Late-onset sepsis (LOS), which occurs 72 hours after birth, remains an important cause of mortality and morbidity in the neonatal intensive care unit (NICU). Differences in infant populations and the complexity of care at various NICU levels may result in varying bacteriological profiles and antibiotic susceptibility patterns. The objective of the current study was to determine and compare the bacteriological profiles, antibiotic susceptibility, and risk factors for LOS in levels III and IV NICU within a single hospital system. This was a retrospective study of infants with LOS and positive blood cultures, admitted to levels III and IV NICUs between 2012 and 2021. Of the 173 infants included in our study, 105 were admitted to the level IV NICU and 68 to the level III NICU. Infants in the level III NICU had a lower gestational age and birth weight at the time of LOS. Seventy percent of the infants had a central line. Gram-positive organisms were responsible for the vast majority of infections (75%), with coagulase-negative Staphylococcus (CoNS) being the most common bacteria in both units. Gram-negative bacteria were more frequently isolated from the level IV NICU (36.2%) compared to the level III NICU (8.8%). Escherichia coli (E. coli) and Enterobacter sp. were the most frequently isolated gram-negative bacteria. All gram-positive bacteria were susceptible to vancomycin, and all gram-negative bacteria were susceptible to meropenem. The prevalent bacteriological profile and antibiotic susceptibility patterns in the NICU should guide the choice of empiric antibiotics for LOS. It is important to monitor sepsis and antimicrobial resistance patterns in the NICU and implement risk-specific strategies to reduce the burden of LOS. · LOS in NICUs is predominantly caused by gram-positive bacteria, mainly CoNS.. · Higher frequency of gram-negative bacteria, including E. coli and Enterobacter, in level IV NICU.. · All gram-negative isolates were meropenem-sensitive; vancomycin effective for gram-positives..

Adult septic patients with substance abuse disorder (SUD) are at increased risk of poor outcomes, but the impact on adolescents is unknown. We aimed to determine if pre-existing SUD is associated with increased adverse outcomes and critical care resources in critically ill adolescents hospitalized with sepsis. We hypothesize that SUD is associated with increased risk of adverse outcomes and usage of critical care resources in this adolescent patient population.

This was a retrospective cohort study utilizing the TriNetX© electronic health record (EHR) database, which consists of EHR from participating healthcare organizations predominantly in the United States. Critically ill adolescents with sepsis aged 12-21 years were divided into two groups (SUD history and no-SUD history). Data related to demographics, diagnostic, procedural, and medication codes were analyzed. The primary outcomes were organ dysfunction, critical care therapies, and all-cause 1-year mortality.

We included 5,436 critically ill adolescents with sepsis [730 (13.43%) SUD history and 4706 (86.57%) no-SUD history]. SUD history was associated with increased odds of organ dysfunction (adjusted odds ratio [aOR] 1.84; 95% confidence interval [CI] 1.56-2.16; p < 0.001), vasoactive/inotropic drug usage (aOR 1.29; 95% CI 1.10-1.52; p = 0.002), mechanical ventilation (aOR 2.19; 95% CI 1.85-2.59; p < 0.001), but not mortality (aOR 1.03; 95% CI 0.76-1.41; p = 0.83).

Our retrospective analysis suggests history of SUD in critically ill septic adolescent patients is associated with increased utilization of critical care resources and organ dysfunction. Further study is needed to determine if substance abuse represents a potentially modifiable risk factor for critical illness in adolescent patients.

Inflammatory bowel disease (IBD), sepsis, and intestinal tumors are major health threats. This study aimed to explore the regulatory role of CD177+ neutrophils in the BMP signaling pathway and its impact on the onset, progression, and treatment of these diseases.

Gene expression data from the Gene Expression Omnibus (GEO) database for IBD and sepsis were retrieved. Bioinformatics methods like background correction, normalization, and differential expression analysis were used. Weighted gene co-expression network analysis (WGCNA), gene functional enrichment analysis, pan-cancer analysis, single-cell analysis, and in vitro experiments including Caco-2 cell culture, cell proliferation assay (CCK-8), flow cytometry apoptosis analysis, quantitative real-time PCR (qRT-PCR), and plate colony formation assay were performed.

Key genes associated with IBD and sepsis, such as BMP2, BMP4, BMP6, BMP8A, and CD177, were identified. WGCNA in sepsis found two significant modules related to key clinical outcomes. Core gene screening revealed seven shared genes between IBD and sepsis, and enrichment analysis showed involvement in important biological processes and pathways. Pan-cancer analysis showed diverse gene expression patterns and correlations with immune dynamics. Single-cell transcriptomics provided insights into the tumor microenvironment. In vitro experiments demonstrated that CD177 knockdown affected BMP signaling pathway-related gene expression, ROS production, apoptosis, and cell proliferation.

CD177+ neutrophils play a crucial role in regulating the BMP signaling pathway in IBD, sepsis, and intestinal tumors. These findings offer potential therapeutic targets, but further clinical validation is required to translate them into effective treatment strategies.

Gender differences exist in the susceptibility, incidence, progression, and prognosis of bacterial infections in males and females, influenced by various factors including lifestyle and habits. Multiple reports have indicated that estrogen plays a crucial immunomodulatory role in many pathogenic microbial infections, highlighting a complex relationship between estrogen, its receptors, and bacterial infections. Estrogen and its receptors regulate host immune responses, affecting the host's ability to clear bacteria and thus influencing the likelihood and difficulty of infection eradication. Variations in estrogen levels may lead to differences in the occurrence and progression of bacterial infections, with estrogen playing varied roles in diseases caused by the same bacterial pathogens. The interaction between estrogen and bacterial infections represents a complex and crucial aspect of human physiology and clinical medicine. Understanding this interaction is essential for advancing infection prevention and treatment strategies. This article reviews the correlation and mechanisms between estrogen and bacterial infections, emphasizing the importance of further research in this field.

