Emergence of multiple fluconazole-resistant Candida parapsilosis sensu stricto clones with persistence and transmission in China.

OBJECTIVES: We explored the epidemiological and molecular characteristics of Candida parapsilosis sensu stricto isolates in China, and their mechanisms of azole resistance. METHODS: Azole susceptibilities of 2318 non-duplicate isolates were determined using CLSI broth microdilution. Isolates were genotyped by a microsatellite typing method. Molecular resistance mechanisms were also studied and functionally validated by CRISPR/Cas9-based genetic alterations. RESULTS: Fluconazole resistance occurred in 2.4% (n = 56) of isolates, and these isolates showed a higher frequency of distribution in ICU inpatients compared with susceptible isolates (48.2%, n = 27/56 versus 27.8%, 613/2208; P = 0.019). Microsatellite-genotyping analysis yielded 29 genotypes among 56 fluconazole-resistant isolates, of which 10 genotypes, including 37 isolates, belonged to clusters, persisting and transmitting in Chinese hospitals for 1-29 months. Clusters harbouring Erg11Y132F (5/10; 50%) were predominant in China. Among these, the second most dominant cluster MT07, including seven isolates, characteristically harbouring Erg11Y132F and Mrr1Q625K, lent its carriage to being one of the strongest associations with cross-resistance and high MICs of fluconazole (>256 mg/L) and voriconazole (2-8 mg/L), causing transmission across two hospitals. Among mutations tested, Mrr1Q625K led to the highest-level increase of fluconazole MIC (32-fold), while mutations located within or near the predicted transcription factor domain of Tac1 (D440Y, T492M and L518F) conferred cross-resistance to azoles. CONCLUSIONS: This study is the first Chinese report of persistence and transmissions of multiple fluconazole-resistant C. parapsilosis sensu stricto clones harbouring Erg11Y132F, and the first demonstration of the mutations Erg11G307A, Mrr1Q625K, Tac1L263S, Tac1D440Y and Tac1T492M as conferring resistance to azoles.

Development and validation of a nomogram to predict the risk of residual low back pain after tubular microdiskectomy of lumbar disk herniation.

OBJECTIVE: Tubular microdiskectomy (tMD) is one of the most commonly used for treating lumbar disk herniation. However, there still patients still complain of persistent postoperative residual low back pain (rLBP) postoperatively. This study attempts to develop a nomogram to predict the risk of rLBP after tMD. METHODS: The patients were divided into non-rLBP (LBP VAS score < 2) and rLBP (LBP VAS score ≥ 2) group. The correlation between rLBP and these factors were analyzed by multivariate logistic analysis. Then, a nomogram prediction model of rLBP was developed based on the risk factors screened by multivariate analysis. The samples in the model are randomly divided into training and validation sets in a 7:3 ratio. The Receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the diskrimination, calibration and clinical value of the model, respectively. RESULTS: A total of 14.3% (47/329) of patients have persistent rLBP. The multivariate analysis suggests that higher preoperative LBP visual analog scale (VAS) score, lower facet orientation (FO), grade 2-3 facet joint degeneration (FJD) and moderate-severe multifidus fat atrophy (MFA) are risk factors for postoperative rLBP. In the training and validation sets, the ROC curves, calibration curves, and DCAs suggested the good diskrimination, predictive accuracy between the predicted probability and actual probability, and clinical value of the model, respectively. CONCLUSION: This nomogram including preoperative LBP VAS score, FO, FJD and MFA can serve a promising prediction model, which will provide a reference for clinicians to predict the rLBP after tMD.

Draft Genome Sequence of Candida saopaulonensis from a Very Premature Infant with Sepsis.

The rare fungus Candida saopaulonensis has never been reported to be associated with human infection. We report the draft genome sequence of the first clinical isolate of C. saopaulonensis, which was isolated from a very premature infant with sepsis. This is the first genome assembly reaching the near-complete chromosomal level with structural annotation for this species, opening up avenues for exploring evolutionary patterns and genetic mechanisms of pathogenesis.

Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury.

