OBJECTIVE: To develop a mortality prediction model for critically ill patients based on multidimensional and dynamic clinical data collected by the hospital information system (HIS) using random forest algorithm, and to compare the prediction efficiency of the model with acute physiology and chronic health evaluation II (APACHE II) model. METHODS: The clinical data of 10 925 critically ill patients aged over 14 years old admitted to the Third Xiangya Hospital of Central South University from January 2014 to June 2020 were extracted from the HIS system, and APACHE II scores of the critically ill patients were extracted. Expected mortality of patients was calculated according to the death risk calculation formula of APACHE II scoring system. A total of 689 samples with APACHE II score records were used as the test set, and the other 10 236 samples were used to establish the random forest model, of which 10% (n = 1 024) were randomly selected as the validation set and 90% (n = 9 212) were selected as the training set. According to the time series of 3 days before the end of critical illness, the clinical characteristics of patients such as general information, vital signs data, biochemical test results and intravenous drug doses were selected to develope a random forest model for predicting the mortality of critically ill patients. Using the APACHE II model as a reference, receiver operator characteristic curve (ROC curve) was drawn, and the discrimination performance of the model was evaluated through the area under the ROC curve (AUROC). According to the precision and recall, Precision-Recall curve (PR curve) was drawn, and the calibration performance of the model was evaluated through the area under the PR curve (AUPRC). Calibration curve was drawn, and the consistency between the predicted event occurrence probability of the model and the actual occurrence probability was evaluated through the calibration index Brier score. RESULTS: Among the 10 925 patients, there were 7 797 males (71.4%) and 3 128 females (28.6%). The average age was (58.9±16.3) years old. The median length of hospital stay was 12 (7, 20) days. Most patients (n = 8 538, 78.2%) were admitted to intensive care unit (ICU), and the median length of ICU stay was 66 (13, 151) hours. The hospitalized mortality was 19.0% (2 077/10 925). Compared with the survival group (n = 8 848), the patients in the death group (n = 2 077) were older (years old: 60.1±16.5 vs. 58.5±16.4, P < 0.01), the ratio of ICU admission was higher [82.8% (1 719/2 077) vs. 77.1% (6 819/8 848), P < 0.01], and the proportion of patients with hypertension, diabetes and stroke history was also higher [44.7% (928/2 077) vs. 36.3% (3 212/8 848), 20.0% (415/2 077) vs. 16.9% (1 495/8 848), 15.5% (322/2 077) vs. 10.0% (885/8 848), all P < 0.01]. In the test set data, the prediction value of random forest model for the risk of death during hospitalization of critically ill patients was greater than that of APACHE II model, which showed by that the AUROC and AUPRC of random forest model were higher than those of APACHE II model [AUROC: 0.856 (95% confidence interval was 0.812-0.896) vs. 0.783 (95% confidence interval was 0.737-0.826), AUPRC: 0.650 (95% confidence interval was 0.604-0.762) vs. 0.524 (95% confidence interval was 0.439-0.609)], and Brier score was lower than that of APACHE II model [0.104 (95% confidence interval was 0.085-0.113) vs. 0.124 (95% confidence interval was 0.107-0.141)]. CONCLUSIONS The random forest model based on multidimensional dynamic characteristics has great application value in predicting hospital mortality risk for critically ill patients, and it is superior to the traditional APACHE II scoring system.
Female ; Male ; Humans ; Aged ; Adult ; Middle Aged ; Adolescent ; Critical Illness ; Hospitalization ; Length of Stay ; APACHE ; Hospital Information Systems

Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores. In this study, we demonstrate that the upregulated intestinal transporter (PCFT), which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats, mediates the uptake of the folic acid-grafted nanoparticles (FNP). Specifically, the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway, Golgi-targeting pathway and basolateral exocytosis, featuring a high oral insulin bioavailability of 14.4% in the diabetic rats. Conversely, in cells with relatively low PCFT expression, the positive surface charge contributes to the cellular uptake of FNP, and FNP are mainly degraded in the lysosomes. Overall, we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway. This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.