Background: The long-term effects of a perinatal high-fat diet on the cardiovascular function of offspring are not well elucidated. We hypothesize that perinatal exposure to a high-fat diet alters adult cardiovascular and immune responses in a sex-specific manner. Methods: Male and female offspring were born to perinatal high-fat (pHFD) or control diet (pCD)-fed C57BL/6 mothers and weaned to a control diet. Cardiovascular function (baseline and response to an acute isoproterenol stress test) was quantified at 8 weeks of age, and acute blood inflammatory response to a single low dose of lipopolysaccharide at 9 weeks of age. Results: Male pHFD offspring had identical baseline cardiovascular function compared to pCD mice but a blunted response to isoproterenol (20-45% reductions in cardiac output, stroke volume, and left ventricular fractional shortening). In contrast, baseline cardiovascular parameters were reduced in female pHFD compared to pCD offspring, but there was no effect of perinatal diet on response to isoproterenol. Concentrations of TNF-α and IL-6 in plasma two hours after a low-dose LPS administration were highest in female pCD mice. Conclusions: Perinatal high-fat diet exposure resulted in sex-specific adaptations in cardiovascular function and immune response. Female offspring displayed baseline impairments, whereas male offspring showed latent vulnerability under stress. These differences may reflect underlying hormonal or epigenetic mechanisms that diverge by sex. Future studies should examine the roles of sex hormones and gene regulation pathways to better understand these dimorphic outcomes. These findings emphasize the importance of maternal diet in shaping offspring cardiometabolic risks and highlight potential avenues for nutritional interventions during pregnancy.

The aim of this study was to evaluate long-term inflammatory, biochemical and behavioral parameters in adult male and female Wistar rats submitted to a model of high-fat and high fructose diet and sepsis. In the study we used 8-month-old male and female rats. High-fat and high fructose diet was provided for 4 months, and sepsis was induced shortly afterwards. Behavioral tests were performed at 10, 30 and 60 days after sepsis induction, at 30- and 60-days metabolic parameters, leptin and cytokines (prefrontal cortex and hippocampus) were determined. High-fat and high-fructose diet was able to induce glucose intolerance. Sepsis favored anxious behavior at 10 days after sepsis, remaining at 30 days and with apparent improvement at 60 days in females and maintenance of behavior in males. Cognitive damage was observed both at 30 and 60 days in animals from both groups. Plasma metabolic parameters were elevated only males exposed to a high-fat high-fructose diet and submitted to CLP only at 30 days. Long-term brain inflammation was not consistently affected both by sex and high-fat and high fructose diet.The relationship between high-fat and high fructose diet, gender and sepsis is still contradictory, as are the mechanisms involved in this paradox. Models and analyses need to be standardized in order to better understand how this event occurs.

Peptidylarginine deiminase 4 (PAD4) citrullinates histones, enabling the release of neutrophil extracellular traps. While neutrophil extracellular traps capture and kill pathogens, they also drive immunothrombosis, potentially worsening sepsis outcomes. However, it remains unclear whether PAD4 deficiency is beneficial or harmful in sepsis.

To evaluate the impact of PAD4 deficiency in a fecal-induced peritonitis sepsis model, with and without antibiotic treatment, and incorporating fluid resuscitation in both sexes.

Wild-type and PAD4 knockout (PAD4-/-) C57Bl/6 mice received intraperitoneal injections of fecal slurry (0.6 mg/g). Mice received buprenorphine every 8 hours and antibiotics/fluids every 12 hours. Survival studies were also conducted without antibiotics at a reduced fecal dose (0.4 mg/g). Mice were culled at 8 hours or 48 hours after infection. Organs, blood, and peritoneal cavity fluid were collected. Plasma levels of interleukin (IL)-6, IL-10, cell-free DNA, and thrombin-antithrombin were quantified, as well as bacterial loads in blood and peritoneal cavity fluid. Organ histology/immunohistochemistry was performed.

Female PAD4-/- mice had worsened survival compared with female wild-type mice. Male mice exhibited worse survival than females in both strains. Antibiotics eliminated survival differences between strains and sexes. Septic PAD4-/- mice had reduced IL-10 in the early phase of sepsis, increased lung myeloperoxidase, and exacerbated lung injury compared with septic wild-type mice.

PAD4 deficiency in female mice worsened survival in the fecal-induced peritonitis sepsis model. In both strains, male mice exhibited worse survival compared with their female counterparts. PAD4 deficiency is associated with reduced IL-10, increased neutrophil infiltration, and exacerbated lung injury. Antibiotics eliminated survival differences between strains and sexes.

No animal models fully replicate the pathogenesis and clinical features of sepsis-associated disseminated intravascular coagulation (DIC), which hinders mechanistic understanding and treatment development. Kappa-carrageenan (KCG) and lipopolysaccharides (LPS) induce thrombosis and systemic inflammation in mice, respectively. The combination of LPS and KCG provides a promising method for establishing a mouse model of sepsis-associated DIC.

This study aimed to establish a standardized mouse model of sepsis-associated DIC using KCG and LPS.

Kunming (KM) mice were intraperitoneally injected with KCG (25-200 mg/kg) alone or in combination with LPS (50-1250 μg/kg) to determine optimal dose. The effects of ambient temperature, gender and mouse strains on the mouse model were evaluated. Time-dependent changes in the model were examined.

The combined injection of KCG (100 mg/kg) and LPS (50 μg/kg) effectively induced tail thrombosis and prolonged activated partial thromboplastin time. Mice housed at 16 ± 1℃ exhibited more severe thrombosis and hypocoagulability than those at 24 ± 1℃. Male and female mice exhibited similar responses. Time-course analysis revealed inflammation and blood hypocoagulability beginning from 1.5 to 24 h, with fibrinolysis inhibition occurring within 1 h. Tail thrombosis and auricle petechial developed at 3 and 6 h, respectively, and stabilized by 12 h. Thrombi in the tail, lung and liver along with organ dysfunction were obeserved at 12 h. KM and BALB/c mice exhibited longer tail thrombi than Institute of Cancer Research (ICR) mice. KM mice showed more severe blood hypocoagulability than ICR and BALB/c mice.

This study establishes a standardized mouse model of sepsis-associated DIC using KCG and LPS, which more accurately replicates the key clinical and pathological characteristics of sepsis-associated DIC compared to existing models. This model serves as a novelty and valuable tool for investigating the mechanisms of sepsis-associated DIC and therapeutic evaluation.

Sepsis is a severe complication in patients with malignant tumors, leading to high mortality and increased need for intensive care. This study aimed to investigate the clinical characteristics and prognostic factors influencing sepsis outcomes in patients with malignant tumors. We included 4,858 patients with cancer diagnosed with sepsis between September 2019 and February 2020 whose data were collected from the Korean Sepsis Alliance, a nationwide multicenter cohort study. Cox regression analysis was used to identify predictors of 30-day and in-hospital mortality. In total, 65% of the patients survived, whereas 35% did not. Non-survivors were more likely to require intensive care, including mechanical ventilation and continuous renal replacement therapy. Key predictors of mortality included renal dysfunction, higher Sequential Organ Failure Assessment scores, and reliance on life-sustaining treatments. Non-survivors exhibited lower adherence to the implementation of sepsis care bundles, particularly to later-stage interventions. Gram-negative bacterial infections and multidrug resistance were more prevalent in non-survivors, complicating treatment efficacy. In conclusion, tailored treatment strategies that consider specific patient characteristics and disease dynamics are needed in managing sepsis with malignancy. Early identification and treatment of organ dysfunction, coupled with strict adherence to sepsis treatment protocols, are critical to improving survival in this population.

