Therapeutic Drug Monitoring-Guided Vancomycin Therapy of a Pediatric Patient after Liver Transplantation: a Case Report.

BACKGROUND: Vancomycin administration is challenging in critically ill patients because of pharmacokinetic changes and requires careful therapeutic drug monitoring (TDM) to guide the appropriate dosing for an effective serum concentration and to avoid toxicity. METHODS: We reported a one-year-old female pediatric patient with a body mass index of 15.4 had successful TDM-guided vancomycin therapy after a living donor liver transplantation for biliary atresia. RESULTS: The patient was admitted to the Intensive Care Unit for sepsis after her second liver transplantation. Even with the administration of the maximum approved vancomycin dosage (40 mg/kg/day), the serum trough levels were less than the recommended therapeutic level. After several adjustments based on TDM, a continuous pump infusion of up to 800 mg/day was needed to reach the desired serum trough concentration of > 10 µg/mL. Sepsis was controlled, and the patient was transferred from the Intensive Care Unit to the general ward and finally discharged home on a regular follow-up plan. CONCLUSIONS: TDM-guided vancomycin continuous infusion may be an effective therapeutic option for pediatric patients after liver transplantation.

Ulinastatin Improves Renal Microcirculation by Protecting Endothelial Cells and Inhibiting Autophagy in a Septic Rat Model.

INTRODUCTION: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. METHODS: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 h after the operation. Histological staining was used to evaluate kidney injury scores. Western blot was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors (interleukin-1ß, interleukin-6, and tumor necrosis factor-α) in kidney tissue, and enzyme-linked immunosorbent assay detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. RESULTS: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. CONCLUSION: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

Successful Treatment of Severe Community-Acquired Pneumonia caused by Chlamydia Psittaci: a Case Report.

BACKGROUND: Community acquired pneumonia is a common and deadly condition, which remains a major cause of morbidity and mortality throughout the world. Chlamydia psittaci pneumonia is responsible for less than 5% of community-acquired pneumonia with a fatality rate of 1%. Nonetheless, it is underestimated due to low awareness of the disease and atypical clinical presentation in a majority of the cases. Metagenomic next-generation sequencing can help us diagnose and clarify the etiology in time. METHODS: We reported a case of an 85-year-old man who presented with intermittent fever and cough with wheezing for 4 days and did a review of related literature. RESULTS: The patient was admitted to our department due to severe CAP and multiple organ dysfunction. After admission, we applied an empirical antibiotic strategy, performed intubation and invasive ventilation, fluid resuscitation, vasoactive drugs and supportive care. On the third day of admission, metagenomic next-generation sequencing results of blood and bronchoalveolar lavage fluid suggested Chlamydia psittaci. We made a diagnosis of sever Chlamydia psittaci pneumonia and adjusted antibiotics to minocycline combined with azithromycin two days after admission. The patient was successfully cured with a good prognosis. CONCLUSIONS: Detecting the pathogen as early as possible and achieving accurate diagnosis are essential in infected patients. We can benefit from careful application of metagenomic next-generation sequencing.

Role of HMGB1-PTEN Signaling in T Lymphocytes and Monocytes Upon Sepsis.

