Incorporating preoperative frailty to assist in early prediction of postoperative pneumonia in elderly patients with hip fractures: an externally validated online interpretable machine learning model.

BACKGROUND: This study aims to implement a validated prediction model and application medium for postoperative pneumonia (POP) in elderly patients with hip fractures in order to facilitate individualized intervention by clinicians. METHODS: Employing clinical data from elderly patients with hip fractures, we derived and externally validated machine learning models for predicting POP. Model derivation utilized a registry from Nanjing First Hospital, and external validation was performed using data from patients at the Fourth Affiliated Hospital of Nanjing Medical University. The derivation cohort was divided into the training set and the testing set. The least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression were used for feature screening. We compared the performance of models to select the optimized model and introduced SHapley Additive exPlanations (SHAP) to interpret the model. RESULTS: The derivation and validation cohorts comprised 498 and 124 patients, with 14.3% and 10.5% POP rates, respectively. Among these models, Categorical boosting (Catboost) demonstrated superior discrimination ability. AUROC was 0.895 (95%CI: 0.841-0.949) and 0.835 (95%CI: 0.740-0.930) on the training and testing sets, respectively. At external validation, the AUROC amounted to 0.894 (95% CI: 0.821-0.966). The SHAP method showed that CRP, the modified five-item frailty index (mFI-5), and ASA body status were among the top three important predicators of POP. CONCLUSION: Our model's good early prediction ability, combined with the implementation of a network risk calculator based on the Catboost model, was anticipated to effectively distinguish high-risk POP groups, facilitating timely intervention.

A risk prediction model based on machine learning for postoperative cognitive dysfunction in elderly patients with non-cardiac surgery.

BACKGROUND: Early identification of elderly patients undergoing non-cardiac surgery who may be at high risk for postoperative cognitive dysfunction (POCD) can increase the chances of prevention for them, as extra attention and limited resources can be allocated more to these patients. AIM: We performed this analysis with the aim of developing a simple, clinically useful machine learning (ML) model to predict the probability of POCD at 3 months in elderly patients after non-cardiac surgery. METHODS: We collected information on patients who received surgical treatment at Nanjing First Hospital from May 2020 to May 2021. We used LASSO regression to select key features and built 5 ML models to assess the risk of POCD at 3 months in elderly patients after non-cardiac surgery. The Shapley Additive exPlanations (SHAP) and methods were introduced to interpret the best model. RESULTS: A total of 415 patients with non-cardiac surgery were included. The support vector machine (SVM) was the best-performing model of the five ML models. The model showed excellent performance compared to the other four models. The SHAP results showed that VAS score, age, intraoperative hypotension, and preoperative hemoglobin were the four most important features, indicating that the SVM model had good interpretability and reliability. The website of the web-based calculator was https://modricreagan-non-3-pocd-9w2q78.streamlit.app/ . CONCLUSION: Based on six important perioperative variables, we successfully established a series of ML models for predicting POCD occurrence at 3 months after surgery in elderly non-cardiac patients, with SVM model being the best-performing model. Our models are expected to serve as decision aids for clinicians to monitor screened high-risk patients more closely or to consider further interventions.

The Impact on 30-Day Mortality From a Brief Focused Ultrasound-Guided Management Protocol Immediately Before Emergency Noncardiac Surgery in Critically Ill Patients: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To determine whether brief ultrasound-guided treatment of hemodynamic shock and respiratory failure immediately before emergency noncardiac surgery reduced 30-day mortality. DESIGN: Parallel, nonblinded, randomized trial with 1:1 allocation to control and intervention groups. SETTING: Twenty-eight major hospitals within China. PARTICIPANTS: Six-hundred sixty patients ≥14 years of age, scheduled for emergency noncardiac surgery with evidence of shock (heart rate >120 beat/min, systolic blood pressure< 90 mmHg or requiring inotrope infusion), or respiratory failure (Pulse Oxygen Saturation <92%, respiratory rate >20 beat/min, or requiring mechanical ventilation). INTERVENTIONS: A brief (<15 minutes) focused ultrasound of ventricular filling and function, lung, and peritoneal spaces, with predefined treatment recommendation based on the ultrasound was performed before surgery or standard care. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 30-day mortality. Secondary outcomes included changes in medical or surgical diagnosis and management due to ultrasound, intensive care unit, and hospital stay and cost, and Short Form-8 quality-of-life scores. Although there were frequent changes in diagnosis (82%) and management (49%) after the ultrasound, mortality at 30 days was not different between groups (50 [15.7%] v 53 [16.3%]; odds ratio 1.05, 0.69-1.6, p = 0.826). There were no differences in the secondary outcomes of the days spent in the hospital (mean 13.8 days, 95% confidence interval [CI] 12.1-15.6 v 14.4 d, 11.8-17.1, p = 0.718) or intensive care unit (mean 9.3 days, 95% CI 7.7-11.0 v 8.7 d, 7.2-10.2, p = 0.562), hospital cost (USD$14.5K, 12.2-16.7 v 13.7, 11.5-15.9, p = 0.611) or Short Form-8 scores at one year (mean 80.9, 95% CI 78.4-83.3 v 79.7, 76.9-82.5, p = 0.54) between participants allocated to the ultrasound and control groups. CONCLUSIONS: In critically ill patients with hemodynamic shock or respiratory failure, a focused ultrasound-guided management did not reduce 30-day mortality but led to frequent changes in diagnosis and patient management.