Sepsis is a risk factor for acute kidney injury (AKI) in neonates, for which no effective treatment exists. The phosphodiesterase inhibitor pentoxifylline (PTX) has demonstrated renal protection from ischemia and inflammation in adult rodents. We hypothesized that addition of PTX to antibiotics may attenuate immune and histological AKI in a murine neonatal sepsis model.

Postnatal (PN) day 1 C57BL/6J mice were injected with E. coli K1 strain at 105 colony forming units per gram weight or saline control. After 1.5 hours, septic pups randomly received saline, gentamicin or cefotaxime, with/without PTX. 5.5h after sepsis initiation, kidneys and blood were harvested for measurements of biomarkers of inflammation and kidney injury. Renal sections from PN7 mice were used for histology and immunofluorescence. Linear mixed effect models were employed to fit the outcomes including interaction between treatment group and sex.

Septic mice demonstrated robust expression of pro-inflammatory cytokines, chemokines and biomarkers of tubular injury in renal tissue, which were attenuated in response to combined PTX and antibiotics (gentamicin or cefotaxime): chemokines (p<0.001), plasma (p<0.01) and tissue IL-6 (p<0.05), plasma TNF (p<0.001), NGAL (p<0.01), CXCL10 (p<0.01), osteopontin (p<0.05), and VEGF (p<0.05), with a trend for KIM-1 (tissue concentration: p=0.21, fluorescence area: p=0.12). Interactions between treatment and sex were present for several cytokines and kidney injury biomarkers. Immunofluorescence findings for the tubular injury markers (NGAL and KIM-1) were consistent with biomarker expression in tissue lysates.

Neonatal E. coli sepsis leads to increased expression of renal tissue inflammation and injury biomarkers consistent with AKI, which may be attenuated with PTX combined with antibiotic treatment.

Sepsis-induced neurodegeneration and cognitive dysfunction remain critical challenges worldwide. Vitamin D was reported to reduce neuronal injury and neurotoxicity and its deficiency was associated with neurocognitive disorders. This study investigates the mechanisms by which vitamin D exerts neuroprotective potential against damage-associated molecular patterns (DAMPs), specifically extracellular histones, in sepsis-related brain dysfunction.

The cultured mouse hippocampal neuronal HT22 cells were exposed to 20 µg/ml exogenous histone for 24 h to induce pyroptosis and ferroptosis in the presence or absence of the active form of vitamin D, calcitriol (1 nM). A cecal ligation and puncture mouse sepsis model was used to evaluate histone release and pyroptosis/ferroptosis biomarkers in the brain together with neurobehavioral performance with or without calcitriol treatment (1 µg/kg, i.p. injection) at 24 h or 1 week after sepsis onset.

In vitro, histone exposure triggered both pyroptosis and ferroptosis in neuronal cells, which was significantly suppressed by calcitriol treatment with the reduced expression of caspase-1 by 38 %, GSDMD by 30 %, ACSL4 by 33 %, and the increased expression of GPX4 by 35 % (n = 6, P < 0.05). Similarly, in vivo, calcitriol treatment inhibited both neuronal pyroptosis and ferroptosis by reducing expression of pyroptosis marker, GSDMD/NeuN (11.6 ± 1.2 % vs. 19.4 ± 1.1 %) and increasing expression of ferroptosis marker, GPX4/NeuN (21.4 ± 1.7 % vs. 13.5 ± 1.1 %), in the brain of septic mice (n = 6, P < 0.01). In addition, calcitriol increased survival rate (72 % vs. 41 %) and ameliorated cognitive dysfunction of septic mice (n = 8-13, P < 0.05).

This study demonstrates that vitamin D exerts a neuroprotective effect against sepsis by attenuating histone-induced pyroptosis and ferroptosis. These findings highlight the potential therapeutic role of vitamin D supplementation in mitigating brain dysfunction associated with sepsis which needs for further investigation.

Studies have shown associations between Body Mass Index (BMI), High-Sensitivity C-reactive protein (HSCRP), and depressive symptoms(DP). However, the complex relationship between them remains uncertain. The objective of this research is to examine the correlation between them in a substantial sample that is representative of the national level.

Our analysis was based on the 2015-2016National Health and Nutrition Examination Survey (NHANES).DP was measured by the Patient Health Questionnaire-9 (PHQ-9). Using multivariable logistic regression analysis and stratified analysis, we examined the relationship between BMI, HSCRP, and DP. We applied generalized additive models to explore the non-linear relationships among variables.

This study included a total of 4834 participants. The results revealed that BMI (P=0.002) and HSCRP (P=0.008) were risk factors for DP. The relationship between BMI and DP (P=0.035), BMI and HSCRP (P<0.001) were non-linear. The nonlinear association between HSCRP and DP (P=0.031), BMI and DP (P=9e-04) is significant in females when stratified by gender. No nonlinear association was found between BMI and DP (P =0.677) and between HSCRP and DP (P =0.439) in males. The results of the interaction test reveal a significant interaction between HSCRP and gender.

Research has found both BMI and HSCRP are risk factors for DP and the relationship between them was non-linear. The nonlinear associations between BMI and DP, as well as between HSCRP and DP, are gender-dependent.

Clinical and experimental evidence indicates that alcohol use causes various abnormalities in the immune system and compromises immune functions. However, the mechanistic understanding of ethanol's effects on the immune system remains limited. Cyclic AMP (cAMP) regulates multiple processes, including immune responses. Earlier research indicated that type 7 adenylyl cyclase (AC7) regulates the immune system and is highly responsive to ethanol. Therefore, we hypothesized that AC7 is a central player in regulating the effects of alcohol on innate immune responses. To test this hypothesis, we utilized a myeloid lineage-specific AC7 KO mouse model and compared the effects of acute and chronic ethanol treatment on their innate immune responses induced by systemic lipopolysaccharide (LPS) challenge. Our results demonstrate that AC7 KO mice had significantly lower survival rates under LPS challenge. Chronic ethanol consumption rescued AC7 KO mice from LPS-induced death. AC7 KO and ethanol, acute and chronic, affected several measurements of cytokine mRNA expressions, including IL-1β, TNFα, IL-6, and IL-10 in the lung and liver. In a few cases, statistical analysis indicated that these two factors interacted, suggesting that AC7 played some role in ethanol's effect on cytokine expression. Thus, this study demonstrated AC7's role in ethanol's effect on the innate immune response.