Traumatic brain injury (TBI) survivors suffer from long-term disability and neuropsychiatric sequelae due to irreparable brain tissue destruction. However, there are still few efficient therapies to promote neurorestoration in damaged brain tissue. This study aimed to investigate whether the pro-oncogenic gene ski can promote neurorestoration after TBI. We established a ski-overexpressing experimental TBI mouse model using adenovirus-mediated overexpression through immediate injection after injury. Hematoxylin-eosin staining, MRI-based 3D lesion volume reconstruction, neurobehavioral tests, and analyses of neuronal regeneration and astrogliosis were used to assess neurorestorative efficiency. The effects of ski overexpression on the proliferation of cultured immature neurons and astrocytes were evaluated using imaging flow cytometry. The Ski protein level increased in the perilesional region at 3 days post injury. ski overexpression further elevated Ski protein levels up to 14 days post injury. Lesion volume was attenuated by approximately 36-55% after ski overexpression, with better neurobehavioral recovery, more newborn immature and mature neurons, and less astrogliosis in the perilesional region. Imaging flow cytometry results showed that ski overexpression elevated the proliferation rate of immature neurons and reduced the proliferation rate of astrocytes. These results show that ski can be considered a novel neurorestoration-related gene that effectively promotes neurorestoration, facilitates neuronal regeneration, and reduces astrogliosis after TBI.

Development and validation of a deep neural network-based model to predict acute kidney injury following intravenous administration of iodinated contrast media in hospitalized patients with chronic kidney disease: a multicohort analysis.

BACKGROUND: Stratification of chronic kidney disease (CKD) patients [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2] at risk for post-contrast acute kidney injury (PC-AKI) following intravenous administration of iodinated contrast media (ICM) is important for clinical decision-making and clinical trial enrollment. METHODS: The derivation and internal validation cohorts originated from the Second Xiangya Hospital. The external validation cohort was generated from the Xiangya Hospital and the openly accessible database Medical Information Mart for Intensive CareIV. PC-AKI was defined based on the serum creatinine criteria of the Kidney Disease: Improving Global Outcomes (KDIGO). Six feature selection methods were used to identify the most influential predictors from 79 candidate variables. Deep neural networks (DNNs) were used to establish the model and compared with logistic regression analyses. Model discrimination was evaluated by area under the receiver operating characteristic curve (AUC). Low-risk and high-risk cutoff points were set to stratify patients. RESULTS: Among 4218 encounters studied, PC-AKI occurred in 10.3, 10.4 and 11.4% of encounters in the derivation, internal and external validation cohorts, respectively. The 14 variables-based DNN model had significantly better performance than the logistic regression model with AUC being 0.939 (95% confidence interval: 0.916-0.958) and 0.940 (95% confidence interval: 0.909-0.954) in the internal and external validation cohorts, respectively, and showed promising discrimination in subgroup analyses (AUC ≥ 0.800). The observed PC-AKI risks increased significantly from the low- to intermediate- to high-risk group (<1.0 to >50%) and the accuracy of patients not developing PC-AKI was 99% in the low-risk category in both the internal and external validation cohorts. CONCLUSIONS: A DNN model using routinely available variables can accurately discriminate the risk of PC-AKI of hospitalized CKD patients following intravenous administration of ICM.

Effects of intravenous hydration in preventing post-contrast acute kidney injury in patients with eGFR < 30 mL/min/1.73 m2.

OBJECTIVES: To investigate the effects of intravenous hydration in preventing post-contrast outcomes in patients with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 undergoing intravenous administration of iodinated contrast media (ICM). METHODS: Hospitalized patients with eGFR < 30 mL/min/1.73 m2 and intravenous ICM exposure between 2015 and 2021 were included. Post-contrast outcomes include post-contrast acute kidney injury (PC-AKI) (defined by 2012 Kidney Disease: Improving Global Outcomes (KDIGO) or European Society of Urogenital Radiology (ESUR)), chronic dialysis at discharge, and in-hospital mortality. Confounding effects between the two groups were reduced to a minimum using propensity score-based matching and overlap weighting. Association between intravenous hydration and outcomes was analyzed using logistic regression. RESULTS: In total, 794 patients were included in the study, with 284 receiving intravenous hydration, and 510 not. After 1:1 propensity score matching, 210 pairs were generated. No significant differences were found in the outcomes between the intravenous hydration and no intravenous hydration groups: PC-AKI by KDIGO, 25.2% vs 24.8% (odds ratio (OR), 0.93; 95% confidence interval (CI), 0.57-1.50); PC-AKI by ESUR, 31.0% vs 25.2% (OR, 1.34; 95% CI, 0.86-2.08); chronic dialysis at discharge, 4.3% vs 3.3% (OR, 1.56; 95% CI, 0.56-4.50); in-hospital mortality, 1.9% vs 0.5% (OR, 4.08; 95% CI, 0.58-81.08). Overlap propensity score-weighted analysis also showed no significant effects of intravenous hydration on the incidences of the post-contrast outcomes. CONCLUSIONS: Intravenous hydration was not associated with lower risks of PC-AKI, chronic dialysis at discharge, and in-hospital mortality in patients with eGFR < 30 mL/min/1.73 m2 undergoing intravenous administration of ICM. CLINICAL RELEVANCE STATEMENT: This study provides new evidence in supporting that intravenous hydration is not beneficial to patients with eGFR < 30 mL/min/1.73 m2 before and after intravenous administration of iodinated contrast media. KEY POINTS: • Intravenous hydration before and after intravenous administration of ICM is not associated with lower risks in PC-AKI, chronic dialysis at discharge, and in-hospital mortality in patients with eGFR < 30 mL/min/1.73 m2. • Withholding intravenous hydration may be considered in patients with eGFR < 30 mL/min/1.73 m2 around intravenous administration of ICM.