CXCR5 down-regulation alleviates cognitive dysfunction in a mouse model of sepsis-associated encephalopathy: potential role of microglial autophagy and the p38MAPK/NF-κB/STAT3 signaling pathway.

BACKGROUND: Cognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits. METHODS: Sepsis was induced in adult male C57BL/6 J and CXCR5-/- mice by cecal ligation and puncture (CLP). At 14-18 days after surgery, animals were tested in a Morris water maze, followed by a fear conditioning test. Transmission electron microscopy of hippocampal sections was used to assess levels of autophagy. Primary microglial cultures challenged with lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting CXCR5, and to investigate the possible involvement of the p38MAPK/NF-κB/STAT3 signaling pathway. RESULTS: CLP impaired learning and memory and up-regulated CXCR5 in hippocampal microglia. CLP activated hippocampal autophagy, as reflected by increases in numbers of autophagic vacuoles, conversion of microtubule-associated protein 1 light chain 3 (LC3) from form I to form II, accumulation of beclin-1 and autophagy-related gene-5, and a decrease in p62 expression. CLP also shifted microglial polarization to the M1 phenotype, and increased levels of IL-1ß, IL-6 and phosphorylated p38MAPK. CXCR5 knockout further enhanced autophagy but partially reversed all the other CLP-induced effects, including cognitive deficits. Similar effects on autophagy and cytokine expression were observed after knocking down CXCR5 in LPS-challenged primary microglial cultures; this knockdown also partially reversed LPS-induced up-regulation of phosphorylated NF-κB and STAT3. The p38MAPK agonist P79350 partially reversed the effects of CXCR5 knockdown in microglial cultures. CONCLUSIONS: CXCR5 may act via p38MAPK/NF-κB/STAT3 signaling to inhibit hippocampal autophagy during sepsis and thereby contribute to cognitive dysfunction. Down-regulating CXCR5 can restore autophagy and mitigate the proinflammatory microenvironment in the hippocampus.

Thermographic follow-up of postherpetic neuralgia (PHN) subsequent to Ramsay Hunt syndrome with multicranial nerve (V, VII, VIII and IX) involvement: a case report.

BACKGROUND: Ramsay Hunt syndrome (RHS) is caused by a reactivation of varicella-zoster virus (VZV) infection, and it is characterized by the symptoms of facial paralysis, otalgia, auricular rash, and/or an oral lesion. Elderly patients or immunocompromised patients, deep pain at the initial visit and no prompt treatment are significant predictors of postherpetic neuralgia (PHN). When PHN occurs, especially involved cranial polyneuropathy, multiple modalities should be administered for patients with the intractable PHN. The use of thermography in the follow-up of PHN secondary to RHS with multicranial nerve involvement has not yet been described yet in the literature. CASE PRESENTATION: The patient was a 78-year-old man with the chief complaint of a 3-month history of PHN secondary to RHS with polycranial nerve (V, VII, VIII, and IX) involvement. Multimodality therapy with oral gabapentin, pulsed radiofrequency (PRF) application to the Gasserian ganglion for pain in the trigeminal nerve region, linear-polarized near-infrared light irradiation for pain in the facial nerve region, and 2% lidocaine spray for pain in the glossopharyngeal nerve region was used to the treat patient, and follow-up evaluations included thermography. This comprehensive treatment obviously improved the quality of life, resulting in considerable pain relief, as indicated by a decrease in the numerical rating scale (NRS) score from 9 to 3 and a decrease in thermal imaging temperature from higher to average temperature on the ipsilateral side compared with the contralateral side. Lidocaine spray on the tonsillar branches of the glossopharyngeal nerve resulted in an improvement in odynophagia, and the NRS score decreased from 9 to 0 for glossopharyngeal neuralgia after three applications. CONCLUSION: Although the use of thermography in the follow-up of RHS with multiple cranial nerve (V, VII, VIII, and IX) involvement is very rare, in this patient, thermal imaging showed the efficacy of combination therapy (oral gabapentin, 2% lidocaine sprayed, PRF application and linear-polarized near-infrared light irradiation) and that is a good option for treatment.

