Mortality Prediction in Severe Traumatic Brain Injury Using Traditional and Machine Learning Algorithms.

Abstract Prognostic prediction of traumatic brain injury (TBI) in patients is crucial in clinical decision and health care policy making. This study aimed to develop and validate prediction models for in-hospital mortality after severe traumatic brain injury (sTBI). We developed and validated logistic regression (LR), LASSO regression, and machine learning (ML) algorithms including support vector machines (SVM) and XGBoost models. Fifty-four candidate predictors were included. Model performance was expressed in terms of discrimination (C-statistic) and calibration (intercept and slope). For model development, 2804 patients with sTBI in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) China Registry study were included. External validation was performed in 1113 patients with sTBI in the CENTER-TBI European Registry study. XGBoost achieved high discrimination in mortality prediction, and it outperformed logistic and LASSO regression. The XGBoost model established in this study also outperformed prediction models currently available, including the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) core and International Mission for Prognosis and Analysis of Clinical Trials (CRASH) basic models. When including 54 variables, XGBoost and SVM reached C-statistics of 0.87 (95% confidence interval [CI]: 0.81-0.92) and 0.85 (95% CI: 0.79-0.90) at internal validation, and 0.88 (95% CI: 0.87-0.88) and 0.86 (95% CI: 0.85-0.87) at external validation, respectively. A simplified version of XGBoost and SVM using 26 variables selected by recursive feature elimination (RFE) reached C-statistics of 0.87 (95% CI: 0.82-0.92) and 0.86 (95% CI: 0.80-0.91) at internal validation, and 0.87 (95% CI: 0.87-0.88) and 0.87 (95% CI: 0.86-0.87) at external validation, respectively. However, when the number of variables included decreased, the difference between ML and LR diminished. All the prediction models can be accessed via a web-based calculator. Glasgow Coma Scale (GCS) score, age, pupillary light reflex, Injury Severity Score (ISS) for brain region, and the presence of acute subdural hematoma were the five strongest predictors for mortality prediction. The study showed that ML techniques such as XGBoost may capture information hidden in demographic and clinical predictors of patients with sTBI and yield more precise predictions compared with LR approaches.

Effect of Copper Exposure on the Cholesterol Metabolism in Broiler Liver.

Copper (Cu) is a kind of widely used dietary supplement in poultry production, and a common environmental pollutant at the same time. Excess Cu exposure has been reported to accumulate in the liver and induce cytotoxicity, but the effect of Cu toxicity on hepatic cholesterol metabolism is still uncertain. Herein, we aimed to reveal the effect of excess Cu on the liver and primary hepatocytes of broilers at various concentrations. We found that 110 mg/kg Cu supplement remarkably increased blood cholesterol levels by detecting serum TC, LDL-C, and HDL-C in the broilers, while there was no significant difference in 220 and 330 mg/kg Cu supplements. In addition, high Cu exposure resulted in severe hepatic steatosis and hepatic cord derangement in the broilers. Oil red O staining of primary hepatocytes showed that Cu treatment caused intracellular neutral lipid accumulation. However, the hepatic TC content indicated a downward trend in both liver tissues and hepatocytes after Cu exposure. Furthermore, the expression of cholesterol metabolism-related indicators (SREBP2, HMGCR, LDLR, and CYP7A1) was notably decreased in the Cu-treated groups. While the expression of the key enzyme of cholesterol esterification (ACAT2) did not change significantly. Taken together, our findings preliminarily revealed excess Cu-induced hepatic cholesterol metabolism dysfunction, providing a deeper understanding of the molecular mechanisms of Cu-induced hepatotoxicity.

Toxicological mechanism of large amount of copper supplementation: Effects on endoplasmic reticulum stress and mitochondria-mediated apoptosis by Nrf2/HO-1 pathway-induced oxidative stress in the porcine myocardium.