Since the cluster of the 2019 novel coronavirus (2019-nCoV) pneumonia, a large number of patients gathered, the mortality of critical patients has remained high and the treatment was unclear. In this outbreak, Hunan Changde region immediately set up a hospital and intensive care unit. The patients relieved through respiratory support, hemodynamics management, nutritional support, the application of antiviral drugs, analgesic and sedation. The treatment experience in severe cases of 2019-nCov pneumonia patients were summarized as follows: in terms of respiratory support, we needed to pay attention to the advantages of high-flow nasal cannula oxygen therapy (HFNC) and the intervention of mechanical ventilation, pay attention to the ventilator parameters, and adopt prone position timely. In the aspects of fluid resuscitation and volume management, we should pay attention to the characteristics of severe patients' volume status, perform early evaluation, and clinicians should focused on hemodynamic management beside the bed. In the aspect of nutritional support and evaluation and maintenance of intestinal function, early enteral nutrition should be adopted in time. However, the trade-off between the risk of intestinal function and nutritional support in patients with mechanical ventilation and the antiviral benefits of Kaletra needed to be reevaluated, the optimized way of analgesia and sedation was adopted, at the same time, the usage and side effects of antiviral drugs should be paid attention to. We should grasp the opportunity of transportation for severe patients. It is suggested that some warning scores should be used to facilitate early recognition of patients with severe infection and then they should be earlier transferred to the designated hospital for intensive care.

To determine expression levels of glial fibrillary acidic protein in patients of sepsis-associated encephalopathy (SAE) and its clinical significance.
 Methods: Patients, admitted to intensive care units and diagnosed as sepsis, were recruited to our study from October 2016 to August 2018 in the Third Xiangya Hospital, Central South University. SAE is defined as a brain dysfunction secondary to sepsis and without evidence of a primary central nervous system infection or encephalopathy due to other reasons. The SAE group and non-SAE group were classed by Confusion Assessment Method for the ICU (CAM-ICU) score. We measured the levels of serum GFAP, S100β and neuron-specific enolase (NSE) within 24 hours after diagnosis of sepsis, and compared the patients' general clinical data, ICU stay time, 28-day and 180-day mortality.
 Results: Among 152 enrolled patients, 58 and 94 were assigned to the SAE group and the non-SAE group, respectively. There were a significantly higher Sequential Organ Failure Assessment (SOFA) scores, 28-day mortality rate, as well as 180-day mortality rate in the SAE group (all P<0.001). The levels of GFAP, NSE and S100β in the SAE group were significantly higher than those in the non-SAE group (all P<0.001). The diagnostic values of GFAP was 0.67 μg/L, with sensitivity at 75.9% and specificity at 77.7%. Area under the receiver operating characteristic curve (AUROC) of GFAP, NSE and S100β were 0.803, 0.795 and 0.750, respectively. Pearson analysis showed that serum GFAP level was positively correlated with Acute Physiology and Chronic Health Evaluation II (APACHE II) score, but it was negatively correlated with Glasgow Coma Scale (GCS) score, 28-day survival rate and 180-day survival rate.
 Conclusion: The level of serum GFAP is significantly increased in SAE, which shows certain correlation with incidence, severity and prognosis of the disease.
APACHE ; Glial Fibrillary Acidic Protein ; blood ; Humans ; Intensive Care Units ; Organ Dysfunction Scores ; Prognosis ; ROC Curve ; Sepsis ; Sepsis-Associated Encephalopathy ; diagnosis

To investigate the effect of sinomenine on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages and the underlying mechanisms.
 Methods: The mouse RAW264.7 macrophages were treated with sinomenine and/or LPS with or without heme oxygenase-1 (HO-1) inhibitor Znpp. Real-time PCR, ELISA, immunofluenscence, and Western blot were used to detect the mRNA expression of TNF-α and IL-6, the release of TNF-α and IL-6, the protein expression of HO-1 and autophagy, respectively.
 Results: Compared with the control group, the mRNA expression and release of inflammatory cytokines TNF-α and IL-6 were increased, the green fluorescence of autophagy-related protein LC3 was accumulated and the protein expression of HO-1 was increased in RAW264.7 cells after LPS treatment (P<0.05). Compared with the LPS group, sinomenine treatment could reduce the mRNA expression and release of TNF-α and IL-6, accompanied by increasess in green fluorescence aggregation of LC3 and HO-1 production (P<0.05). HO-1 inhibitor Znpp could weaken the ability of sinomenine through suppressing TNF-α and IL-6 expression and decreasing the aggregation of LC3 green fluorescence (P<0.05).
 Conclusion: Sinomenine could alleviate LPS-induced inflammation in RAW264.7 macrophages, which might be related to HO-1 mediated autophagy. This study provides an experimental and theoretical basis for the clinical application of sinomenine in prevention and treatment of inflammation.
Animals ; Anti-Inflammatory Agents ; pharmacology ; Autophagy ; drug effects ; Gene Expression Regulation, Enzymologic ; drug effects ; Heme Oxygenase-1 ; genetics ; Inflammation ; chemically induced ; Lipopolysaccharides ; Macrophages ; drug effects ; Mice ; Morphinans ; pharmacology