Association of underweight and obesity with adverse postoperative renal outcomes in infants and young children undergoing congenital heart surgery.

Postoperative acute kidney injury (AKI) is a prevalent condition and associated with increased morbidity and mortality following cardiac surgery. This study aimed to investigate the association of underweight and obesity with adverse postoperative renal outcomes in infants and young children undergoing congenital heart surgery. This retrospective cohort study included patients aged from 1 month to 5 years who underwent congenital heart surgery with cardiopulmonary bypass at the Second Xiangya Hospital of Central South University from January 2016 to March 2022. On the basis of the percentile of body mass index (BMI) for age and sex, eligible participants were divided into three nutritional groups: normal bodyweight, underweight (BMI P5), and obesity (BMI P95). Primary outcomes included postoperative AKI and major adverse kidney events within 30 days (MAKE30). Multivariable logistic regression was performed to determine the association of underweight and obesity with postoperative outcomes. The same analyses were reproduced for classifying patients using weight-for-height instead of BMI. A total of 2,079 eligible patients were included in the analysis, including 1,341 (65%) patients in the normal bodyweight group, 683 (33%) patients in the underweight group, and 55 (2.6%) patients in the obesity group. Postoperative AKI (16% vs. 26% vs. 38%; P < 0.001) and MAKE30 (2.5% vs. 6.4% vs. 9.1%; P < 0.001) were more likely to occur in the underweight and obesity groups. After adjusting for potential confounders, underweight (OR1.39; 95% CI 1.08-1.79; P = 0.008) and obesity (OR 3.85; 95% CI 1.97-7.50; P < 0.001) were found to be associated with an increased risk of postoperative AKI. In addition, both underweight (OR 1.89; 95% CI 1.14-3.14; P = 0.014) and obesity (OR 3.14; 95% CI 1.08-9.09; P = 0.035) were independently associated with MAKE30. Similar results were also found when weight-for-height was used instead of BMI.    Conclusion: In infants and young children undergoing congenital heart surgery, underweight and obesity are independently associated with postoperative AKI and MAKE30. These results may help assess prognosis in underweight and obese patients, and will guide future quality improvement efforts. What is Known: • Postoperative acute kidney injury (AKI) is prevalent and associated with increased morbidity and mortality following pediatric cardiac surgery. • Major adverse kidney events within 30 days (MAKE30) have been recommended as a patient-centered endpoint for evaluating AKI clinical trajectories. A growing concern arises for underweight and obesity in children with congenital heart disease. What is New: • Prevalence of underweight and obesity among infants and young children undergoing congenital heart surgery was 33% and 2.6%, respectively. • Both underweight and obesity were independently associated with postoperative AKI and MAKE30 following congenital heart surgery.