Copper (Cu) is an essential micronutrient that is required by all living organisms. However, Cu can also be a potentially toxic metal if excessive dietary supplementation occurs. The current study aimed to investigate the mechanism of Cu toxicity in the cardiomyocytes of large mammal pigs. Here, we used pigs to explore Cu toxicity in the control group (10 mg/kg Cu) and treatment groups (125 mg/kg and 250 mg/kg Cu) for a period of 80 days. Consequently, we identified that large amount intake of Cu led to in oxidative damage, and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)-mediated antioxidant pathway, indicating an imbalanced redox status in the myocardium. Furthermore, Cu exposure activated endoplasmic reticulum (ER) stress through upregulating levels of glucose-regulated protein 78 (GRP78), c-Jun N-terminal kinase (JNK), glucose-regulated protein 94 (GRP94), X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP). Additionally, mitochondrial fission and fusion homeostasis was disrupted and the copy number of mitochondrial DNA (mtDNA) was reduced under Cu exposure. Furthermore, Cu exposure could induce apoptosis, evidenced by the increased terminal deoxynucleotidyl transferase biotin-d UTP nick end labeling (TUNEL)-positive staining, the upregulated expression levels of Cytoplasm-cytochrome C (Cytc), Bcl-2-associated X protein (Bax), and Cleaved-caspase3, and decreased expression level of B-cell lymphoma-2 (Bcl-2) and Mitochondrial-cytc. In summary, large amount of Cu could trigger Nrf2/HO-1 pathway-mediated oxidative stress, which promotes ER stress and mitochondrial damage pathways, causing apoptosis in cardiomyocytes.

Toxic effects of copper on the jejunum and colon of pigs: mechanisms related to gut barrier dysfunction and inflammation influenced by the gut microbiota.

Copper (Cu) is an essential trace mineral, but its excessive intake can lead to potentially toxic effects on host physiology. The mammalian intestine harbors various microorganisms that are associated with intestinal barrier function and inflammation. In this study, the influences of Cu on barrier function, microbiota, and its metabolites were examined in the jejunum and colon of pigs. Here, we identified that the physical and chemical barrier functions were impaired both in the jejunum and colon, as evidenced by the decreased expression of tight junction proteins (ZO-1, Occludin, Claudin-1, and JAM-1) and mucous secretion-related genes, positive rate of Muc2, and secretion of SIgA and SIgG. Additionally, inflammatory cytokines were overexpressed in the jejunum and colon. Furthermore, Cu might increase the abundances of Mycoplasma, Actinobacillus and unidentified_Enterobacteriaceae in the jejunum, which significantly affected pentose and glucoronate interconversions, histidine metabolism, folate biosynthesis, porphyrin metabolism, and purine metabolism. Meanwhile, the abundances of Lactobacillus and Methanobrevibacter were remarkably decreased and Streptococcus, unidentified_Enterobacteriaceae, and unidentified_Muribaculaceae were significantly increased in the colon, with an evident impact on glycerophospholipid metabolism, retinol metabolism, and steroid hormone biosynthesis. These findings revealed that excess Cu had significant effects on the microbiota and metabolites in the jejunum and colon, which were involved in intestinal barrier dysfunction and inflammation.

Copper induces mitochondria-mediated apoptosis via AMPK-mTOR pathway in hypothalamus of Pigs.

Copper (Cu), one of the heavy metals, is far beyond the carrying capacity of the environment with Cu mining, industrial wastewater discharging and the use of Cu-containing pesticides. Intaking excess Cu can cause toxic effects on liver, kidney, heart, but few studies report Cu toxicity on brain tissue. It is noteworthy that most toxicity tests are based on rodent models, but large mammals chosen as animal models has no reported. To explore the relationship of the Cu toxicity and mitochondria-mediated apoptosis on hypothalamus in pigs, the content of Cu, histomorphology, mitochondrial related indicators, apoptosis, and AMPK-mTOR signaling pathway were detected. Results showed that Cu could accumulate in hypothalamus and lead to mitochondrial dysfunction, evidenced by the decrease of ATP production, activities of respiratory chain complex I-IV, and mitochondrial respiratory function in Cu-treated groups. Additionally, the genes and proteins expression of Bax, Caspase-3, Cytc in treatment group were higher than control group. Furthermore, the protein level of p-AMPK was enhanced significantly and p-mTOR was declined, which manifested that AMPK-mTOR signaling pathway was activated in Cu-treated groups. In conclusion, this study illuminated that the accumulation of Cu could cause mitochondrial dysfunction, induce mitochondria-mediated apoptosis and activate AMPK-mTOR pathway in hypothalamus.

AQP2 as a target of lycopene protects against atrazine-induced renal ionic homeostasis disturbance.