BACKGROUND: The aim of the study was to evaluate the role of high-mobility group box 1 (HMGB1)-phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling in T lymphocytes and monocytes upon sepsis. METHODS: Thirty C57BL/6 male mice aged 8 - 10 weeks old were randomly divided into sham, model, and inhibitor groups (n = 10). The model of sepsis was established through cecal ligation and perforation. Sham group was only subjected to cecum exposure, and then the wound was sutured without cecal ligation. After the operation, the inhibitor group was intraperitoneally injected with HMGB1-specific inhibitor glycyrrhizic acid (dose: 10 mg/kg) every 6 hours for 4 consecutive times, while sham and model groups were intraperitoneally injected with an equal dose of normal saline. The histopathological changes, cell apoptosis in spleen and thymus tissues, proliferative activity and apoptosis of T lymphocytes, chemotactic activity of monocytes, expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-10, and expressions of HMGB1 and PTEN in mice were detected using hematoxylineosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, MTT assay, flow cytometry, transwell chemotaxis assay, enzyme-linked immunosorbent assay, and western blotting, respectively. RESULTS: The cell apoptosis rate in spleen and thymus tissues, proliferative activity and apoptosis rate of T lymphocytes, chemotactic activity of monocytes, protein expressions of TNF-α, IL-6 and IL-10, and expressions of HMGB1 and PTEN significantly increased in the model group compared with those in the sham group (p < 0.05). However, the cell apoptosis rate in spleen and thymus tissues, T lymphocyte apoptosis rate, protein expressions of TNF-α and IL-6, and expressions of HMGB1 and PTEN were significantly lower, while the proliferative activity of T lymphocytes, chemotactic activity of monocytes and protein expression of IL-10 were significantly higher in the inhibitor group than those in the model group (p < 0.05). CONCLUSIONS: Repressing HMGB1-PTEN signaling can effectively reduce the apoptosis rate of T cells, increase the proliferative activity of T cells, and enhance the function of monocytes in the case of sepsis.

Epidemiology of sepsis in Beijing from 2012 to 2018: analysis of hospital homepage databases derived from the Beijing Public Health System.

BACKGROUND: We aimed to evaluate the epidemiology of sepsis in secondary and tertiary hospitals in Beijing, China between 2012 and 2018 using information derived from the Beijing Public Health System. METHODS: The Beijing Public Health System accessed hospital homepage databases and identify patients who diagnosed sepsis or associated condition according to the International Classification of Diseases, 10th Edition, Clinical Modification codes. There are 125 hospitals involved in this study, including 61 secondary hospitals, accounting for 49.2%, and 63 tertiary hospitals, accounting for 50.8%. Patients were stratified by age as minors (0-17 years old), adults (18-64 years old), seniors (65-84 years old), and the elderly (≥ 85 years old). Patient's demographic information, treatments, outcomes, and all-cause hospitalization cost were evaluated. RESULTS: This study involved 8,597 patients. Patients treated in tertiary hospitals or received blood transfusion decreased with age, while patients who were male, received ventilation, or took Traditional Chinese Medicine, and in-hospital mortality and hospitalization cost, increased with age. There were 2,729 (31.7%) deaths in this study. A slight increase in in-hospital mortality occurred from 2012 to 2018. Median hospitalization cost for all patients was ¥29,453 (15,011, 65,237). Hospitalization cost showed no significant change from 2012 to 2016, but increased in 2017 and 2018. CONCLUSION: Sepsis is associated with high mortality and cost. From 2012 to 2018, in-hospital mortality and hospitalization cost of sepsis in Beijing increased significantly with age, and slightly by year.

Individualized resuscitation strategy for septic shock formalized by finite mixture modeling and dynamic treatment regimen.

BACKGROUND: Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. METHODS: Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. RESULTS: A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. CONCLUSIONS: Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

Perfusion microvessel density in the cerebral cortex of septic rats is negatively correlated with endothelial microparticles in circulating plasma.

In sepsis, endothelial microparticles (EMPs) released from endothelial cells (ECs) participate in microcirculation dysfunction through pro-coagulant and pro-inflammatory effects, which can lead to sepsis-associated brain dysfunction. However, the relationship between EMPs and cerebral cortical perfusion microvessel density has not been explored. A closed cranial window was created in rats who were tended to until the cerebral cortex edema caused by preparation of the cranial window subsided, and the microvessel density was stable. A cecal ligation and puncture (CLP) sepsis procedure was then performed on day 6, post-surgery. At 12 and 24 h after the CLP, cerebral cortical perfusion microvessel density was measured with optical coherence tomography angiography (OCTA), followed by measurement of EMPs to evaluate the relationship between these factors. Microvessel density changed from 46.38 % ± 7.65 % on the day of surgery to 35.87 % ± 11.05 % on the second day and 36.71 % ± 11.38 % on the third day after surgery, and then increased daily. The microvessel density decreased to 27.20 % ± 8.50 % 24 h after CLP, which was significantly lower than that immediately and 12 h after CLP (P < 0.001). EMPs increased progressively at 12 and 24 h after CLP. Moreover, there was a negative correlation between EMPs and microvessel density (r=-0.56, P = 0.01). Edema and microvessel density decreased in the local cerebral cortex of the window and then gradually recovered after cranial window surgery. In sepsis, the perfusion microvessel density of the cerebral cortex negatively correlated with the EMPs. Therefore, the perfusion microvessel density can be indirectly evaluated by detecting the plasma EMP level.