Machine Learning-Based Prediction of Acute Kidney Injury Following Pediatric Cardiac Surgery: Model Development and Validation Study.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication following pediatric cardiac surgery, which is associated with increased morbidity and mortality. The early prediction of CSA-AKI before and immediately after surgery could significantly improve the implementation of preventive and therapeutic strategies during the perioperative periods. However, there is limited clinical information on how to identify pediatric patients at high risk of CSA-AKI. OBJECTIVE: The study aims to develop and validate machine learning models to predict the development of CSA-AKI in the pediatric population. METHODS: This retrospective cohort study enrolled patients aged 1 month to 18 years who underwent cardiac surgery with cardiopulmonary bypass at 3 medical centers of Central South University in China. CSA-AKI was defined according to the 2012 Kidney Disease: Improving Global Outcomes criteria. Feature selection was applied separately to 2 data sets: the preoperative data set and the combined preoperative and intraoperative data set. Multiple machine learning algorithms were tested, including K-nearest neighbor, naive Bayes, support vector machines, random forest, extreme gradient boosting (XGBoost), and neural networks. The best performing model was identified in cross-validation by using the area under the receiver operating characteristic curve (AUROC). Model interpretations were generated using the Shapley additive explanations (SHAP) method. RESULTS: A total of 3278 patients from one of the centers were used for model derivation, while 585 patients from another 2 centers served as the external validation cohort. CSA-AKI occurred in 564 (17.2%) patients in the derivation cohort and 51 (8.7%) patients in the external validation cohort. Among the considered machine learning models, the XGBoost models achieved the best predictive performance in cross-validation. The AUROC of the XGBoost model using only the preoperative variables was 0.890 (95% CI 0.876-0.906) in the derivation cohort and 0.857 (95% CI 0.800-0.903) in the external validation cohort. When the intraoperative variables were included, the AUROC increased to 0.912 (95% CI 0.899-0.924) and 0.889 (95% CI 0.844-0.920) in the 2 cohorts, respectively. The SHAP method revealed that baseline serum creatinine level, perfusion time, body length, operation time, and intraoperative blood loss were the top 5 predictors of CSA-AKI. CONCLUSIONS: The interpretable XGBoost models provide practical tools for the early prediction of CSA-AKI, which are valuable for risk stratification and perioperative management of pediatric patients undergoing cardiac surgery.

Utilization of interpretable machine learning model to forecast the risk of major adverse kidney events in elderly patients in critical care.

Major adverse kidney events within 30 d (MAKE30) implicates poor outcomes for elderly patients in the intensive care unit (ICU). This study aimed to predict the occurrence of MAKE30 in elderly ICU patients using machine learning. The study cohort comprised 2366 elderly ICU patients admitted to the Second Xiangya Hospital of Central South University between January 2020 and December 2021. Variables including demographic information, laboratory values, physiological parameters, and medical interventions were used to construct an extreme gradient boosting (XGBoost) -based prediction model. Out of the 2366 patients, 1656 were used for model derivation and 710 for testing. The incidence of MAKE30 was 13.8% in the derivation cohort and 13.2% in the test cohort. The average area under the receiver operating characteristic curve of the XGBoost model was 0.930 (95% CI: 0.912-0.946) in the training set and 0.851 (95% CI: 0.810-0.890) in the test set. The top 8 predictors of MAKE30 tentatively identified by the Shapley additive explanations method were Acute Physiology and Chronic Health Evaluation II score, serum creatinine, blood urea nitrogen, Simplified Acute Physiology Score II score, Sequential Organ Failure Assessment score, aspartate aminotransferase, arterial blood bicarbonate, and albumin. The XGBoost model accurately predicted the occurrence of MAKE30 in elderly ICU patients, and the findings of this study provide valuable information to clinicians for making informed clinical decisions.

Temporal trends of post-contrast acute kidney injury in patients with intravenous administration of iodinated contrast medium.

Little is known about whether preventative practices for post-contrast acute kidney injury (PC-AKI) recommended in guidelines have been adopted in clinical practice and translated into a lower incidence of PC-AKI. The aim of this study was to examine the yearly trends in the incidence of PC-AKI, and comorbidities and care practices associated with PC-AKI in hospitalized patients who received intravenous administration of iodinated contrast medium (ICM). Adult patients receiving intravenous ICM at the Second Xiangya Hospital of Central South University in China between 2015 and 2021 were included. Temporal trends in the incidence and risk factors for PC-AKI were evaluated using logistic regression analyses with adjustments for relevant variables. The incidence of PC-AKI has declined significantly from 5.3% in 2015 to 4.1% in 2021 (p < 0.001). This decreasing trend persisted after extensive multivariable adjustments. Of the comorbidities associated with PC-AKI, the proportion of patients with congestive heart failure or hypertension increased, while the proportion of patients older than 75 years, or with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, diabetic nephropathy, or renal stone disease decreased. Among the care practices associated with PC-AKI, the proportion of patients using nephrotoxic drugs decreased, whereas the proportion of patients receiving intravenous fluids > 1000 mL on the day of ICM administration or using iso-osmolar ICM increased. In conclusion, a declining trend in PC-AKI incidence was observed in patients receiving intravenous ICM between 2015 and 2021, which may be related to increased awareness and efforts to prevent PC-AKI.