Sepsis-associated acute kidney injury (SA-AKI) presents a severe challenge in the elderly due to increasing incidence, high mortality, and the lack of specific effective treatments. Exploring novel and secure preventive and/or therapeutic approaches is critical and urgent. Berberine (BBR), an isoquinoline alkaloid with anti-inflammatory, antioxidant, and immunomodulatory properties, has shown beneficial effects in various kidney diseases. This study examined whether BBR could protect against SA-AKI in aged rats. Sepsis was induced in 26-month-old male Wistar rats by cecal ligation and puncture (CLP), either with or without BBR pretreatment. CLP induction led to SA-AKI, as indicated by elevated serum levels of malondialdehyde, tumor necrosis factor-alpha, urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL), along with histopathological features of kidney damage. Key indicators of kidney oxidative stress, mitochondrial dysfunction, apoptosis, and activations of the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling, including the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome pathway, were also elevated following CLP induction. BBR pretreatment substantially mitigated these adverse effects, suggesting that it protects against SA-AKI in aged rats by reducing oxidative stress, preserving mitochondrial integrity, and inhibiting key inflammatory pathways. These findings highlight the potential of BBR as a therapeutic agent for managing SA-AKI in elderly populations.

We aimed to clarify the controversial relationship between levels of high-sensitivity C-reactive protein (hs-CRP) and severity of depression in men and women.

Medical records were retrospectively analyzed for 1,236 inpatients at our medical center who were diagnosed with depression at discharge between January 2018 and August 2022. Depression severity was assessed during hospitalization using the 24-item Hamilton Depression Rating Scale. Potential associations between severity scores and hs-CRP levels were explored using multivariate linear regression as well as smooth curve fitting to detect non-linear patterns.

In male patients, hs-CRP levels between 2.00 mg/L and 10.00 mg/L showed a non-linear association with depression severity overall (fully adjusted β = 1.69, 95% CI 0.65 to 2.72), as well as with severity of specific symptoms such as hopelessness, sluggishness, and cognitive disturbance. In female patients, hs-CRP levels showed a linear association with severity of cognitive disturbance (fully adjusted β = 0.07, 95% CI 0.01 to 0.12). These results remained significant after adjusting for age, body mass index, diabetes, hypertension, history of drinking, history of smoking, and estradiol levels.

Levels of hs-CRP show sex-specific associations with depression severity, particularly levels between 2.00 and 10.00 mg/L in men. These findings may help develop personalized anti-inflammatory treatments for depression, particularly for men with hs-CRP levels of 2.00-10.00 mg/L.

Sepsis-associated acute kidney injury (AKI) is a health complication, encompassing excessive inflammatory response, oxidative stress, and tubular necrosis; leading to kidney failure and death. Sepsis treatments are nonspecific and palliative. In this study, we evaluated the effect of morin, a flavonoid with known nephroprotective capabilities, on sepsis-induced AKI by dividing eighty male mice into: normal, morin-treated, septic, and septic mice treated with morin. Half of the groups were sacrified 3 days post sepsis induction, while the rest was sacrified on the 7th day. Treating septic mice with morin resulted in the amelioration of sepsis-associated pathophysiological renal alterations and the increase of the survival and recovery rates compared with those of septic control group. These findings indicate that morin has a therapeutic effect against sepsis-associated AKI via its anti-inflammatory, antioxidant and regenerative effects. Thus, it could be used as potential pharmacological intervention for preventing renal complications of sepsis.

Background and Objectives: The predictive value of changes in C-reactive protein (CRP), procalcitonin, and leukocyte levels, which are commonly used in the diagnosis of infection in sepsis and septic shock, remains a topic of debate. The aim of this study was to evaluate the effectiveness of changes in CRP, procalcitonin, and leukocyte counts on the prognosis of 230 patients admitted to the intensive care unit (ICU) with the diagnosis of sepsis and pneumonia-related septic shock between 1 April 2022 and 31 December 2023, and to investigate whether any of these markers have a superior predictive value over the others in forecasting prognosis. Materials and Methods: This single-center, retrospective, cross-sectional observational study included patients who developed sepsis and septic shock due to community-acquired pneumonia and were admitted to the ICU. Demographic data, 1-month and 90-day mortality rates, length of stay in the ICU, discharge to the ward or an outside facility, need for dialysis after sepsis, need for invasive or noninvasive mechanical ventilation during the ICU stay and the duration of this support, whether patients admitted with sepsis or septic shock required inotropic agent support during their stay in the ICU and whether they received monotherapy or combination therapy with antibiotics during their admission to the ICU, the Comorbidity Index score (CCIS), CURB-65 score (confusion, uremia, respiratory rate, BP, age ≥ 65), and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score were analyzed. Additionally, CRP, procalcitonin, and leukocyte levels were recorded, and univariate and multivariate logistic regression analyses were performed to evaluate their effects on 1- and 3-month mortality outcomes. In all statistical analyses, a p-value of <0.05 was accepted as a significant level. Results: According to multivariate logistic regression analysis, low BMI, male gender, and high CCIS, CURB-65, and APACHE-II scores were found to be significantly associated with both 1-month and 3-month mortality (p < 0.05). Although there was no significant relationship between the first-day levels of leukocytes, CRP, and PCT and mortality, their levels on the third day were observed to be at their highest in both the 1-month and 3-month mortality cases (p < 0.05). Additionally, a concurrent increase in any two or all three of CRP, PCT, and leukocyte values was found to be higher in patients with 3-month mortality compared with those who survived (p = 0.004). Conclusions: In patients with pneumoseptic or pneumonia-related septic shock, the persistent elevation and concurrent increase in PCT, CRP, and leukocyte values, along with male gender, advanced age, low BMI, and high CCIS, CURB-65, and APACHE-II scores, were found to be significantly associated with 3-month mortality.

Infection is a commonplace, usually self-limiting, condition but can lead to sepsis, a severe life-threatening dysregulated host response. We investigate the individual phenotypic predisposition to developing uncomplicated infection or sepsis in a large cohort of non-infected patients undergoing major elective surgery. Whole-blood RNA sequencing analysis was performed on preoperative samples from 267 patients. These patients developed postoperative infection with (n = 77) or without (n = 49) sepsis, developed non-infectious systemic inflammatory response (n = 31), or had an uncomplicated postoperative course (n = 110). Machine learning classification models built on preoperative transcriptomic signatures predict postoperative outcomes including sepsis with an area under the curve of up to 0.910 (mean 0.855) and sensitivity/specificity up to 0.767/0.804 (mean 0.746/0.769). Our models, confirmed by quantitative reverse-transcription PCR (RT-qPCR), potentially offer a risk prediction tool for the development of postoperative sepsis with implications for patient management. They identify an individual predisposition to developing sepsis that warrants further exploration to better understand the underlying pathophysiology.

