. aureus growth was higher in destructured than in unaltered tampons. We observed higher levels of S. aureus growth and toxin production in menstrual cups than in tampons, potentially due to the additional air introduced into the bag by cups, with differences based on cup composition and size. IMPORTANCE Menstrual toxic shock syndrome is a rare but severe disease. It occurs in healthy women vaginally colonized by Staphylococcus aureus producing toxic shock syndrome toxin 1 using intravaginal protection, such as tampons or menstrual cups. Intravaginal protection induces TSS by the collection of catamenial products, which act as a growth medium for S. aureus Previous studies evaluated the impact of tampon composition on S. aureus producing toxic shock syndrome toxin 1, but they are not recent and did not include menstrual cups. This study demonstrates that highly reproducible results for S. aureus growth and TSST-1 production can be obtained by using a simple protocol that reproduces the physiological conditions of tampon and cup usage as closely as possible, providing recommendations for tampon or cup use to both manufacturers and consumers. Notably, our results do not show that menstrual cups are safer than tampons and suggest that they require similar precautions., (Copyright © 2018 American Society for Microbiology.)

Objective: To investigate the protective effect of intermedin1-53 (IMD1-53) on cardiac function in rats with septic shock and its underlying mechanism., Materials and Methods: Twenty-four male Sprague-Dawley (SD) rats were randomly assigned into three groups, namely the control group (NC group), septic shock group (ET group) and IMD1-53 treatment group (IMD group), with 8 rats in each group. Levels of hemodynamic indicators, blood glucose, lactate acid, CK-MB (creatine kinase-MB) and cTnI (cardiac troponin I) in rats were determined. Cardiac tissues of rats were collected for TUNEL (terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling) staining. Protein levels of caspase-3, caspase-9, Bax, Bcl2, iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) in cardiac tissues were detected by Western blot. Moreover, activities of SOD (superoxide dismutase), CAT (catalase) and MDA (malondialdehyde) in myocardial homogenate were determined, thereby exploring the effect of IMD1-53 on oxidative stress and cardiomyocyte apoptosis in rats with septic shock induced by endotoxin., Results: Lower levels of mean arterial blood pressure (MABP), maximum rate of left ventricular diastolic pressure (+LVdp/dtmax) and left ventricular systolic pressure (LVSP) were observed in ET group than those of NC group (p < 0.05). Levels of lactic acid, blood glucose, CK-MB and cTnI in ET group were remarkably increased than those of NC group (p < 0.05). Moreover, activities of SOD and CAT in myocardial homogenate of ET group were remarkably reduced in comparison with those of NC group (p < 0.05). Protein levels of caspase-3, caspase-9, Bcl-2, Bax, iNOS and COX-2 in ET group were all remarkably elevated than those of NC group (p < 0.05). The above indicators were all significantly improved in IMD group than those of ET group (p < 0 05)., Conclusions: IMD1-53 can protect cardiac function in rats with septic shock via inhibiting oxidative stress and cardiomyocyte apoptosis.

Coffee roasting affects the taste, color, and aroma of coffee. The Maillard reaction, a major reaction during the roasting process, produces melanoidin, which affects the overall antioxidant capacity and anti-inflammatory effects of coffee. In this experiment, coffee roasting was divided into four degrees: Light, Medium, City, and French. To examine the in vivo antioxidant and anti-inflammatory effects of coffee extracts with different roasting degrees, we used 10-week-old male C57BL/6 mice. Mice were pre-treated with coffee extracts for 10 days by oral gavage (300 mg/Kg.B.W). After the last pre-treatment, lipopolysaccharide (LPS, 15 mg/Kg.B.W) was injected intraperitoneally for immune stimulation. Histopathological analysis showed that hepatic portal vein invasion and liver necrosis were severe in the LPS-treated group. However, these phenomena were greatly ameliorated when mice were pre-treated with Light- or Medium-roasted coffee extracts. Hepatic glutathione level was increased in the French group but decreased in the LPS-stimulated group. When mice were treated with LPS, mRNA expression level of tumor necrosis factor-alpha (TNF-α) was increased, whereas TNF-α expression was significantly reduced in the Light and Medium groups. Treatment with coffee extracts decreased the mRNA expression levels of interleukin 6 (IL-6) in mice stimulated by LPS, regardless of coffee roasting degrees. These effects decreased with the increasing coffee roasting degree. Results of luciferase reporter assay revealed that these effects of coffee extracts were transcriptionally regulated by the NF-κB pathway. Taken together, these results suggest that the roasting degree affects the antioxidant and anti-inflammatory effects of coffee extracts., Competing Interests: There are no conflicts of interest in this research.

Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non-canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non-canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis.