SOFA coagulation score and changes in platelet counts in severe acute kidney injury: Analysis from the randomized evaluation of normal versus augmented level (RENAL) study.

AIM: To evaluate the prognostic value of baseline SOFA coagulation score (SOFA-CS) and change in platelet counts in patients with severe acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). METHODS: We performed a secondary analysis from the Randomized Evaluation of Normal versus Augmented Level of RRT (RENAL) study. The primary endpoint was all-cause mortality at 90 days after randomization. The association between baseline SOFA-CS, changes in platelet counts, process of care, and clinical outcomes were analyzed using multivariate Cox model adjusted for baseline variables. RESULTS: The complete SOFA-CS data were available in 1454 out of 1508 patients from the RENAL study. Among them, 708 patients had an abnormal SOFA-CS (defined as SOFA-CS ≥ 1), while 746 patients had normal SOFA-CS at baseline (SOFA-CS = 0). An abnormal SOFA-CS was independently associated with an increased risk of death at 90 days (HR = 1.27, 95% CI = 1.05-1.53, P = 0.015). An abnormal SOFA-CS was associated with prolonged length of ICU stay and duration of mechanical ventilation as well. Furthermore, there was no significant association between changes in platelet counts in patients who survived beyond 4 days and 90 day mortality (HR = 1.26, 95% CI = 0.29-5.56, P = 0.76). However, on multivariable analysis a decline of ≥60% (HR = 1.93, 95% CI = 1.23-3.05, P = 0.004) was associated with 90 day mortality in patients who survived beyond the first 4 days. CONCLUSIONS: In the RENAL study, thrombocytopaenia is a common phenomenon in patients with severe AKI receiving CRRT. An abnormal baseline SOFA-CS and reductions in platelet counts were associated with increased mortality at 90 days.

Dietary approach to stop hypertension diet and risk of coronary artery disease: a meta-analysis of prospective cohort studies.

Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet can lower blood pressure, but its role in preventing coronary artery disease (CAD) remains in debate. Thus, we performed a meta-analysis of prospective cohort studies to address this issue. We carried out a systematical search in databases of PubMed and Embase to screen out eligible publications. Relative risks (RRs) of CAD in the included studies were summarised using random-effect meta-analysis. Dose-response association between DASH diet score and CAD risk was also evaluated. Seven prospective studies were finally included, with a total of 377,725 participants and 15,074 CAD cases. Compared to lower adherence, higher adherence to the DASH diet was associated a decreased risk of CAD (RR 0.82, 95% confidence interval [CI]: 0.78-0.87). Subgroup and sensitivity analyses supported the preventive effects of DASH diet against CAD, and there was no indication of publication bias. For a curvilinear dose-response pattern, the RRs (95% CIs) of CAD for the 4 knots (5th, 35th, 65th and 95th percentiles) of DASH diet score were 0.93 (0.89-0.98), 0.87 (0.80-0.95), 0.81 (0.72-0.90) and 0.74 (0.68-0.82), respectively. For a linear dose-response manner, each 4-point increase in the DASH diet score could reduce the risk of CAD by 5% (RR 0.95, 95% CI: 0.94-0.97). The results of our study indicate that higher adherence to the DASH diet confers a reduced risk of developing CAD.

A rare case of spontaneous hepatic rupture in a pregnant woman.

BACKGROUND: Spontaneous hepatic rupture in pregnancy is a rare and life-threatening event during the perinatal period. CASE PRESENTATION: We report a case of a 33-year-old woman with 36 + 6 weeks' gestation that present with elevated blood pressure before delivery, who was admitted to our hospital due to irregular abdominal pain. Diagnosed with abdominal paracentesis, the emergent caesarean section and laparotomy were performed. Postoperatively, the patient experienced 22-day intensive therapy in ICU and was transferred to the General Surgery Department in good physical condition without post-operative complications. CONCLUSIONS: This case indicates that making an accurate and timely diagnosis and taking multidisciplinary approach contribute to a successful clinical outcome.