A novel classification based on magnetic resonance imaging for individualized surgical strategies of lumbar disc herniation.

INTRODUCTION: Although the anatomy and pathology of lumbar disc herniation (LDH) have been clearly defined and classified in many studies, its imaging definition and classification still needs further clarification. This study intends to propose a novel classification and individualized surgical strategy for LDH based on preoperative magnetic resonance imaging (MRI). MATERIALS AND METHODS: According to MRI features, LDH types were identified, and the corresponding surgical strategies were formulated to accurately remove the herniated discs while minimizing the disturbance to the normal disc. We retrospectively analyzed prospectively collected data of LDH patients who underwent surgery guided by this classification system. RESULTS: This study included 357 patients with LDH who underwent tubular microdiscectomy. LDH was classified into four types based on MRI features. The inter- and intra-observer agreement using this classification was good. The follow-up results showed that surgery improved visual analog scale scores for low-back and leg pain and the Oswestry disability index in patients with different LDH types. The average recurrence rate at 1-5 years postoperatively was 5.62%. There was no significant difference in recurrence rates among the four LDH types (3.7-6.2%). MRI showed no significant differences in the Pfirrmann grade and disc height index of the operated segment between before surgery and 1-3 years after surgery. The operated segments did not show faster disc degeneration rates compared to adjacent proximal segments. CONCLUSIONS: We proposed a novel classification system and an individualized surgical strategy for LDH based on preoperative MRI. Further, the surgical suitable interventions guided by this system achieved good clinical outcomes and mild recurrence rates.

Is intravenous iodinated contrast medium administration really harmful in hospitalized acute kidney injury patients: a propensity score-matched study.

OBJECTIVES: To evaluate the effects of intravenous iodinated contrast medium (ICM) administration on the deterioration of renal function (DRF), new renal replacement therapy (RRT) induction and mortality of hospitalized acute kidney injury (AKI) patients. METHODS: Adult hospitalized patients undergoing a contrast-enhanced or unenhanced CT scan within 7 days after AKI diagnosis from January 2015 to December 2019 were identified in this retrospective study. Propensity score matching was performed. Outcomes in 7 and 30 days after CT scan were compared between the contrast and non-contrast groups. Additional analyses were also performed in patients stratified by SCr levels at AKI diagnosis, times and time of CT scan, and in patients without chronic kidney disease or RRT requirement prior to CT scan. RESULTS: In total, 1172 pairs were generated after 1:1 propensity score matching from 1336 cases exposed to ICM and 2724 unexposed. No significant differences were found in the outcomes between the two groups: DRF, 7.8% vs 9.0% (odds ratio (OR) 0.83, 95% confidence interval (CI) 0.62-1.11) in 7 days, 5.1% vs 5.4% (OR 0.93, 95%CI 0.64-1.34) in 30 days; new RRT induction, 2.3% vs 3.3% (OR 0.72,95%CI 0.43-1.18) in 7 days, 4.2% vs 4.5% (OR 0.95,95%CI 0.64-1.41) in 30 days; and mortality, 3.9% vs 4.8% (OR 0.83,95%CI 0.56-1.22) in 7 days, 9.0% vs 10.2% (OR 0.88,95%CI 0.68-1.15) in 30 days. Subset analyses showed similar results. CONCLUSION: Intravenous ICM administration during AKI duration did not increase the risks of DRF, new RRT induction, and mortality in 7 and 30 days after CT scan. KEY POINTS: • Intravenous ICM administration in hospitalized AKI patients does not increase the risks of deterioration of renal function, RRT induction, and mortality in 7 and 30 days after CT scan. • The effects of intravenous ICM on adverse outcomes are minimal even in AKI patients with high level of SCr values or multiple CT scans.

The efficacy of Raman spectroscopy in lung cancer diagnosis: the first diagnostic meta-analysis.