Objective: Sex differences exist in sepsis, but the commitment of neutrophils to these differences remains unclear. Neutrophil extracellular traps (NETs) function to remove pathogens, yet excessive NETs release can contribute to organ damage. This study explores effects of the gender hormones on endotoxin-induced NETs using neutrophils from both male and female sources. Methods: Blood samples were collected from healthy volunteers. Isolated neutrophils were seeded in collagen-coated cell culture plates, and NETs were induced by lipopolysaccharide (LPS) treatment. After 15 minutes of LPS treatment, 17β-estradiol (0.03-272.4 ng/mL), testosterone enanthate (0.01-10 ng/mL), dimethyl sulfoxide, or ethanol (vehicle control) was added to the plates. These were incubated for three hours at 37°C with 5% CO2. Neutrophil extracellular traps formation was assessed using immunofluorescence staining. Results: Lipopolysaccharide-induced NETs formation was significantly greater in females than in males. In male-derived neutrophils, 17β-estradiol at above the blood concentrations significantly suppressed LPS-induced NETs. No effect was seen while using testosterone enanthate to NETs at any concentration. In female-derived neutrophils, 17β-estradiol, which was near to the highest concentration of non-pregnant women's blood, tended to increase NETs. Testosterone enanthate, which was near to female blood concentration, significantly promoted NETs. Conclusions: Sex differences existed in LPS-induced NETs of human neutrophil. In males, high concentrations of 17β-estradiol administration may have a suppressive effect on excessive NETs during infection. In females, endogenous gender hormones may promote NETs during infection. Sex differences in neutrophils may need to be considered in organ damage owing to NETs excess such as sepsis.

Among the non-communicable neurological diseases, epilepsy is characterized by abnormal brain activity with several peripheral implications. The role of peripheral inflammation in the relationship between seizure development and nonalcoholic fatty liver disease based on sex difference remains still overlooked. Severe early-life infections lead to increased inflammation that can aggravate epilepsy and hepatic damage progression, both related to increased odds of hospitalization for epileptic patients with liver diseases. Here, we induced a post-natal-day 3 (PND3) infection by LPS (1 mg/kg, i.p.) to determine the hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45). We evaluated intra- and inter-gender differences in systemic and liver inflammation, hepatic lipid dysmetabolism, and oxidative damage related to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Endotoxin challenge triggered a more severe inflammatory and immune response in male epileptic rats, compared to females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-treated female rats showed significant alterations in systemic and hepatic lipid profiles and reduced mitochondrial fatty acid oxidation. The two different sex-dependent mechanisms of LPS-induced liver injury converge in increased ROS production and related mitochondrial oxidative damage in both sexes. Notably, a compensatory increase in antioxidant defense was evidenced only in female rats. Our study with a translational potential demonstrates, for the first time, that early post-natal infections in epileptic rats induced or worsened hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment.

The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis.

Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days.

Either left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice.

For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.

Low-grade inflammation (LGI) mainly acted as the mediator of the association of obesity and inflammatory diet with numerous chronic diseases, including neuropsychiatric diseases. However, the evidence about the effect of LGI on brain structure is limited but important, especially in the context of accelerating aging. This study was then designed to close the gap, and we leveraged a total of 37,699 participants from the UK Biobank and utilized inflammation score (INFLA-score) to measure LGI. We built the longitudinal relationships of INFLA-score with brain imaging phenotypes using multiple linear regression models. We further analyzed the interactive effects of specific covariates. The results showed high level inflammation reduced the volumes of the subcortex and cortex, especially the globus pallidus (β [95% confidence interval] = -0.062 [-0.083, -0.041]), thalamus (-0.053 [-0.073, -0.033]), insula (-0.052 [-0.072, -0.032]), superior temporal gyrus (-0.049 [-0.069, -0.028]), lateral orbitofrontal cortex (-0.047 [-0.068, -0.027]), and others. Most significant effects were observed among urban residents. Furthermore, males and individuals with physical frailty were susceptive to the associations. The study provided potential insights into pathological changes during disease progression and might aid in the development of preventive and control targets in an age-friendly city to promote great health and well-being for sustainable development goals.

Sepsis is a life-threatening condition mainly caused by gram-negative and gram-positive bacteria. Understanding the type of causative agent in the early stages is essential for precise antibiotic therapy. This study sought to identify a host gene set capable of distinguishing between sepsis induced by gram-negative bacteria; Escherichia coli and gram-positive bacteria; Staphylococcus aureus in community-onset adult patients. In the present study, microarray expression information was used to apply the Least Absolute Shrinkage and Selection Operator (Lasso) technique to select the predictive gene set for classifying sepsis induced by E. coli or S. aureus pathogens. We identified 25 predictive genes, including LILRA5 and TNFAIP6, which had previously been associated with sepsis in other research. Using these genes, we trained a logistic regression classifier to distinguish whether a sample contains an E. coli or S. aureus infection or belongs to a healthy control group, and subsequently assessed its performance. The classifier achieved an Area Under the Curve (AUC) of 0.96 for E. coli and 0.98 for S. aureus-induced sepsis, and perfect discrimination (AUC of 1) for healthy controls from the other conditions in a 10-fold cross-validation. The genes demonstrated an AUC of 0.75 in distinguishing between sepsis patients with E. coli and S. aureus pathogens. These findings were further confirmed in two distinct independent validation datasets which gave high prediction AUC ranging from 0.72-0.87 and 0.62 in distinguishing three groups of participants and two groups of patients respectively. These genes were significantly enriched in the immune system, cytokine signaling in immune system, innate immune system, and interferon signaling. Transcriptional patterns in blood can differentiate patients with E. coli-induced sepsis from those with S. aureus-induced sepsis. These diagnostic markers, upon validation in larger trials, may serve as a foundation for a reliable differential diagnostics assay.

Clinically, septic males tend to have higher mortality rates, but it is unclear if this is due to sex differences in cardiac dysfunction, possibly influenced by hormonal variations. Cardiac dysfunction significantly contributes to sepsis-related mortality, primarily influenced by metabolic imbalances. Peroxisome proliferator-activated receptor delta (PPARδ) is a key player in cardiac metabolism and its activation has been demonstrated to favor sepsis outcomes. While estradiol (E2) is abundant and beneficial in females, its impact on PPARδ-mediated metabolism in the heart with regards to sex during sepsis remains unknown.