Population-Based Epidemiology of Sepsis in a Subdistrict of Beijing.

OBJECTIVE: Information about the epidemiology of sepsis in community residents in China remains scarce and incomplete. The purpose of this study was to describe the occurrence rate and outcome of sepsis in Yuetan Subdistrict of Beijing and to estimate the occurrence rate of sepsis in China. DESIGN: Retrospective cohort study. SETTING: All public hospitals serving residents in Yuetan Subdistrict, Beijing. PATIENTS: All patients (n = 1,716) meeting criteria for sepsis based on American College of Chest Physicians/Society of Critical Care Medicine consensus definition. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We screened all adult residents in Yuetan Subdistrict who were hospitalized from July 1, 2012, to June 30, 2014, and reviewed medical records. Patients with sepsis were included in the analysis. We enrolled 1,716 patients with sepsis out of 21,191 hospitalized adults screened, among whom severe sepsis developed in 256 patients, and septic shock developed in 233 patients. The crude annual occurrence rates of sepsis, severe sepsis, and septic shock in Yuetan Subdistrict were 667, 103, and 91 cases per 100,000 population, corresponding to standardized occurrence rates of 461, 68, and 52 cases per 100,000 population per year, respectively. Both occurrence rate and mortality increased significantly with age, although males had higher age-adjusted occurrence rate and mortality. The occurrence rate of sepsis also exhibited seasonal variation, peaking in winter season. The overall hospital mortality rate of sepsis was 20.6%, yielding a standardized mortality rate of 79 cases per 100,000 population per year. CONCLUSIONS: Sepsis is a common and frequently fatal syndrome in Yuetan Subdistrict, Beijing. The occurrence rate and mortality of sepsis are significantly higher in males and elderly people.

BAP31 Promotes Adhesion Between Endothelial Cells and Macrophages Through the NF-κB Signaling Pathway in Sepsis.

Purpose: To investigate the role of B cell receptor associated protein 31 (BAP31) in the pathogenesis of sepsis. Methods: Cecal ligation and puncture (CLP)-induced C57BL/6J mice, and LPS-challenged endothelial cells (HUVECs) were established to mimic a sepsis animal model and a sepsis cell model, respectively. Cre/LoxP and shRNA methods were used for BAP31 knockdown in vivo and in vitro respectively. Neutrophils/macrophages-endothelial cocultures were used to evaluate neutrophils or macrophages infiltration and adhesion to endothelial cells. Cox proportional hazards model was used to evaluate the survival time of mice. Western blotting (WB) and Quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect toll-like receptor (TLR) signaling pathway, transforming growth factor ß activated kinase 1 (TAK1) signaling pathway and phosphoinositide-3 kinases-protein kinase B (PI3K/AKT) signaling pathway. Results: Deletion of BAP31 reduced CLP-induced mortality of mice, histological damage with less interstitial edema, and neutrophils and macrophages infiltration. IHC and IF showed that BAP31 knockdown significantly decreases the expressions of ICAM1 and VCAM1 both in vivo and in vitro. Coculture showed that LPS-induced neutrophils or macrophages adhesion to endothelial cells was significantly weakened in BAP31 knockdown cells. In addition, BAP31 knockdown of endothelial cells decreased the expression of CD80 and CD86 on the surface of macrophages as well as interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) during sepsis. Mechanistically, LPS-induced the activation of TLR4, MyD88 and TRAF6, and the phosphorylation of TAK1, PI3K, AKT, IκBα and IKKα/ß, resulting in activation of nuclear factor kappa B (NF-κB) p65 in endothelial cells. However, BAP31 knockdown significantly reversed the expressions of associated proteins. Conclusion: BAP31 up-regulated the expressions of ICAM1 and VCAM1 in endothelial cells leading to sepsis-associated organ injury. This may be involved in activation of TLR signaling pathway, TAK1 pathway, and PI3K-AKT signaling pathway.

Development and validation a nomogram prediction model for early diagnosis of bloodstream infections in the intensive care unit.