Chemokine CXCL13 acts via CXCR5-ERK signaling in hippocampus to induce perioperative neurocognitive disorders in surgically treated mice.

BACKGROUND: Perioperative neurocognitive disorders (PNDs) occur frequently after surgery and worsen patient outcome. How C-X-C motif chemokine (CXCL) 13 and its sole receptor CXCR5 contribute to PNDs remains poorly understood. METHODS: A PND model was created in adult male C57BL/6J and CXCR5-/- mice by exploratory laparotomy. Mice were pretreated via intracerebroventricular injection with recombinant CXCL13, short hairpin RNA against CXCL13 or a scrambled control RNA, or ERK inhibitor PD98059. Then surgery was performed to induce PNDs, and animals were assessed in the Barnes maze trial followed by a fear-conditioning test. Expression of CXCL13, CXCR5, and ERK in hippocampus was examined using Western blot, quantitative PCR, and immunohistochemistry. Levels of interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in hippocampus were assessed by Western blot. RESULTS: Surgery impaired learning and memory, and it increased expression of CXCL13 and CXCR5 in the hippocampus. CXCL13 knockdown partially reversed the effects of surgery on CXCR5 and cognitive dysfunction. CXCR5 knockout led to similar cognitive outcomes as CXCL13 knockdown, and it repressed surgery-induced activation of ERK and production of IL-1ß and TNF-α in hippocampus. Recombinant CXCL13 induced cognitive deficits and increased the expression of phospho-ERK as well as IL-1ß and TNF-α in hippocampus of wild-type mice, but not CXCR5-/- mice. PD98059 partially blocked CXCL13-induced cognitive dysfunction as well as production of IL-1ß and TNF-α. CONCLUSIONS: CXCL13-induced activation of CXCR5 may contribute to PNDs by triggering ERK-mediated production of pro-inflammatory cytokines in hippocampus.

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Aberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. In the current study, we examined the potential role of the long noncoding RNA (lncRNA) sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2OT), a known regulator of adult neurogenesis in sepsis-induced deficits in hippocampal neurogenesis and cognitive function. METHODS: Sepsis was induced in adult C57BL/6 J male mice by cecal ligation and perforation (CLP) surgery. Randomly selected CLP mice were transfected with short interfering RNAs (siRNAs) against SOX2OT or SOX2, or with scrambled control siRNA. Cognitive behavior was tested 8-12 days post-surgery using a Morris water maze. Western blotting and RT-qPCR were used to determine expression of SOX2, Ki67, doublecortin (DCX), nestin, brain lipid-binding protein, and glial fibrillary acidic protein (GFAP) in the hippocampus. The number of bromodeoxyuridine (BrdU)+/DCX+ cells, BrdU+/neuronal nuclei (NeuN)+ neurons, and BrdU+/GFAP+ glial cells in the dentate gyrus were assessed by immunofluorescence. RESULTS: CLP mice showed progressive increases in SOX2OT and SOX2 mRNA levels on days 3, 7, and 14 after CLP surgery, accompanied by impaired cognitive function. Sepsis led to decrease in all neuronal markers in the hippocampus, except GFAP. Immunofluorescence confirmed the decreased numbers of BrdU+/DCX+ cells and BrdU+/NeuN+ neurons, and increased numbers of BrdU+/GFAP+ cells. SOX2OT knockdown partially inhibited the effects of CLP on levels of SOX2 and neuronal markers, neuronal populations in the hippocampus, and cognitive function. SOX2 deficiency recapitulated the effects of SOX2OT knockdown. CONCLUSION: SOX2OT knockdown improves sepsis-induced deficits in hippocampal neurogenesis and cognitive function by downregulating SOX2 in mice. Inhibiting SOX2OT/SOX2 signaling may be effective for treating or preventing neurodegeneration in sepsis-associated encephalopathy.

Risk factors for early postoperative cognitive dysfunction after colorectal surgery.

BACKGROUND: It has been reported that postoperative cognitive dysfunction (POCD) is correlated with the degeneration of the central nervous system, oxidative stress, inflammation, and endocrine and immune dysfunction. Increased age, predisposed comorbidity, long surgery time, and prolonged stay in the intensive care unit have been reported to be risk factors for developing POCD for cardiac surgery. In the present study, the risk factors of early POCD after colorectal surgery were investigated. METHODS: Eighty patients, who provided informed consents for their participation in this study, were enrolled and received colorectal surgery under general anesthesia. Neuropsychological tests were performed preoperatively and on postoperative day seven. The risk factors for POCD were analyzed using a multivariate logistic regression model. RESULTS: Nineteen patients were diagnosed with POCD (24.7%). Diabetes history (OR = 8.391 [2.208-31.882], P = 0.012), fasting over 3 days after surgery (OR = 5.236 [1.998-13.721], P = 0.001) and an SIRS score of > 3 on the second day after surgery (OR = 6.995 [1.948-25.111], P = 0.003) were risk factors for early POCD in colorectal cancer patients. CONCLUSION: The risk factors for early POCD after colorectal surgery included diabetes history, fasting over 3 days, and an SIRS score of > 3 on the second day.