Here, we unveil that while sepsis diminishes PPARδ nuclear translocation and induces metabolic dysregulation, oxidative stress, apoptosis and dysfunction in the heart thereby enhancing mortality, these effects are notably more pronounced in males than females. Mechanistic experiments employing ovariectomized(OVX) mice, E2 administration, and G protein-coupled estrogen receptor 1(GPER-1) knockout (KO) mice revealed that under lipopolysaccharide (LPS)-induced sepsis, E2 acting via GPER-1 enhances cardiac electrical activity and function, promotes PPARδ nuclear translocation, and subsequently ameliorates cardiac metabolism while mitigating oxidative stress and apoptosis in females. Furthermore, PPARδ specific activation using GW501516 in female GPER-1-/- mice reduced oxidative stress, ultimately decreasing NLRP3 expression in the heart. Remarkably, targeted GPER-1 activation using G1 in males mirrors these benefits, improving cardiac electrical activity and function, and ultimately enhancing survival rates during LPS challenge. By employing NLRP3 KO mice, we demonstrated that the targeted GPER-1 activation mitigated injury, enhanced metabolism, and reduced apoptosis in the heart of male mice via the downregulation of NLRP3.

Our findings collectively illuminate the sex-specific cardiac mechanisms influencing sepsis mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries advance our understanding of the sex differences in sepsis-induced cardiac dysfunction and also present a novel avenue for targeted interventions with potential translational impact.

The disruption of the circadian clock is associated with inflammatory and immunological disorders. BMAL2, a critical circadian protein, forms a dimer with CLOCK, activating transcription. Extracellular cold-inducible RNA-binding protein (eCIRP), released during sepsis, can induce macrophage endotoxin tolerance. We hypothesized that eCIRP induces BMAL2 expression and promotes macrophage endotoxin tolerance through triggering receptor expressed on myeloid cells-1 (TREM-1).

C57BL/6 wild-type (WT) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Serum levels of eCIRP 20 h post-CLP were assessed by ELISA. Peritoneal macrophages (PerM) were treated with recombinant mouse (rm) CIRP (eCIRP) at various doses for 24 h. The cells were then stimulated with LPS for 5 h. The levels of TNF-α and IL-6 in the culture supernatants were assessed by ELISA. PerM were treated with eCIRP for 24 h, and the expression of PD-L1, IL-10, STAT3, TREM-1 and circadian genes such as BMAL2, CRY1, and PER2 was assessed by qPCR. Effect of TREM-1 on eCIRP-induced PerM endotoxin tolerance and PD-L1, IL-10, and STAT3 expression was determined by qPCR using PerM from TREM-1-/- mice. Circadian gene expression profiles in eCIRP-treated macrophages were determined by PCR array and confirmed by qPCR. Induction of BMAL2 activation in bone marrow-derived macrophages was performed by transfection of BMAL2 CRISPR activation plasmid. The interaction of BMAL2 in the PD-L1 promoter was determined by computational modeling and confirmed by the BIAcore assay.

Serum levels of eCIRP were increased in septic mice compared to sham mice. Macrophages pre-treated with eCIRP exhibited reduced TNFα and IL-6 release upon LPS challenge, indicating macrophage endotoxin tolerance. Additionally, eCIRP increased the expression of PD-L1, IL-10, and STAT3, markers of immune tolerance. Interestingly, TREM-1 deficiency reversed eCIRP-induced macrophage endotoxin tolerance and significantly decreased PD-L1, IL-10, and STAT3 expression. PCR array screening of circadian clock genes in peritoneal macrophages treated with eCIRP revealed the elevated expression of BMAL2, CRY1, and PER2. In eCIRP-treated macrophages, TREM-1 deficiency prevented the upregulation of these circadian genes. In macrophages, inducible BMAL2 expression correlated with increased PD-L1 expression. In septic human patients, blood monocytes exhibited increased expression of BMAL2 and PD-L1 in comparison to healthy subjects. Computational modeling and BIAcore assay identified a putative binding region of BMAL2 in the PD-L1 promoter, suggesting BMAL2 positively regulates PD-L1 expression in macrophages.

eCIRP upregulates BMAL2 expression via TREM-1, leading to macrophage endotoxin tolerance in sepsis. Targeting eCIRP to maintain circadian rhythm may correct endotoxin tolerance and enhance host resistance to bacterial infection.

Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized.

In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants.

The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice.

This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.

An increasing number of studies have highlighted the existence of a sex-specific immune response, wherein men experience a worse prognosis in cases of acute inflammatory diseases. Initially, this sex-dependent inflammatory response was attributed to the influence of sex hormones. However, a growing body of evidence has shifted the focus toward the influence of chromosomes rather than sex hormones in shaping these inflammatory sex disparities. Notably, certain pattern recognition receptors, such as Toll-like receptors (TLRs), and their associated immune pathways have been implicated in driving the sex-specific immune response. These receptors are encoded by genes located on the X chromosome. TLRs are pivotal components of the innate immune system, playing crucial roles in responding to infectious diseases, including bacterial and viral pathogens, as well as trauma-related conditions. Importantly, the TLR-mediated inflammatory responses, as indicated by the production of specific proteins and cytokines, exhibit discernible sex-dependent patterns. In this review, we delve into the subject of sex bias in TLR activation and explore its clinical implications relatively to both the X chromosome and the hormonal environment. The overarching objective is to enhance our understanding of the fundamental mechanisms underlying these sex differences.

The pathogenesis of acute lung injury is not fully understood. Stimulator of interferon genes (STING) and ferroptosis have been implicated in various pathological and physiological processes, including acute lung injury (ALI). However, the relationship between STING and ferroptosis in lipopolysaccharide (LPS)-induced ALI is unclear. We found that LPS stimulation activated STING and ferroptosis. Furthermore, STING knockout and ferroptosis inhibitor alleviated lung inflammation and epithelial cell damage. Also, STING knockout reduced inflammation injury and ferroptosis. Notably, the ferroptosis inducer reversed the alleviation of inflammation caused by STING knockout. These results show that STING participates in the inflammation injury of ALI by regulating ferroptosis. Results also showed that p-STAT3 levels increased after STING knockout, suggesting that STING negatively regulates STAT3 activation. Besides, STAT3 inhibitor aggravated ferroptosis after STING knockout, indicating that STING regulates ferroptosis through STAT3 signaling. In conclusion, STING mediates LPS-induced ALI by regulating ferroptosis, indicating that STING and ferroptosis may be new targets for ALI treatment.