Purpose: This study aims to develop and validate a nomogram for predicting the risk of bloodstream infections (BSI) in critically ill patients based on their admission status to the Intensive Care Unit (ICU). Patients and methods: Patients' data were extracted from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database (training set), the Beijing Friendship Hospital (BFH) database (validation set) and the eICU Collaborative Research Database (eICU-CRD) (validation set). Univariate logistic regression analyses were used to analyze the influencing factors, and lasso regression was used to select the predictive factors. Model performance was assessed using area under receiver operating characteristic curve (AUROC) and Presented as a Nomogram. Various aspects of the established predictive nomogram were evaluated, including discrimination, calibration, and clinical utility. Results: The model dataset consisted of 14930 patients (1444 BSI patients) from the MIMIC-IV database, divided into the training and internal validation datasets in a 7:3 ratio. The eICU dataset included 2100 patients (100 with BSI) as the eICU validation dataset, and the BFH dataset included 419 patients (21 with BSI) as the BFH validation dataset. The nomogram was constructed based on Glasgow Coma Scale (GCS), sepsis related organ failure assessment (SOFA) score, temperature, heart rate, respiratory rate, white blood cell (WBC), red width of distribution (RDW), renal replacement therapy and presence of liver disease on their admission status to the ICU. The AUROCs were 0.83 (CI 95%:0.81-0.84) in the training dataset, 0.88 (CI 95%:0.88-0.96) in the BFH validation dataset, and 0.75 (95%CI 0.70-0.79) in the eICU validation dataset. The clinical effect curve and decision curve showed that most areas of the decision curve of this model were greater than 0, indicating that this model has a certain clinical effectiveness. Conclusion: The nomogram developed in this study provides a valuable tool for clinicians and nurses to assess individual risk, enabling them to identify patients at a high risk of bloodstream infections in the ICU.

Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.

Development and validation of a machine-learning model for predicting the risk of death in sepsis patients with acute kidney injury.

The mortality rate of patients with sepsis-induced acute kidney injury (S-AKI) is notably elevated. The initial categorization of prognostic indicators has a beneficial impact on elucidating and enhancing disease outcomes. This study aimed to predict the mortality risk of S-AKI patients by employing machine learning techniques. The sample size determined by a four-step procedure yielded 1508 samples. The research design necessitated the inclusion of individuals with S-AKI from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The patients were initially admitted to the Intensive Care Unit (ICU) for their hospital stay. Additionally, these patients (aged from 18 to 89 years old) had encountered S-AKI on the day of their admittance. Forty-two predictive factors were analyzed, with hospitalization death as the outcome variable. The training set (4001 cases) consisted of 70 % of the participants, and the remaining (1714 cases) participants were allocated to the validation set. Furthermore, an additional validation set (MIMIC-III) consisted of 1757 patients from the MIMIC-III database. Moreover, an external validation set from the Intensive Care Department of Beijing Friendship Hospital (BFH) comprised 72 patients. Six machine learning models were employed in the prediction, namely the logistic, lasso, rpart, random forest, xgboost, and artificial neural network models. The comparative efficacy of the newly developed model in relation to the APACHE II model for predicting mortality risk was also assessed. The XGBoost model exhibited a superior performance with the training set. With the internal validation set and the two external validation sets (MIMIC-III and BFH), the xgboost algorithm demonstrated the highest performance. Meanwhile, APACHE II performed poorly at predicting the mortality risk with the BFH validation set. The mortality risk was influenced by three primary clinical parameters: urine volume, lactate, and Glasgow Coma Scale (GCS) score. Thus, we developed a prediction model for the risk of death among S-AKI patients that has an improved performance compared to previous models and is a potentially valuable tool for S-AKI prediction and treatment in the clinic.

Protective effects of Dioscin against sepsis-induced cardiomyopathy via regulation of toll-like receptor 4/MyD88/p65 signal pathway.