Superantigens (SAgs) are extremely potent bacterial toxins, which evoke a virulent immune response, inducing nonspecific T-cell proliferation, rapid cytokine release, and lethal toxic shock, for which there is no effective treatment. We previously developed a small molecule, S101, which potently inhibits proliferating T cells. In a severe mouse model of toxic shock, a single injection of S101 given together with superantigen challenge rescued 100% of the mice. Even when given 2 hours after challenge, S101 rescued 40% of the mice. S101 targets the T-cell receptor, inflammatory response, and actin cytoskeleton pathways. S101 inhibits the aryl hydrocarbon receptor, a ligand-activated transcription factor that is involved in the differentiation of T-helper cells, especially Th17, and regulatory T cells. Our results provide the rationale for developing S101 to treat superantigen-induced toxic shock and other pathologies characterized by T-cell activation and proliferation., (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Pectin, a water-soluble dietary fiber, has been found to improve survival in endotoxin shock. However, the underlying mechanism by which pectin exerts its protective effect against endotoxin shock remains unknown. Apart from its prebiotic effects, it has been suggested that pectin directly affects immune cells to regulate inflammatory responses. In this study, we investigated the direct effect of pectin in murine model of endotoxin shock. Citrus pectin solution was administered to male C57BL/6 mice for 10 days. Thereafter, hypothermia was induced in the mice with intraperitoneal injection of lipopolysaccharide (LPS). The pectin-treated mice showed attenuation of both the decrease in rectal temperature and increase in serum IL-6 level as compared to vehicle control mice. Simultaneously, the pectin-treated mice showed reduced levels of inflammatory cytokine mRNA in Peyer's patches and mesenteric lymph nodes, but not in the spleen. Peyer's patch cells from the pectin-treated mice were sorted and their levels of IL-6 production on LPS stimulation were measured. The results of ex vivo analysis indicated that IL-6 secretion from CD11c + cells was suppressed by oral administration of pectin. Furthermore, IL-6 secretion from Toll-like receptor (TLR)-activated RAW264.7 cells was suppressed by pretreatment with pectin in vitro. This suppression was observed even with degraded pectin pretreatment but not with polygalacturonic acid, as the principal constituent of the pectin backbone. Taken together, these results suggest that pectin intake suppresses TLR-induced inflammatory cytokine expression in Peyer's patch myeloid cells, presumably through inhibition of TLR signaling by the pectin side chains., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Despite of proven LPS neutralizing activity, intravenous polymyxin use was waned due to experience of associated nephrotoxicity. But, increasing resistance to all available antibiotics has necessitated their resurgence and the prodrug of colistin sulfate (CS), known as colistin-methanesulfonate (CMS), is increasingly used as the only therapeutic option in many infections. Currently available CMS employ very different dose definitions and thus because of complex pharmacokinetics/pharmacodynamics information and short half-life, this drug use remains confusing. We aimed to expose CS in endotoxic shock models by micro-osmotic pump and evaluated its effectiveness., Methods: We used micro-osmotic pumps to deliver either sterile saline or CS at different dosages ranging from 0.25mg/day to 7mg/day for consecutive 3days in LPS (8mg/kg body weight) induced endotoxic mice and observed their outcome twice daily for a week to determine the survival rate. Serum pro-inflammatory cytokine levels and apoptosis in renal tissues in these models were evaluated., Results: We showed endotoxic shock was reversed and all mice survived with a CS administration at a dosage of 2mg/day for 3 days, in comparison to survival rate with saline administration (p≤0.0001) in endotoxic models. CS infusion in shock models using micro-osmotic pump ameliorated rising of serum TNF-α, IL-12p70 and IL-6 levels. Nephrotoxicity was evident only with a higher dosage, but not with a lower dosage which was optimum to control endotoxic shock in models., Conclusions: These results highlighted that an optimal dosage of CS effectively improved outcome in endotoxic shock models without causing nephrotoxicity when administered at a slow and sustained manner. And a higher CS dosage administration was nephrotoxic and fatal. Thus this study bought an opportunity to consider future investigations with CS administration in murine Gram-negative bacterial infections in a novel way., (Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with severe pneumonia often develop septic shock. IgM-enriched immunoglobulins have been proposed as a potential adjuvant therapy for septic shock. While in vitro data are available on the possible mechanisms of action of IgM-enriched immunoglobulins, the results of the in vivo experimental studies are non-univocal and, overall, unconvincing. We designed this double blinded randomized controlled study to test whether IgM-enriched immunoglobulins administered as rescue treatment in a pneumonia model developing shock, could either limit lung damage and/or contain systemic inflammatory response., Methods: Thirty-eight Sprague Dawley rats were ventilated with injurious ventilation for 30min to prime the lung. The rats were subsequently randomized to received intratracheal instillation of either lipopolysaccharide (LPS) (12mg/kg) or placebo followed by 3.5h of protective mechanical ventilation. IgM-enriched immunoglobulins at 25mg/h (0.5mL/h) or saline were intravenously administered in the last hour of mechanical ventilation. During the experiment, gas exchange and hemodynamic measurements were recorded. Thereafter, the animals were sacrificed, and blood and organs were stored for cytokines measurements., Results: Despite similar lung and hemodynamic findings, the administration of IgM-enriched immunoglobulins compared to placebo significantly modulates the inflammatory response by increasing IL-10 levels in the bloodstream and by decreasing TNF-α in bronchoalveolar lavage (BAL) fluid. Furthermore, in vitro data suggest that IgM-enriched immunoglobulins induce monocytes production of IL-10 after LPS stimulation., Conclusions: In an in vivo model of pneumonia developing shock, IgM-enriched immunoglobulins administered as rescue treatment enhance the anti-inflammatory response by increasing blood levels of IL-10 and reducing TNF-α in BAL fluid., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Objective: To review studies of systemic antibiotic prophylaxis in burn patients., Methods: Electronic databases were searched for human clinical trials performed between 1966 and 2016 that compared prophylactic systemic antibiotics with placebo or no intervention., Results: Nineteen trials met the selection criteria. Early postburn prophylaxis was assessed in non-severe burn patients (six trials) and severe burn patients (seven trials). Antimicrobial prophylaxis showed no effectiveness for the prevention of toxic shock syndrome or burn wound infection (Grade 1C), but could be useful in patients with severe burns and requirement for mechanical ventilation (Grade 2B). Perioperative prophylaxis was assessed in six trials. Antimicrobial prophylaxis during resection of devitalized tissue is of no benefit in most burn patients (Grade 2B); however, there is insufficient evidence to make a recommendation for patients with extensive burns. Antibiotic prophylaxis may also be effective in preventing split-thickness skin graft infections in selected procedures (Grade 2B)., Conclusions: The available evidence does not support the role of systemic antibiotic prophylaxis in the management of the majority of burn patients. Nevertheless, it may be useful in patients with severe burns who require mechanical ventilation, and in selected split-thickness skin grafting procedures., (Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Dual-specificity phosphatase 3 (DUSP3) is a small phosphatase with poorly known physiological functions and for which only a few substrates are known. Using knockout mice, we recently reported that DUSP3 deficiency confers resistance to endotoxin- and polymicrobial-induced septic shock. We showed that this protection was macrophage dependent. In this study, we further investigated the role of DUSP3 in sepsis tolerance and showed that the resistance is sex dependent. Using adoptive-transfer experiments and ovariectomized mice, we highlighted the role of female sex hormones in the phenotype. Indeed, in ovariectomized females and in male mice, the dominance of M2-like macrophages observed in DUSP3 -/- female mice was reduced, suggesting a role for this cell subset in sepsis tolerance. At the molecular level, DUSP3 deletion was associated with estrogen-dependent decreased phosphorylation of ERK1/2 and Akt in peritoneal macrophages stimulated ex vivo by LPS. Our results demonstrate that estrogens may modulate M2-like responses during endotoxemia in a DUSP3-dependent manner., (Copyright © 2017 by The American Association of Immunologists, Inc.)