Objective: Neutrophil extracellular traps (NETs) defend against acute infections. However, their overexpression causes organ failure during sepsis. Control of NET formation may improve the outcomes of patients with sepsis. Equol, a soybean isoflavone, is a female hormone analog, which prevents inflammation. We evaluated the effects of equol on NET formation in human neutrophils during inflammatory stimulation in vitro . Methods: Healthy volunteers provided blood samples. An enzyme-linked immunosorbent assay assessed serum equol concentrations. Neutrophil extracellular trap formation in neutrophils was induced by lipopolysaccharide treatment. Enzyme-linked immunosorbent assay quantified DNA-binding elastase, and immunostaining assessed NET formation. Reverse-transcription quantitative polymerase chain reaction and Western blotting detected G-protein-coupled receptor 30 (GPR30) or peptidyl arginine deiminase 4 (PAD4) expression. Flow cytometry assessed neutrophil phagocytic ability with inactivated Escherichia coli . Results: In neutrophils derived from males with low-serum equol levels (low-serum equol group), equol significantly decreased DNA-binding elastase levels and NET formation. Equol did not decrease NETs in neutrophils from males with high-serum equol levels. GPR30 expression of neutrophils was higher in the low-serum than in the high-serum equol group. PAD4 mRNA levels and nuclear PAD4 protein expression also decreased more than the vehicle control in the low-serum equol group. Equol did not alter the phagocytic ability of neutrophils. In neutrophils from young females, equol had no inhibitory effect on NET formation. Conclusions: Equol decreases lipopolysaccharide-induced NET formation in neutrophils from males via inhibition of PAD4 expression. Our findings provide a rationale for investigating a new therapeutic approach using equol to control neutrophil activity during sepsis.

Gender disparities in intensive care unit (ICU) treatment approaches and outcomes are evident. However, clinicians often pay little attention to the importance of biological sex and sociocultural gender in their treatment courses. Previous studies have reported that differences between sexes or genders can significantly affect the manifestation of diseases, diagnosis, clinicians' treatment decisions, scope of treatment, and treatment outcomes in the intensive care field. In addition, numerous reports have suggested that immunomodulatory effects of sex hormones and differences in gene expression from X chromosomes between genders might play a significant role in treatment outcomes of various diseases. However, results from clinical studies are conflicting. Recently, the need for customized treatment based on physical, physiological, and genetic differences between females and males and sociocultural characteristics of society have been increasingly emphasized. However, interest in and research into this field are remarkably lacking in Asian countries, including South Korea. Through this review, we hope to enhance our awareness of the importance of sex and gender in intensive care treatment and research by briefly summarizing several principal issues, mainly focusing on sex and sex hormone-based outcomes in patients admitted to the ICU with sepsis and septic shock.

Testosterone is an anabolic and androgenic steroid hormone therapeutically used to produce male sex characteristics. It has also been shown to have a modulating effect on proinflammatory biomarkers. Critical illness is characterised by a proinflammatory and catabolic state and is accompanied by altered testosterone production, which may persist into the recovery phase. Testosterone may, therefore be a potential therapeutic option in critical illness. This paper reviews normal testosterone physiology, and the changes seen during critical illness and systematically reviews testosterone therapy during both the acute and chronic phases of critical illness.

This article explains the pathophysiology of testosterone during critical illness and explores the therapeutic value of testosterone in the management of critically ill patients.

The development of preventive and therapeutic vaccines has played a crucial role in preventing infections and treating chronic and non-communicable diseases, respectively. For a long time, the influence of sex differences on modifying health and disease has not been addressed in clinical and preclinical studies. The interaction of genetic, epigenetic, and hormonal factors plays a role in the sex-related differences in the epidemiology of diseases, clinical manifestations, and the response to treatment. Moreover, sex is one of the leading factors influencing the gut microbiota composition, which could further explain the different predisposition to diseases in men and women. In the same way, differences between sexes occur also in the immune response to vaccines. This narrative review aims to highlight these differences, focusing on the immune response to vaccines. Comparative data about immune responses, vaccine effectiveness, and side effects are reviewed. Hence, the intricate interplay between sex, immunity, and the gut microbiota will be discussed for its potential role in the response to vaccination. Embracing a sex-oriented perspective in research may improve the efficacy of the immune response and allow the design of tailored vaccine schedules.

A potentially fatal complication of sepsis is septic acute kidney injury. Stem cell therapy is a potential new method of treating sepsis and has been applied to treat some human diseases.

This study investigated the effects of secretome-MSCs on NGAL, CRP, NF-κB, and MMP-9 proteins, and histopathology in mice with septic AKI.

A post-test-only group design was conducted in 30 Balb/C male mice, which were randomly assigned to five groups: the control group was intraperitoneally injected with 0.5 ml of 0.9 % NaCl, the septic AKI, and the treatment groups (T1, T2, and T3) were intraperitoneally injected with 0.5 ml of 0.9 % NaCl and 0.3 mg/kg BW LPS single dose for three days. Three-day treatments of 150, 300, and 600 µl secretome-MSCs were administered intraperitoneally into the treatment groups. Furthermore, kidney and blood samples were collected for biochemical and histopathological analyses.

The T1, T2, and T3 groups had lower expression of NF-κB and MMP-9 and significantly lower CRP and NGAL levels than that of septic AKI group. T1 (1.21 ± 0.19), T2 (0.75 ± 0.22), and T3 (0.38 ± 0.14) groups demonstrated lower average scores for inflammation, necrosis, hemorrhage, and degeneration compared to septic AKI group (2.17 ± 0.13).

Administration of 600 µl/20 g BW secretome-MSCs suppresses NF-κB and MMP-9 expression and reduces CRP and NGAL levels. Meanwhile, the 150 and 300 µl/20 g BW doses also indicated a greater improvement in renal tissue damage of mice with septic AKI.

Staphylococcus aureus is the leading cause of death due to bacterial bloodstream infection. Female sex has been identified as a risk factor for mortality in S aureus bacteremia (SAB) in some studies, but not in others.

To determine whether female sex is associated with increased mortality risk in SAB.

MEDLINE, Embase, and Web of Science were searched from inception to April 26, 2023.

Included studies met the following criteria: (1) randomized or observational studies evaluating adults with SAB, (2) included 200 or more patients, (3) reported mortality at or before 90 days following SAB, and (4) reported mortality stratified by sex. Studies on specific subpopulations (eg, dialysis, intensive care units, cancer patients) and studies that included patients with bacteremia by various microorganisms that did not report SAB-specific data were excluded.