BACKGROUND: Dioscin has many pharmacological effects; however, its role in sepsis-induced cardiomyopathy (SIC) is unknown. Accordingly, we concentrate on elucidating the mechanism of Dioscin in SIC rat model. METHODS: The SIC rat and H9c2 cell models were established by lipopolysaccharide (LPS) induction. The heart rate (HR), left ventricle ejection fraction (LVEF), mean arterial blood pressure (MAP), and heart weight index (HWI) of rats were evaluated. The myocardial tissue was observed by hematoxylin and eosin staining. 4-Hydroxy-2-nonenal (4-HNE) level in myocardial tissue was detected by immunohistochemistry. Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities in serum samples of rats and H9c2 cells were determined by colorimetric assay. Bax, B-cell lymphoma-2 (Bcl-2), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), phosphorylated-p65 (p-p65), and p65 levels in myocardial tissues of rats and treated H9c2 cells were measured by quantitative real-time PCR and Western blot. Viability and reactive oxygen species (ROS) accumulation of treated H9c2 cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and dihydroethidium staining assays. RESULTS: Dioscin decreased HR and HWI, increased LVEF and MAP, alleviated the myocardial tissue damage, and reduced 4-HNE level in SIC rats. Dioscin reversed LPS-induced reduction on SOD, CAT, GSH, and Bcl-2 levels, and increment on Bax and TLR4 levels in rats and H9c2 cells. Overexpressed TLR4 attenuated the effects of Dioscin on promoting viability, as well as dwindling TLR4, ROS and MyD88 levels, and p-p65/p65 value in LPS-induced H9c2 cells. CONCLUSION: Protective effects of Dioscin against LPS-induced SIC are achieved via regulation of TLR4/MyD88/p65 signal pathway.

Beta 2-microglobulin is an independent risk marker of acute kidney injury in adult patients with hemophagocytic lymphohistiocytosis.

BACKGROUND AND AIMS: The role of beta2-microglobulin (ß2-MG) in predicting acute kidney injury (AKI) in hemophagocytic lymphohistiocytosis patients has been poorly studied. This study aimed to analyze the clinical characteristics of hemophagocytic lymphohistiocytosis patients and identify risk factors that predict AKI development. METHODS: This retrospective observational cohort study conducted at a single-center involved 938 patients diagnosed with hemophagocytic lymphohistiocytosis, who were divided into AKI  group and non-AKI group. Patient data were collected and analyzed using univariate and multivariate binary logistic regression to identify potiential risk factors associated with AKI occurrence.   RESULTS: Among the enrolled patients, 486 were male (51.9%), the median age was 37 years (interquartile range, 28.0, 52.0), 58.4% experienced AKI. Mechanical ventilation (8.0% vs. 0.8%) and vasopressor support (21.7% vs. 4.1%) occurred at significantly higher rates in the AKI group compared to the non-AKI group, with significantly higher in-hospital mortality (5.5% vs. 1.3%) and 28-day mortality (12.8% vs. 5.4%). When ß2-MG was used as a continuous variable, multifactorial analysis showed that ß2-MG, transplantation, and vasopressor support were independently associated with risk for the development of AKI. CONCLUSIONS: The incidence of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis complicated by AKI remains high. Monitoring levels of ß2-MG may provide clinicians with timely indicators of changes in renal function,  facilitating adjustments to treatment strategies.

COMPARISON AMONG PRESEPSIN, PROCALCITONIN, AND C-REACTIVE PROTEIN IN PREDICTING BLOOD CULTURE POSITIVITY AND PATHOGEN IN SEPSIS PATIENTS.