Regulation of Sirtuin 3-Mediated Deacetylation of Cyclophilin D Attenuated Cognitive Dysfunction Induced by Sepsis-Associated Encephalopathy in Mice.

The present study aimed to investigate cognitive dysfunction in the hippocampus induced by sepsis-associated encephalopathy (SAE) via acetylation of cyclophilin D (CypD) and opening of mitochondrial permeability transition pore. It also explored whether activating sirtuin 3 (SIRT3) can mediate deacetylation of CypD and prevent the development of SAE. Male mice were randomly assigned to six groups: sham group, cecal ligation puncture group, CypD siRNA transfection (CypD-si) group, CypD control siRNA transfection (CypD-c) group, SIRT3 overexpression vector pcDNA3.1 (SIRT3-p) group, and SIRT3 empty vector pcDNA3.1 (SIRT3-v) group (n = 18). The CypD-si and CypD-c groups were transfected with CypD siRNA and CypD control siRNA, respectively. The SIRT3-p and SIRT3-v groups were injected with SIRT3 pcDNA3.1 and vector pcDNA3.1, respectively. The learning and memory function was assessed using the learning version of the Morris water maze test. Then, cell apoptosis and the levels of CypD, acetylated CypD, SIRT-3, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and caspase-3 in the hippocampus were determined. The levels of CypD and acetylation of CypD increased in the hippocampus induced by SAE. Increasing SIRT3 and decreasing CypD can attenuate cognitive impairment and neuroapoptosis, and protect the integrity of mitochondrial membrane from damage and restore the protein expressions of IL-6, TNF-α, and caspase-3. Activating SIRT3-mediated deacetylation of CypD attenuated learning and memory dysfunction induced by SAE.

[Mechanisms for the regulatory effect of prostaglandin E2/prostaglandin E receptor 4 on high mobility group box-1 protein in lipopolysaccharide-induced sepsis in mouse peritoneal macrophage].

OBJECTIVE: To explore the effect of prostaglandin E2 (PGE2) on the expression of high mobility group box-1 protein (HMGB1) in peritoneal macrophages of septic mice and its possible mechanisms.
 Methods: The mouse peritoneal macrophages were isolated and cultured by conventional methods.The model of inflammation was established by using lipopolysaccharide (LPS) to incubate with mouse peritoneal macrophages. The PGE2, prostaglandin E receptor (EP) 4 agonist, EP4 RNAi, and DN.CREB inhibitory plasmid were used to interfere with the LPS-treated mouse peritoneal macrophage. The levels of HMGB1 was determined by Western blot.
 Results: Compared with LPS alone treatment, the expression of HMGB1 in peritoneal macrophages was increased obviously after 24 h by treatment with PGE2 and LPS, and it was also increased after the combined treatment of EP4 receptor agonist with LPS for 24 h (both P<0.05); compared with the PGE2+LPS treatment, the level of HMGB1 was decreased after knockdown of EP4 receptor expression (P<0.05); compared with EP4 receptor agonist +LPS treatment, there was no difference in HMGB1 levels in mice after the treatment with DN.CREB plasmid to suppress CREB function (P>0.05); compared with LPS alone treatment, the combined treatment of EP4 receptor agonist with LPS for 24 h could up-regulate the phosphorylation of epidermal growth factor receptor (EGFR) and protein kinase B (Akt) thr308 (P<0.05), which were blocked by EGFR inhibitor. Once Akt specific inhibitor was used before EP4 and LPS treatment, the expression of HMGB1 was declined (P<0.05).
 Conclusion: PGE2 can up-regulate the expression of HMGB1 in sepsis of peritoneal macrophages through EP4 receptor, which may be related to the activation of EGFR/PI3K/Akt signaling pathway.

Online interpretable dynamic prediction models for postoperative delirium after cardiac surgery under cardiopulmonary bypass developed based on machine learning algorithms: A retrospective cohort study.