: Editor's note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives highlights articles selected to fit today's topics and times.This month's article, from the September 1908 issue, describes the nursing management of shock and hemorrhage. Hospital nurses are instructed to employ measures that today would be described as prehospital first aid. The author (a "Graduate of Bellevue Hospital, New York") directs the nurse to "work quickly and quietly, dismiss every one from the room who cannot be of intelligent assistance, and… in no way impart to the patient the serious nature of his or her condition." More than a century later, nursing interventions for shock are considerably more intense and complex, as illustrated in the feature article in this issue, "Assessing Patients During Septic Shock Resuscitation."

: In 2015, the Surviving Sepsis Campaign six-hour bundle was updated. The revised version now recommends documenting the reassessment of volume status and tissue perfusion after initial fluid resuscitation through a repeated focused examination. This article addresses the practice and interpretation of two components of this examination in adults: capillary refill time and skin mottling score. It further discusses how to best integrate these noninvasive parameters into the care of patients undergoing resuscitation for septic shock.

Purpose: The World Health Organization (WHO) has developed a simplified algorithm specific to resource-limited settings for the treatment of severe sepsis emphasizing early fluids and antibiotics. However, this protocol's clinical effectiveness is unknown. We describe patient outcomes before and after implementation of an adapted WHO severe sepsis protocol at a community hospital in Haiti., Materials and Methods: Using a before-and-after study design, we retrospectively enrolled 99 adult Emergency Department patients with severe sepsis from January through March 2012. After protocol implementation in January 2014, we compared outcomes to 67 patients with severe sepsis retrospectively enrolled from February to April 2014. We defined sepsis according to the WHO's Integrated Management of Adult Illness guidelines and severe sepsis as sepsis plus organ dysfunction., Results: After protocol implementation, quantity of fluid administered increased and the physician's differential diagnoses more often included sepsis. Patients were more likely to have follow-up vital signs taken sooner, a radiograph performed, and a lactic acid tested. There were no improvements in mortality, time to fluids or antimicrobials., Conclusions: Use of a simplified sepsis protocol based primarily on physiologic parameters allows for substantial improvements in process measures in the care of severely septic patients in a resource-constrained setting., (Copyright © 2017 Elsevier Inc. All rights reserved.)