ABSTRACT: Background: Sepsis is caused by the invasion of the bloodstream by microorganisms from local sites of infection, leading to high mortality. This study aimed to compare the predictive ability of the biomarkers presepsin, procalcitonin (PCT), and C-reactive protein for bacteraemia. Methods: In this retrospective, multicentre study, a dataset of patients with sepsis who were prospectively enrolled between November 2017 and June 2021 was analyzed. The performances of the biomarkers for predicting positive blood cultures and infection with specific pathogens were assessed by the areas under the receiver operating characteristic curves (AUCs). The independent effects of the pathogen and foci of infection on presepsin and PCT levels were assessed by linear logistic regression models. Results: A total of 577 patients with 170 positive blood cultures (29.5%) were enrolled. The AUC achieved using PCT levels (0.856) was significantly higher than that achieved using presepsin (0.786, P = 0.0200) and C-reactive protein (0.550, P < 0.0001) levels in predicting bacteraemia. The combined analysis of PCT and presepsin levels led to a significantly higher AUC than the analysis of PCT levels alone for predicting blood culture positivity (0.877 vs. 0.856, P = 0.0344) and gram-negative bacteraemia (0.900 vs. 0.875, P = 0.0216). In a linear regression model, the elevated concentrations of presepsin and PCT were both independently related to Escherichia coli , Klebsiella species, Pseudomonas species, and Streptococcus species infections and Sequential Organ Failure Assessment score. Presepsin levels were also associated with Acinetobacter species and abdominal infection, and PCT levels were positively associated with other Enterobacteriaceae and negatively associated with respiratory infection. Combined analysis of presepsin and PCT levels provided a high sensitivity and specificity in identifying E. coli or Klebsiella species infection. Conclusions: Presepsin and PCT were promising markers for predicting bacteraemia and common pathogens at the time of sepsis onset with a synergistic effect.

Antibiotic combinations prediction based on machine learning to multicentre clinical data and drug interaction correlation.

BACKGROUND: With increasing antibiotic resistance and regulation, the issue of antibiotic combination has been emphasised. However, antibiotic combination prescribing lacks a rapid identification of feasibility, while its risk of drug interactions is unclear. METHODS: We conducted statistical descriptions on 16 101 antibiotic coprescriptions for inpatients with bacterial infections from 2015 to 2023. By integrating the frequency and effectiveness of prescriptions, we formulated recommendations for the feasibility of antibiotic combinations. Initially, a machine learning algorithm was utilised to optimise grading thresholds and habits for antibiotic combinations. A feedforward neural network (FNN) algorithm was employed to develop antibiotic combination recommendation model (ACRM). To enhance interpretability, we combined sequential methods and DrugBank to explore the correlation between antibiotic combinations and drug interactions. RESULTS: A total of 55 antibiotics, covering 657 empirical clinical antibiotic combinations were used for ACRM construction. Model performance on the test dataset showed AUROCs of 0.589-0.895 for various antibiotic recommendation classes. The ACRM showed satisfactory clinical relevance with 61.54-73.33% prediction accuracy in a new independent retrospective cohort. Antibiotic interaction detection showed that the risk of drug interactions was 29.2% for strongly recommended and 43.5% for not recommended. A positive correlation was identified between the level of clinical recommendation and the risk of drug interactions. CONCLUSIONS: Machine learning modelling of retrospective antibiotic prescriptions habits has the potential to predict antibiotic combination recommendations. The ACRM plays a supporting role in reducing the incidence of drug interactions. Clinicians are encouraged to adopt such systems to improve the management of antibiotic usage and medication safety.

Emodin improves lipopolysaccharide-induced microcirculatory disturbance in rat mesentery.

OBJECTIVE: Sepsis is a systemic inflammatory response syndrome. Emodin is a major ingredient of Rheum Palmatum, a Chinese herb that is widely used in China for treatment of endotoxemia-related diseases. This study intended to examine the effect of Emodin on LPS-induced rat mesenteric microcirculatory disturbance and the underlying mechanisms. METHODS: The male Wistar rats received LPS (5 mg/kg/hr) for 90 min, with or without administration of Emodin (10 mg/kg/hr) by enema 30 min before (pre-treatment) or after (post-treatment) LPS infusion, and the dynamics of mesenteric microcirculation were determined by inverted intravital microscopy. Expression of adhesion molecules and TLR4, NF-κB p65, ICAM-1, MPO, and AP-1 in mesentery tissue was evaluated by flow cytometry and Western-blot, respectively. RESULTS: Pre or post-treatment with Emodin significantly ameliorated LPS-induced leukocyte emigration, reactive oxygen species production and albumin leakage, and the expression of TLR4, NF-κB p65, ICAM-1, MPO and AP-1 in mesentery. CONCLUSIONS: These results demonstrate the beneficial role of Emodin in attenuating the LPS-induced microcirculatory disturbance, and support the use of Emodin for patients with endotoxemia.