OBJECTIVE: Postoperative delirium (POD) is strongly associated with poor early and long-term prognosis in cardiac surgery patients with cardiopulmonary bypass (CPB). This study aimed to develop dynamic prediction models for POD after cardiac surgery under CPB using machine learning (ML) algorithms. METHODS: From July 2021 to June 2022, clinical data were collected from patients undergoing cardiac surgery under CPB at Nanjing First Hospital. A dataset from the same center (October 2022 to November 2022) was also used for temporal external validation. We used ML and deep learning to build models in the training set, optimized parameters in the test set, and finally validated the best model in the validation set. The SHapley Additive exPlanations (SHAP) method was introduced to explain the best models. RESULTS: Of the 885 patients enrolled, 221 (25.0%) developed POD. 22 (22.0%) of 100 validation cohort patients developed POD. The preoperative and postoperative artificial neural network (ANN) models exhibited optimal performance. The validation results demonstrated satisfactory predictive performance of the ANN model, with area under the receiver operator characteristic curve (AUROC) values of 0.776 and 0.684 for the preoperative and postoperative models, respectively. Based on the ANN algorithm, we constructed dynamic, highly accurate, and interpretable web risk calculators for POD. CONCLUSIONS: We successfully developed online interpretable dynamic ANN models as clinical decision aids to identify patients at high risk of POD before and after cardiac surgery to facilitate early intervention or care.

A machine learning stacking model accurately estimating gastric fluid volume in patients undergoing elective sedated gastrointestinal endoscopy.

BACKGROUND: The current point-of-care ultrasound (POCUS) assessment of gastric fluid volume primarily relies on the traditional linear approach, which often suffers from moderate accuracy. This study aimed to develop an advanced machine learning (ML) model to estimate gastric fluid volume more accurately. METHODS: We retrospectively analyzed the clinical data and POCUS data (D1: craniocaudal diameter, D2: anteroposterior diameter) of 1386 patients undergoing elective sedated gastrointestinal endoscopy (GIE) at Nanjing First Hospital to predict gastric fluid volume using ML techniques, including six different ML models and a stacking model. We evaluated the models using the adjusted Coefficient of Determination (R2), mean absolute error (MAE) and root mean square error (RMSE). The SHapley Additive exPlanations (SHAP) method was used to interpret the importance of the variables. Finally, a web calculator was constructed to facilitate its clinical application. RESULTS: The stacking model (Linear regression + Multilayer perceptron) performed best, with the highest adjusted R2 of 0.718 (0.632 to 0.804). The mean prediction bias was 4 ml (MAE: 4.008 (3.68 to 4.336)), which is better than that of the linear model. D1 and D2 ranked high in the SHAP plot and performed better in the right lateral decubitus (RLD) than in the supine position. The web calculator can be accessed at https://cheason.shinyapps.io/Stacking_regressor/. CONCLUSION: The stacking model and its web calculator can serve as practical tools for accurately estimating gastric fluid volume in patients undergoing elective sedated GIE. It is recommended that anesthesiologists measure D1 and D2 in the patient's RLD position.

Development and validation of a novel nomogram model to assess the risk of gastric contents in outpatients undergoing elective sedative gastrointestinal endoscopy procedures.

BACKGROUND: Gastric contents may contribute to patients' aspiration during anesthesia. Ultrasound can accurately assess the risk of gastric contents in patients undergoing sedative gastrointestinal endoscopy (GIE) procedures, but its efficiency is limited. Therefore, developing an accurate and efficient model to predict gastric contents in outpatients undergoing elective sedative GIE procedures is greatly desirable. METHODS: This study retrospectively analyzed 1501 patients undergoing sedative GIE procedures. Gastric contents were observed under direct gastroscopic vision and suctioned through the endoscope. High-risk gastric contents were defined as having solid content or liquid volume > 25 ml and pH < 2.5; otherwise, they were considered low-risk gastric contents. Univariate analysis and multivariate analysis were used to select the independent risk factors to predict high-risk gastric contents. Based on the selected independent risk factors, we assigned values to each independent risk factor and established a novel nomogram. The performance of the nomogram was verified in the testing cohort by the metrics of discrimination, calibration, and clinical usefulness. In addition, an online accessible web calculator was constructed. RESULTS: We found BMI, cerebral infarction, cirrhosis, male, age, diabetes, and gastroesophageal reflux disease were risk factors for gastric contents. The AUROCs were 0.911 and 0.864 in the development and testing cohort, respectively. Moreover, the nomogram showed good calibration ability. Decision curve analysis and Clinical impact curve demonstrated that the predictive nomogram was clinically useful. The website of the nomogram was https://medication.shinyapps.io/dynnomapp/. CONCLUSIONS: This study demonstrates that clinical variables can be combined with algorithmic techniques to predict gastric contents in outpatients. Nomogram was constructed from routine variables, and the web calculator had excellent clinical applicability to assess the risk of gastric contents accurately and efficiently in outpatients, assist anesthesiologists in assessment and identify the most appropriate patients for ultrasound.