Atrazine (ATR), a ubiquitous environmental contaminant in water and soil, causes environmental nephrosis. To reveal the toxic effect of ATR on the kidney and the potential chemical nephroprotective effect of lycopene (LYC), Kun-Ming mice of specific pathogen-free (SPF) grade were treated with LYC (5 mg kg-1) and/or ATR (50 mg kg-1 or 200 mg kg-1) for 21 days. The degree of renal injury was evaluated by measuring the ion concentration, ATPase activities and the mRNA expressions/levels of associated ATPase subunits. In addition, the expression of renal aquaporins (AQPs) was analyzed. The results showed that the renal tubular epithelial cells of ATR-exposed mice were swollen, the glomeruli were significantly atrophied, and the ion concentrations were obviously changed. The activity of Na+-K+-ATPase and the transcription of its subunits were downregulated. The activity of Ca2+-Mg2+-ATPase and the transcription of its subunits were upregulated. The expression of AQPs, especially the critical AQP2, was affected. Notably, ATR-induced nephrotoxicity was significantly improved by LYC supplementation. Therefore, LYC could protect the kidney against ATR-induced nephrotoxicity via maintaining ionic homeostasis, reversing the changes in ATPase activity and controlling the expression of AQPs on the cell membrane. These results suggested that AQP2 was a target of LYC and protected against ATR-induced renal ionic homeostasis disturbance.

Effects of copper on oxidative stress and autophagy in hypothalamus of broilers.

The purpose of this research was to discuss the effects of copper (Cu)-induced toxicity on oxidative stress and autophagy in hypothalamus of broilers. In this study, 240 one-day-old broilers were randomly divided into 4 groups and the contents of dietary Cu in 4 groups were 11 mg/kg (control group), 110 mg/kg (group I), 220 mg/kg (group II), and 330 mg/kg (group III). The experiment lasted for 49 days and the hypothalamus tissues were collected for histological observation and detection of Cu content. Additionally, the indicators related to oxidative stress in hypothalamus were determined. Moreover, the mRNA expression levels of autophagy-related genes and the protein expression levels of Beclin1, LC3-II/LC3-I, and p62 in hypothalamus were measured. Results showed that the treated groups were observed vacuolar degeneration in hypothalamus compared to control group, and the Cu content in hypothalamus was increased with the increase of dietary Cu. Furthermore, the activities of SOD, CAT, T-AOC were increased in group I and group II and then decreased in group III, and the content of MDA and the mRNA levels of Nrf2, HO-1, SOD-1, CAT, GCLC, GCLM, and GST in treated groups were elevated compared to control group. Moreover, the mRNA expression levels of Beclin1, Atg5, LC3-I, LC3-II and the protein expression levels of Beclin1 and LC3-II/LC3-I up-regulated significantly with the increasing levels of Cu. However, the mRNA expression levels of p62 and mTOR and the protein expression level of p62 down-regulated remarkably. Taken together, our present study evidenced that excessive intake of Cu could induce oxidative stress and autophagy in hypothalamus of broilers.

Liver mitochondrial dysfunction and electron transport chain defect induced by high dietary copper in broilers.

Copper is an important trace mineral in the diet of poultry due to its biological activity. However, limited information is available concerning the effects of high copper on mitochondrial dysfunction. In this study, 72 broilers were used to investigate the effects of high dietary copper on liver mitochondrial dysfunction and electron transport chain defect. Birds were fed with different concentrations [11, 110, 220, and 330 mg of copper/kg dry matter (DM)] of copper from tribasic copper chloride (TBCC). The experiment lasted for 60 d. Liver tissues on d 60 were subjected to histopathological observation. Additionally, liver mitochondrial function was recorded on d 12, 36, and 60. Moreover, a site-specific defect in the electron transport chain in liver mitochondria was also identified by using various chemical inhibitors of mitochondrial respiration. The results showed different degrees of degeneration, mitochondrial swelling, and high-density electrons in hepatocytes. In addition, the respiratory control ratio (RCR) and oxidative phosphorylation rate (OPR) in liver mitochondria increased at first and then decreased in high-dose groups. Moreover, hydrogen peroxide (H2O2) generation velocity in treated groups was higher than that in control group, which were magnified by inhibiting electron transport at Complex IV. The results indicated that high dietary copper could decline liver mitochondrial function in broilers. The presence of a site-specific defect at Complex IV in liver mitochondria may be responsible for liver mitochondrial dysfunction caused by high dietary copper.

Anticoagulant effect of Huisheng Oral Solution in a rat model of thrombosis.