Data extraction and quality assessment were performed by 1 reviewer and verified by a second reviewer. Risk of bias and quality were assessed with the Newcastle-Ottawa Quality Assessment Scale. Mortality data were combined as odds ratios (ORs).

Mortality at or before 90-day following SAB, stratified by sex.

From 5339 studies retrieved, 89 were included (132 582 patients; 50 258 female [37.9%], 82 324 male [62.1%]). Unadjusted mortality data were available from 81 studies (109 828 patients) and showed increased mortality in female patients compared with male patients (pooled OR, 1.12; 95% CI, 1.06-1.18). Adjusted mortality data accounting for additional patient characteristics and treatment variables were available from 32 studies (95 469 patients) and revealed a similarly increased mortality risk in female relative to male patients (pooled adjusted OR, 1.18; 95% CI, 1.11-1.27). No evidence of publication bias was encountered.

In this systematic review and meta-analysis, female patients with SAB had higher mortality risk than males in both unadjusted and adjusted analyses. Further research is needed to study the potential underlying mechanisms.

Sepsis is a complicated pathological condition in response to severe infection. It is characterized by a strong systemic inflammatory response, where multiple components of the immune system are involved. Currently, there is no treatment for sepsis. Blood platelets are known for their role in haemostasis, but they also participate in inflammation through cell-cell interaction and the secretion of inflammatory mediators. Interestingly, an increase in platelet activation, secretion, and aggregation with other immune cells (such as monocytes, T-lymphocytes and neutrophils) has been detected in septic patients. Therefore, antiplatelet therapy in terms of P2Y12 antagonists has been evaluated as a possible treatment for sepis. It was found that blocking P2Y12 receptors decreased platelet marker expression and limited attachment to immune cells in some studies, but not in others. This review addresses the role of platelets in sepsis and discusses whether antagonizing P2Y12 signalling pathways can alter the disease outcome. Challenges in studying P2Y12 antagonists in sepsis also are discussed. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

Vitiligo is an autoimmune condition that causes patchy skin depigmentation. Although the mechanism by which vitiligo induces immunocompromise is unclear, other related autoimmune diseases are known to predispose those affected to infection. Individuals with vitiligo exhibit epidermal barrier disruption, which could potentially increase their susceptibility to systemic infections; patients with renal disease also show a predisposition to infection. Nevertheless, there is little research addressing the risk of infection in dialysis patients with vitiligo in comparison to those without it. A retrospective analysis was performed on patients with end-stage renal disease (ESRD) in the United States Renal Data System who started dialysis between 2004 and 2019 to determine if ESRD patients with vitiligo are at an increased risk of bacteremia, cellulitis, conjunctivitis, herpes zoster, or septicemia. Multivariable logistic regression modeling indicated that female sex, black compared to white race, Hispanic ethnicity, hepatitis C infection, and tobacco use were associated with an enhanced risk of vitiligo, whereas increasing age and catheter, versus arteriovenous fistula, and access type were associated with a decreased risk. After controlling for demographics and clinical covariates, vitiligo was found to be significantly associated with an increased risk of bacteremia, cellulitis, and herpes zoster but not with conjunctivitis and septicemia.

Although macrophage depletion is a possible emerging therapeutic strategy for osteoporosis and melanoma, the lack of macrophage functions can lead to inappropriate microbial control, especially the regulation of intestinal microbiota. Cecal ligation and puncture (CLP) sepsis was performed in regular mice and in mice with clodronate-induced macrophage depletion. Macrophage depletion significantly increased the mortality and severity of sepsis-CLP mice, partly through the increased fecal Ascomycota, especially Kazachstania pintolopesii, with polymicrobialbacteremia (Klebsiella pneumoniae, Enterococcus faecalis, and Acinetobacter radioresistens). Indeed, macrophage depletion with sepsis facilitated gut dysbiosis that directly affected gut permeability as yeast cells were located and hidden in the colon crypts. To determine the interactions of fungal molecules on bacterial abundance, the heat-kill lysate of fungi (K. pintolopesii and C. albicans) and purified (1→3)-β-d-glucan (BG; a major component of the fungal cell wall) were incubated with bacteria that were isolated from the blood of macrophage-depleted mice. There was enhanced cytokine production of enterocytes (Caco-2) after the incubation of the lysate of K. pintolopesii (isolated from sepsis mice), the lysate of C. albicans (extracted from sepsis patients), and BG, together with bacterial lysate. These data support a possible influence of fungi in worsening sepsis severity. In conclusion, macrophage depletion enhanced K. pintolopesii in feces, causing the overgrowth of fecal pathogenic bacteria and inducing a gut permeability defect that additively worsened sepsis severity. Hence, the fecal fungus could be spontaneously elevated and altered in response to macrophage-depleted therapy, which might be associated with sepsis severity.

Endotoxic shock (ExSh) and cecal ligature and puncture (CLP) are models that induce sepsis. In this work, we investigated early immunologic and histopathologic changes induced by ExSh or CLP models in female and male mice. Remarkable results showed that females supported twice the LD100 of LPS for males, CLP survival and CFU counts were similar between genders, high circulating LPS levels in ExSh mice and low levels of IgM anti-LPS in males. In the serum of ExSh males, TNF and IL-6 increased in the first 6 h, in CLP males at 12 h. In the liver of ExSh mice, TNF increased at 1.5 and 12 h, IL-1 at 6 h. TGFβ1 increased in females throughout the study and at 12 h in males. In CLP mice, IL-6 decreased at 12 h, TGFβ1 increased at 6-12 h in males and at 12 h in females. In the lungs of ExSh males, IL-1β increased at 1.5-6 h and TGFβ1 at 12 h; in females, TNF decrease at 6 h and TGFβ1 increased from 6 h; in CLP females, TNF and IL-1β decreased at 12 h and 1.5 h, respectively, and TGFβ1 increased from 6 h; in males, TGFβ1 increased at 12 h. In the livers of ExSh mice, signs of inflammation were more common in males; in the CLP groups, inflammation was similar but less pronounced. ExSh females had leucocytes with TGFβ1. The lungs of ExSh males showed patches of hyaline membranes and some areas of inflammatory cells, similar but fewer and smaller lesions were seen in male mice with CLP. In ExSh females, injuries were less extent than in males, similar pulmonary lesions were seen in female mice with CLP. ExSh males had lower levels of TGFβ1 than females, and even lower levels were seen in CLP males. We conclude that the ExSh was the most lethal model in males, associated with high levels of free LPS, low IgM anti-LPS, exacerbated inflammation and target organ injury, while females showed early TGFβ1 production in the lungs and less tissue damage. We didn't see any differences between CLP mice.