Down-regulating nuclear factor of activated T cells 1 alleviates cognitive deficits in a mouse model of sepsis-associated encephalopathy, possibly by stimulating hippocampal neurogenesis.

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has been associated with increased morbidity and mortality. Nuclear factor of activated T cells (NFATs) 1, a transcriptional factor that regulates T cell development, activation and differentiation, has been implicated in neuronal plasticity. Here we examined the potential role of NFAT1 in sepsis-associated encephalopathy in mice. Adult male C57BL/6J mice received intracerebroventricular injections of short interfering RNA against NFAT1 or sex-determining region Y-box 2 (SOX2), or a scrambled control siRNA prior to cecal ligation and perforation (CLP). A group of mice receiving sham surgery were included as an additional control. CLP increased escape latency and decreased the number of crossings into, and total time spent within, the target quadrant in the Morris water maze test. CLP also decreased the freezing time in context-dependent, but not context-independent, fear conditioning test. Knockdown of either NFAT1 or SOX2 attenuated these behavioral deficits. NFAT1 knockdown also attenuated CLP-induced upregulation of SOX2, increased the numbers of nestin-positive cells and newborn astrocytes, reduced the number of immature newborn neurons, and promoted the G1 to S transition of neural stem cells in hippocampus. These findings suggest that NFAT1 may contribute to sepsis-induced behavioral deficits, possibly by promoting SOX2 signaling and neurogenesis.

Machine learning-based risk prediction of hypoxemia for outpatients undergoing sedation colonoscopy: a practical clinical tool.

OBJECTIVES: Hypoxemia as a common complication in colonoscopy under sedation and may result in serious consequences. Unfortunately, a hypoxemia prediction model for outpatient colonoscopy has not been developed. Consequently, the objective of our study was to develop a practical and accurate model to predict the risk of hypoxemia in outpatient colonoscopy under sedation. METHODS: In this study, we included patients who received colonoscopy with anesthesia in Nanjing First Hospital from July to September 2021. Risk factors were selected through the least absolute shrinkage and selection operator (LASSO). Prediction models based on logistic regression (LR), random forest classifier (RFC), extreme gradient boosting (XGBoost), support vector machine (SVM), and stacking classifier (SCLF) model were implemented and assessed by standard metrics such as the area under the receiver operating characteristic curve (AUROC), sensitivity and specificity. Then choose the best model to develop an online tool for clinical use. RESULTS: We ultimately included 839 patients. After LASSO, body mass index (BMI) (coefficient = 0.36), obstructive sleep apnea-hypopnea syndrome (OSAHS) (coefficient = 1.32), basal oxygen saturation (coefficient = -0.14), and remifentanil dosage (coefficient = 0.04) were independent risk factors for hypoxemia. The XGBoost model with an AUROC of 0.913 showed the best performance among the five models. CONCLUSION: Our study selected the XGBoost as the first model especially for colonoscopy, with over 95% accuracy and excellent specificity. The XGBoost includes four variables that can be quickly obtained. Moreover, an online prediction practical tool has been provided, which helps screen high-risk outpatients with hypoxemia swiftly and conveniently.

Colonoscopy under sedation is an effective technique for the inspection and treatment of alimentary canal diseases, but hypoxemia associated with this process cannot be ignored, since prolonged or severe hypoxemia may result in several serious consequences.We wanted to develop a practical and accurate model to predict the risk of hypoxemia for outpatient colonoscopy under sedation, which could help clinicians make more accurate and objective judgments to prevent patients from being harmed.A total of 839 patients were included in our study and we constructed five machine learning models and selected the best one, which demonstrated satisfactory performance. On this basis, a user-friendly data interface has been developed for convenient application. Clinicians can log in to this interface at any time and it will automatically calculate the patient's risk of hypoxemia when entering patient information.This study offers evidence that machine learning algorithms can accurately predict the risk of hypoxemia for outpatient colonoscopy under sedation and the model we developed is a practical and interpretable tool that could be used as a clinical decision-making aid.

Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the JAK/STAT signaling activation.