In recent years, many researches have explored the diagnostic value of Raman spectroscopy in multiple types of tumors. However, as an emerging clinical examination method, the diagnostic performance of Raman spectroscopy in lung cancer remains unclear. Relevant diagnostic studies published before 1 June 2020 were retrieved from the Cochrane Library, PubMed, EMBASE, China National Knowledge Internet (CNKI), and WanFang databases. After the literature was screened, two authors extracted the data from eligible studies according to the inclusion and exclusion criteria. Obtained data were pooled and analyzed using Stata 16.0, Meta-DiSc 1.4, and RevMan 5.3 software. Fourteen diagnostic studies were eligible for the pooled analysis which includes 779 patients. Total pooled sensitivity and specificity of Raman spectroscopy in diagnosing lung cancer were 0.92 (95% CI 0.87-0.95) and 0.94 (95% CI 0.88-0.97), respectively. The positive likelihood ratio was 15.2 (95% CI 7.5-30.9), the negative likelihood ratio was 0.09 (95% CI 0.05-0.14), and the area under the curve was 0.97 (95 % CI 0.95-0.98). Subgroup analysis suggested that the sensitivity and specificity of RS when analyzing human tissue, serum, and saliva samples were 0.95 (95% CI 0.88-0.98), 0.97 (95% CI 0.89-0.99), 0.88 (95% CI 0.80-0.93), 0.87 (95% CI 0.78-0.92), 0.91 (95% CI 0.80-0.96), and 0.95 (95% CI 0.73-0.99), respectively. No publication bias or threshold effects were detected in this meta-analysis. This initial meta-analysis indicated that Raman spectroscopy is a highly specific and sensitive diagnostic technology for detecting lung cancer. Further investigations are also needed to focus on real-time detection using Raman spectroscopy under bronchoscopy in vivo. Moreover, large-scale diagnostic studies should be conducted to confirm this conclusion.

[Activation of the adenosine A2A receptor at the acute stage of moderate traumatic brain injury enhances the neuroprotective effects of oxaloacetate].

The purpose of the present study was to investigate the effect of glutamate scavenger oxaloacetate (OA) combined with CGS21680, an adenosine A2A receptor (A2AR) agonist, on acute traumatic brain injury (TBI), and to elucidate the underlying mechanisms. C57BL/6J mice were subjected to moderate-level TBI by controlled cortical impact, and then were treated with OA, CGS21680, or OA combined with CGS21680 at acute stage of TBI. At 24 h post TBI, neurological severity score, brain water content, glutamate concentration in cerebrospinal fluid (CSF), mRNA and protein levels of IL-1ß and TNF-α, mRNA level and activity of glutamate oxaloacetate aminotransferase (GOT), and ATP level of brain tissue were detected. The results showed that neurological deficit, brain water content, glutamate concentration in CSF, and the inflammatory cytokine IL-1ß and TNF-α production were exacerbated in CGS21680 treated mice. Administrating OA suppressed the rise of both glutamate concentration in CSF and brain water content, and elevated the ATP level of cerebral tissue. More interestingly, neurological deficit, brain edema, glutamate concentration, IL-1ß and TNF-α levels were ameliorated significantly in mice treated with OA combined with CGS21680. The combined treatment exhibited better therapeutic effects than single OA treatment. We also observed that GOT activity was enhanced in single CGS21680 treatment group, and both the GOT mRNA level and GOT activity were up-regulated in early-stage combined treatment group. These results suggest that A2AR can improve the efficiency of GOT and potentiate the ability of OA to metabolize glutamate. This may be the mechanism that A2AR activation in combination group augmented the neuroprotective effect of OA rather than aggravated the brain damages. Taken together, the present study provides a new insight for the clinical treatment of TBI with A2AR agonists and OA.

HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury.

BACKGROUND: Cognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation. Although classical inflammatory pathways have been well-documented in the late stage of TBI (4-8 weeks post-injury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear. METHODS: Mice lacking the gene encoding for NLRP3 (NLRP3-knockout mice) and their wild-type littermates were used in a controlled cortical impact model of TBI. Levels of NLRP3 inflammasome and inflammatory factors such as IL-1ß and HMGB1 were detected in post-injury hippocampal tissue, as well as long-term potentiation. Behaviors were assessed by T-maze test, novel object recognition, and nesting tests. Glycyrrhizin was used to antagonize HMGB1. Calcium imaging were performed on primary neuronal cultures. RESULTS: By using the NLRP3-knockout TBI model, we found that the continuous activation of the NLRP3 inflammasome and high mobility group box 1 (HMGB1) release were closely related to cognitive impairment. We also found that inhibition of HMGB1 improved LTP reduction and cognitive function by increasing the phosphorylation level of the NMDAR1 subunit at serine 896 while reducing NLRP3 inflammasome activation. CONCLUSION: NLRP3 inflammasome damages memory in the late stage of TBI primarily through HMGB1 upregulation and provides an explanation for the long-term progression of cognitive dysfunction.