OBJECTIVE: To investigate whether Huisheng Oral Solution has an anticoagulant effect in a rat model of thrombosis. MATERIALS AND METHODS: A total of 40 male SD rats were equally and randomly divided into four groups: blank group, model group, and two treatment groups (A and B). Rats were subcutaneously injected with carrageenan to induce thrombosis. Rats in the treatment group A were intragastrically administered with Huisheng Oral Solution at a dose of 2 ml/100 g body weight (once per 8 hours), 72 hours after carrageenan injection, while those in the treatment group B were administered with Huisheng Oral Solution both 72 hours before and after induction of thrombosis. Blood samples were collected 24, 48, and 72 hours after carrageenan injection for measurements of prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), fibrinogen (FIB), prothrombin activity (PTA), platelets (PLT), fibrin degradation products (FDPs), and D-dimer. Lung, liver, and mesentery samples were taken 72 hours after carrageenan injection for histopathological analysis. The numbers of microthrombi in sections of different tissue samples were counted under a microscope. Blood parameters among each group were compared using the Welch test, the Kruskal-Wallis test, or the SNK test after testing for normality, while the number of microthrombi was compared using the Bonferroni test. RESULTS: Compared to those in the model group, PT, APTT, and INR were significantly prolonged or increased while FIB was significantly reduced at the majority of time points in the two treatment groups (P < 0.05 for all). The levels of FDPs and D-dimer and PLT counts at the majority of time points were significantly lower (P < 0.05 for all), and the numbers of microthrombi in lung, liver, and mesentery samples were significantly decreased (P < 0.05 for all) in the two treatment groups. The above parameters at the majority of time points showed no significant differences between the two treatment groups. CONCLUSIONS: Huisheng Oral Solution can significantly improve coagulation parameters, fibrinolysis parameters, and PLT count, and reduce blood hypercoagulability and microthrombosis, suggesting that Huisheng Oral Solution has an anticoagulant effect in a rat model of thrombosis.

[Contrast of growth characteristics of different germplasm and correlation between morphologic and individual yield of Isatis indigotica].

OBJECTIVE: To study the growth characteristics of different germplasm and analyze the correlation between morphologic and individual yield of Isatis indigotica. METHOD: The planting samples were collected during the growth period, morphological characteristics and root yield per plant in 13 germplasm of I. indigotica from all over the country were determined by correlation and path analysis. RESULT: The growth characteristics of various I. indigotica germplasm were consistent. The difference of morphological characteristics and root yield with various germplasm were significant. The root yield per plant was positively correlated to the main root length and the number of individual plant leaves. CONCLUSION: The number of leaves per plant and root length are selected for high-yield lines, meanwhile, leaf length and leaf diameter are important factors for breeding high-yield lines as well.

[Effects of sowing date on morphologic characteristics, yield and quality of Radix isatidis].

OBJECTIVE: To study the effects of sowing date on morphologic characteristics, yield and quality of Radix Isatidis, in order to provide a basis for selection of the suitable sowing date. METHOD: The experiment was carried out in a randomized complete block design arranged in split plot, the phonological period of Isatis indigotica was investigated and the morphological indexes, yield and quality at harvest were measured and determined by correlation and variance analysis. RESULT: The different sowing dates showed a great effect on phonological period of I. indigotica. The biological characteristics, yield and active components of Radix Isatidis were negatively correlated with the sowing date, and the difference of morphological characteristics, yield and active compositions with sowing date was significant. CONCLUSION: The suitable sowing date of I. indigotica was during the period of time from late March to beginning of the April in Fuyang area, and considering the factors of rational rotation, the time cloud delayed until late May to the beginning of June.

[Effects of various planting densities on dynamic growth rhythm and root yield of Isatis indigotica].

OBJECTIVE: To study the effects of various planting densities on dynamic growth and root yield of Isatis indigotica. METHOD: The planting samples were collected to measure the growth period of each organ. RESULT AND CONCLUSION: Under different planting densities, both main root length and breadth exhibited a trend of "fast-slow" by stages. However, the number of individual plant leaves were showed a trend of "slow-fast" on growth period. Meanwhile, the leaf length and breadth were exhibited a trend of "increase-decrease". The increase of dry leaf, dry root and whole plant dry matter was faster during the period of 65-76 days after seeding. The differences of root and leaf yields under various densities were significant. Planting densities has a great effect on yield of root. It must be shown that there was a positive development between the individual plant and colony. According to the dry matter of root and leaf, treatment B (i.e., 7 cm x 25 cm) was good choice.