BACKGROUND: The α2-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury. However the underlying molecular mechanisms remain unclear. The purpose of this study was to investigate whether the Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a role in dexmedetomidine's renoprotection. METHODS: I/R model was induced by bilateral renal pedicle clamping for 45 min followed by 48 h of reperfusion in male Wistar rat. Sham laparotomy served as controls. Animals received dexmedetomidine (50 µg/kg, i.p.) in the absence or presence of atipamezole (250 µg/kg, i.p.), or vehicle (DMSO) in the absence or presence of selective JAK2 inhibitor tyrphostin AG490 (10 mg/kg, i.p.) before ischemia. Renal function, histology, apoptosis, expression of cleaved caspase 3 protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and phosphorylations of JAK2, STAT1 and STAT3 were assessed. RESULTS: The animals treated with either dexmedetomidine or AG490 exhibited an improved renal functional recovery, attenuated histological lesions and reduced number of apoptotic tubular epithelial cells. Either dexmedetomidine or AG490 inhibited the phosphorylations of JAK2 and its downstream molecule STAT1 and STAT3, accompanied by down-regulation the expression of cleaved caspase 3, ICAM-1 and MCP-1 proteins, and significantly ameliorated renal I/R injury. CONCLUSIONS: Dexmedetomidine protects kidney against I/R injury, at least in part, through its inhibitory effects on injury-induced activation of JAK/STAT signaling pathway. If our data can be extrapolated to clinical setting, then dexmedetomidine may therefore serve as a clinical strategy to treat/prevent perioperative renal I/R injury.

Effects of dexmedetomidine on early and late cytokines during polymicrobial sepsis in mice.

OBJECTIVE: We investigated whether dexmedetomidine provided protective effects on cecal ligation and puncture (CLP)-induced septic mice, through suppressing the expression of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6)] and high mobility group box 1 (HMGB1). METHODS: The model of sepsis was set up by CLP in 136 male BALB/c mice (40 mice for survival studies and 96 for cytokine studies) which were divided into four groups, including a C, CLP, DEX + CLP and CLP + DEX group. The serum levels of TNF-α, IL-6 and HMGB1 were detected at 6, 12, 24 and 48 h after operations, and lung HMGB1 mRNA were analyzed at 24 and 48 h. The mortality rates were calculated 7 days after the operations. RESULTS: The mortality rates 7 days after operations were significantly lower in the CLP + DEX (50 %) and DEX + CLP (30 %) groups than in the CLP group (90 %). Serum concentrations of IL-6 and TNF-α decreased significantly in dexmedetomidine administration groups compared with the CLP group. The levels of HMGB1 and lung HMGB1 mRNA were lower in the dexmedetomidine administration groups than in the CLP group. There was a significant correlation between lung HMGB1 mRNA and serum HMGB1(r = 0.858). CONCLUSIONS: Dexmedetomidine could reduce the mortality rate and inhibit pro-inflammatory cytokine responses during polymicrobial sepsis in mice.

Effects of adiponectin on acute lung injury in cecal ligation and puncture-induced sepsis rats.

BACKGROUND: The purpose of this study was to elucidate the possible beneficial effects of adiponectin (APN) on acute lung injury in a rat model of sepsis. METHODS: We subjected male Sprague-Dawley rats to cecal ligation and puncture (CLP) to establish sepsis models. We randomly animals divided into four groups: control (C), model (CLP), preemptive APN administration (APN plus CLP), and delayed APN administration (CLP plus APN). We killed the animals 24 h after CLP and collected blood samples to determine PaO2 and PaCO2. Lung samples were taken for histologic assessment and measurement of myeloperoxidase activity. We measured neutrophil and macrophage count and cytokine production (tumor necrosis factor-α and macrophage inflammatory protein-2) in bronchoalveolar lavage fluid. RESULTS: Histology findings and lung injury score analysis revealed acute lung injury in rats in the CLP group, whereas those in the APN-treated group had mild lung injury. The effects of sepsis on the increasing cell number in bronchoalveolar lavage fluid as well as the wet/dry weight ratio, neutrophil infiltration, and myeloperoxidase activity of lung tissue were significantly attenuated by APN administration. Adiponectin also significantly alleviated hypoxemia and hypercapnia resulting from the development of lung injury. In addition, in APN-treated rats, the levels of pulmonary inflammatory molecule (macrophage inflammatory protein-2) and cytokine (tumor necrosis factor-α) were down-regulated compared with the CLP group. CONCLUSIONS: Adiponectin administration ameliorates acute lung injury in a rat model of sepsis induced by CLP, no matter whether it is administrated before or after the onset of sepsis.

Role of nuclear factor of activated T Cells-1 in Sepsis-induced behavioral deficits in mice.

INTRODUCTION: The nuclear factor of activated T cells-1 (NFAT1) is involved in both neuroinflammation and cognitive dysfunction. In this study, we examined the role of NFAT1 in sepsis-induced cognitive impairment in a mouse model. METHODS: Sepsis was established in adult mice by cecal ligation and puncture (CLP). Novel object recognition tests on days 14-21 and fear conditioning tests on days 22-23 post-surgery showed that CLP impaired both behaviors. BV2 microglia cells exposed to lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting NFAT1 on autophagy and inflammatory cytokines. RESULTS: CLP increased the expression of NFAT1 in hippocampal microglia and induced hippocampal autophagy by downregulating p62, upregulating beclin-1 and autophagy-related gene-5, and increasing the ratio of microtubule-associated protein 1 light chain 3-I (LC3-I) to LC3-II. In addition, CLP shifted microglial polarization from M2 to M1 and the production of inflammatory cytokines, similar to the effects of lipopolysaccharide on BV2 microglia cells. Conversely, NFAT1 knockdown or the autophagy inhibitor 3-methyladenine attenuated the effects of CLP on autophagy and inflammation in vitro and in vivo, while rapamycin partially reversed the protective effects of NFAT1 inhibition. CONCLUSION: This study suggests that NFAT1 downregulation attenuates sepsis-induced behavioral deficits by inhibiting autophagy, microglia polarization, and neuroinflammation..