A2A R inhibition in alleviating spatial recognition memory impairment after TBI is associated with improvement in autophagic flux in RSC.

Spatial recognition memory impairment is an important complication after traumatic brain injury (TBI). We previously found that spatial recognition memory impairment can be alleviated in adenosine A2A receptor knockout (A2A R KO) mice after TBI, but the mechanism remains unclear. In the current study, we used manganese-enhanced magnetic resonance imaging and the Y-maze test to determine whether the electrical activity of neurons in the retrosplenial cortex (RSC) was reduced and spatial recognition memory was impaired in wild-type (WT) mice after moderate TBI. Furthermore, spatial recognition memory was damaged by optogenetically inhibiting the electrical activity of RSC neurons in WT mice. Additionally, the electrical activity of RSC neurons was significantly increased and spatial recognition memory impairment was reduced in A2A R KO mice after moderate TBI. Specific inhibition of A2A R in the ipsilateral RSC alleviated the impairment in spatial recognition memory in WT mice. In addition, A2A R KO improved autophagic flux in the ipsilateral RSC after injury. In primary cultured neurons, activation of A2A R reduced lysosomal-associated membrane protein 1 and cathepsin D (CTSD) levels, increased phosphorylated protein kinase A and phosphorylated extracellular signal-regulated kinase 2 levels, reduced transcription factor EB (TFEB) nuclear localization and impaired autophagic flux. These results suggest that the impairment of spatial recognition memory after TBI may be associated with impaired autophagic flux in the RSC and that A2A R activation may reduce lysosomal biogenesis through the PKA/ERK2/TFEB pathway to impair autophagic flux.

Post-contrast acute kidney injury in a hospitalized population: short-, mid-, and long-term outcome and risk factors for adverse events.

OBJECTIVES: To investigate the prognosis including major adverse kidney events within 30 days (MAKE30) and 90-day and 1-year adverse outcome in hospitalized patients with post-contrast acute kidney injury (PC-AKI) to identify high-risk factors. METHODS: This retrospective observational study included 288 PC-AKI patients selected from 277,898 patients admitted to hospitals from January 2015 to December 2015. PC-AKI was defined according to the 2018 guideline of European Society of Urogenital Radiology. Multivariable Cox regression and logistic regression analyses were used to analyze main outcome and risk factors. RESULTS: PC-AKI patients with AKI stage ≥ 2 had much higher incidence of MAKE30 than those with AKI stage 1 (RR = 7.027, 95% CI 4.918-10.039). Persistent renal dysfunction, heart failure, central nervous system failure, baseline eGFR < 60 mL/min/1.73 m2, oliguria or anuria, blood urea nitrogen ≥ 7.14 mmol/L, respiratory failure, and shock were independent risk factors of 90-day or 1-year adverse prognosis (p < 0.05). Compared with transient renal dysfunction, PC-AKI patients with persistent renal dysfunction had a higher all-cause mortality rate (RR = 3.768, 95% CI 1.612-8.810; RR = 4.106, 95% CI 1.765-9.551) as well as combined endpoints of death, chronic kidney disease, or end-stage renal disease (OR = 3.685, 95% CI 1.628-8.340; OR = 5.209, 95% CI 1.730-15.681) within 90 days or 1 year. CONCLUSIONS: PC-AKI is not always a transient, benign creatininopathy, but can result in adverse outcome. AKI stage is independently correlated to MAKE30 and persistent renal dysfunction may exaggerate the risk of long-term adverse events. KEY POINTS: • PC-AKI can result in adverse outcome such as persistent renal dysfunction, dialysis, chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. • AKI stage is independently correlated to MAKE30. • Persistent renal dysfunction may exaggerate the risk of long-term adverse events.

PKC Mediates LPS-Induced IL-1ß Expression and Participates in the Pro-inflammatory Effect of A2AR Under High Glutamate Concentrations in Mouse Microglia.

Pathogens such as bacterial lipopolysaccharide (LPS) play an important role in promoting the production of the inflammatory cytokines interleukin-1 beta (IL-1ß) and tumour necrosis factor-α (TNF-α) in response to infection or damage in microglia. However, whether different signalling pathways regulate these two inflammatory factors remains unclear. The protein kinase C (PKC) family is involved in the regulation of inflammation, and our previous research showed that the activation of the PKC pathway played a key role in the LPS-induced transformation of the adenosine A2A receptor (A2AR) from anti-inflammatory activity to pro-inflammatory activity under high glutamate concentrations. Therefore, in the current study, we investigated the role of PKC in the LPS-induced production of these inflammatory cytokines in mouse primary microglia. GF109203X, a specific PKC inhibitor, inhibited the LPS-induced expression of IL-1ß messenger ribonucleic acid and intracellular protein in a dose-dependent manner. Moreover, 5 µM GF109203X prevented LPS-induced IL-1ß expression but did not significantly affect LPS-induced TNF-α expression. PKC promoted IL-1ß expression by regulating the activity of NF-κB but did not significantly impact the activity of ERK1/2. A2AR activation by CGS21680, an A2AR agonist, facilitated LPS-induced IL-1ß expression through the PKC pathway at high glutamate concentrations but did not significantly affect LPS-induced TNF-α expression. Taken together, these results suggest a new direction for specific intervention with LPS-induced inflammatory factors in response to specific signalling pathways and provide a mechanism for A2AR targeting, especially after brain injury, to influence inflammation by interfering with A2AR.

Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain.

Excitatory amino acid transporters (EAATs) on cerebral vascular endothelial cells play an important role in maintaining glutamate homeostasis in the brain. The dysfunction of endothelial EAATs is an important reason for the dramatically elevated brain glutamate levels after brain injury, such as traumatic brain injury (TBI). The adenosine A2A receptor (A2AR) plays an important role in regulating the brain glutamate level after brain injury; however, researchers have not clearly determined whether this role was related to its ability to regulate endothelial EAATs. Activation of A2AR in vitro not only decreased the PKA- and glutamate level-dependent strengthening of the interaction between NKA-α1 and the FXYD1 subunit and the subsequent decrease in the activity of Na+/K+-ATPases (NKAs) but also enhanced its interaction with EAATs and ultimately aggravated the reverse transport function of endothelial EAATs under oxygen-glucose deprivation (OGD) conditions. Conversely, inhibition of A2AR restored the normal transport of EAAT. Moreover, A2AR inhibition increased NKA activity and decreased its interaction with EAATs in isolated brain capillaries after TBI, further confirming its role in endothelial EAATs in vivo. Based on our results, A2AR played an important role in regulating endothelial EAAT function, and strategies that restore the normal transport of endothelial EAATs through the inhibition of A2AR might serve as an effective treatment for brain injury.

Hsp90 regulation affects the treatment of glucocorticoid for pancreatitis-induced lung injury.

Glucocorticoids are commonly used for the treatment of pancreatitis and complicated acute lung injury and help to reduce the mortality rates of both. The effect of gene variants in heat shock protein 90 (Hsp90), a key chaperone molecule of the glucocorticoid receptor (GR), on the therapeutic effect of glucocorticoids is unclear. Our study aims to investigate the different susceptibility to glucocorticoid treatment in BALB/c and C57BL/6 mice carrying different Hsp90 genotypes in an animal model of pancreatitis-induced lung injury. Compared with BALB/c mice, C57BL/6 mice have lower mortality rates, decreased water content in their lungs, and a lower level of IL-1 beta in an animal model of acute pancreatitis. C57BL/6 mice show a greater therapeutic effect and increased GR binding activities with glucocorticoid responsive element compared to BALB/c mice after a 0.4 mg/kg dexamethasone (DEX) treatment. Treatment with a higher dose of DEX (4 mg/kg) significantly reduced mortality rates and increased GR-GRE binding activity in both strains of mice, and there was no significant difference between the two strains. DEX did not exert a protective role after geldanamycin, a specific inhibitor of Hsp90, was administered in both strains of mice. Our study revealed that Hsp90 gene variants are responsible for the greater therapeutic effect of DEX in C57BL/6 mice compared to BALB/c mice, which implies that combining DEX treatment with Hsp90 regulation would promote the efficiency of DEX and would be an effective way to alleviate the side effects of hormone therapy.