[Phosphate and tension homology-induced kinase 1/Parkin signaling mediates cognitive dysfunction in sepsis-associated encephalopathy through activation of hippocampal mitochondrial autophagy].

OBJECTIVE: To investigate the effects of gene of phosphate and tension homology (PTEN)-induced putative kinase 1 (PINK1)/Parkin pathway on hippocampal mitophagy and cognitive function in mice with sepsis-associated encephalopathy (SAE) and its possible mechanism. METHODS: A total of 80 male C57BL/6J mice were randomly divided into Sham group, cecal ligation puncture (CLP) group, PINK1 plasmid transfection pretreatment groups (p-PINK1+Sham group, p-PINK1+CLP group), empty vector plasmid transfection control group (p-vector+CLP group), with 16 mice in each group. The mice in CLP groups were treated with CLP to reproduce SAE models. The mice in the Sham groups were performed laparotomy only. Animals in the p-PINK1+Sham and p-PINK1+CLP groups were transfected with PINK1 plasmid through the lateral ventricle at 24 hours before surgery, while mice in the p-vector+CLP group were transfected with the empty plasmid. Morris water maze experiment was performed 7 days after CLP. The hippocampal tissues were collected, the pathological changes were observed under a light microscope after hematoxylin-eosin (HE) staining, and the mitochondrial autophagy was observed under a transmission electron microscopy after uranyl acetate and lead citrate staining. The expressions of PINK1, Parkin, Beclin1, interleukins (IL-6, IL-1ß) and microtubule-associated protein 1 light chain 3 (LC3) were detected by Western blotting. RESULTS: Compared with the Sham group, CLP group mice in Morris water maze experiment had longer escape latency, shorter target quadrant residence time, and fewer times of crossing the platform at 1-4 days. Under the light microscope, the hippocampal structure of the mouse was injured, the neuronal cells were arranged in disorder, and the nuclei were pyknotic. Under the electron microscope, the mitochondria appeared swollen, round, and wrapped by bilayer or multilayer membrane structures. Compared with the Sham group, CLP group had higher expressions of PINK1, Parkin, Beclin1, LC3II/LC3I ratio, IL-6 and IL-1ß in hippocampus, indicating that sepsis induced by CLP could activated inflammatory response and caused PINK1/Parkin-mediated mitophagy. Compared with the CLP group, p-PINK1+CLP group had shorter escape latencies, spent more time in the target quadrant and had more number of crossings in the target quadrant at 1-4 days. Under the light microscope, the hippocampal structures of mice was destroyed, the neurons were arranged disorderly, and the nuclei were pyknotic. Under transmission electron microscope, swollen and rounded mitochondria and mitochondrial structure wrapped by double membrane or multilayer membrane structure were observed. Compared with the CLP group, the levels of PINK1, Parkin, Beclin1 and LC3II/LC3 ratio in the p-PINK1+CLP group were significantly increased [PINK1 protein (PINK1/ß-actin): 1.95±0.17 vs. 1.74±0.15, Parkin protein (Parkin/ß-actin): 2.06±0.11 vs. 1.78±0.12, Beclin1 protein (Beclin1/ß-actin): 2.11±0.12 vs. 1.67±0.10, LC3II/LC3I ratio: 3.63±0.12 vs. 2.27±0.10, all P < 0.05], while the levels of IL-6 and IL-1ß were significantly decreased [IL-6 protein (IL-6/ß-actin): 1.69±0.09 vs. 2.00±0.11, IL-1ß protein (IL-1ß/ß-actin): 1.11±0.12 vs. 1.65±0.12, both P < 0.05], suggesting that overexpression of PINK1 protein could further activate mitophagy and reduce the inflammatory response caused by sepsis. There was no statistically significant difference in the above pathological changes and related indicators between Sham group and p-PINK1+Sham group, CLP group and p-vector+CLP group. CONCLUSIONS: PINK1 overexpression can further activate CLP-induced mitophagy by upregulating Parkin, thereby inhibiting inflammation response and alleviate cognitive function impairment in SAE mice.