Objective:To investigate roles of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice.Methods:A total of 152 male Balb/c mice (8-week old) were randomly divided into a sham group,a septic model group,an allicin treatment group,and an autophagy inhibition group.Septic mouse model was established by cecal ligation and puncture (CLP).Mice in the allicin treatment group were given allicin (30 mg/kg,intra-peritoneal injection) at 6 and 12 h,while those in the autophagy inhibition group were given autophagy inhibitor 3-MA (15 mg/kg,intra-peritoneal injection) at half an hour after allicin administration.Mice in the model and sham group were administered with the same amount of saline.Twenty mice in each group were randomly chosen to observe the 7 d survival rate.The other 12 mice were killed at 24 h,and the bronchoalveolar lavage fluid (BALF) (n=6) and lung tissues (n=6) were collected.ELISA was used to detect the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the BALF.Hematoxylin-eosin staining was preformed to show the morphological changes in the lung tissues.Malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) in the lung tissues were examined.The expression of LC3B and Beclin-1 was determined by immunohistochemical analysis.Results:Compared with the sham group,the 7 d survival rate and lung SOD activity were decreased in the CLP group (P<0.05);the lung morphological damage score,the levels of TNF-α and IL-6 in the BALF,MDA content in the lung,and expression of LC3B and Beclin-1 were increased greatly in the CLP group (P<0.05).Compared with the CLP group,the 7 d survival rate,lung SOD activity and the expressions of LC3B and Beclin-1 were increased significantly in the allicin treatment group (P<0.05);the lung morphological damage scores,the levels of TNF-α and IL-6 in the BALF and MDA content in the lung were decreased obviously in the allicin treatment group (P<0.05).Compared with the allicin treatment group,the 7 d survival rate,lung SOD activity,and the expressions of LC3B and Beclin-1 were decreased in the 3-MA group (P<0.05);the lung morphological damage scores,the levels of TNF-α and IL-6 in the BALF,and MDA content in the lung were increased significantly in the 3-MA group (P<0.05).Conclusion:Allicin may ameliorate sepsis-induced acute lung injury in mice by enhancing the level of autophagy.

Objective To investigate the protective effect of allicin on intestinal mucosal barrier of septic rats so as to explore the possible mechanism.Methods Twenty-four male SD rats were randomly (random number) divided into sham,septic model and allicin treatment group.Septic model was established by cecal ligation and puncture (CLP) in rats.Rats in the treatment group were administered with allicin (30 mg/kg,ip)at 6 h and 12 h after modeling,while those in the model and sham groups were treated with equal amount of saline instead.Rats were sacrificed at 24 h and the serum D-lactic acid,diamine oxidase (DAO) and fluorescence isothiocyanate-dextran (FITC-Dextran,FD-40) were determined to evaluate the intestinal mucosal barrier function.The levels of tumor necrosis factor-α (TNF-α),interleukin-6 (IL-6),malondialdehyde (MDA),and the activity of superoxide dismutase (SOD) in intestinal tissue were measured.Histopathological changes of intestinal mucosa injury were assessed by Hematoxylin-eosin staining.Results Compared with the sham group,levels of serum D-lactic acid,DAO and FD-40 increased significantly in the CLP group (D-lactic acid:599.4±101.1 vs.149.2±20.63 nmoL/mL,t=11.84,P＜0.01;DAO:302.1 ±64.5 vs.76.57±14.76 ng/mL,t=9.433,P＜0.01;FD-40:6664.0±1437.0vs.1446.0±205.0 ng/mL,t =9.704,P ＜0.01);intestinal morphology damage occurred in the CLP group;intestinal levels of TNF-α,IL-6 and MDA increased greatly (TNF-αt:186.35 ±20.43 vs.58.76 ±8.94 pg/mL,t=17.23,P＜0.01;IL-6:763.25±85.23vs.125.36±14.37 pg/mL,t=22.54,P＜0.01;MDA:29.36±3.27vs.7.24±0.85 nmol/mg prot,t=16.61,P＜0.01),while SOD activity reduced (35.75±6.53 vs.73.26 ±8.35 U/rmg prot,t =10.57,P ＜0.01) in the CLP group.Allicin treatment greatly inhibited the increase of D-lactic acid,DAO and FD-40 levels in rat plasma caused by CLP (D-lactic acid:330.1 ±81.77 vs.599.4±101.1 nmol/mL,t=7.086,P＜0.01;DAO:171.8±49.70vs.302.1±64.56ng/mL,t=5.45,P＜0.01;FD-40:3349.0±1167.0 vs.6664.0±1437.0 ng/mL,t=6.165,P＜0.01);intestinal morphology damage was improved in the allicin treatment group;allicin treatment greatly inhibited the intestinal levels of TNF-o,IL-6 and MDA and preserved the intestinal SOD activity compared with the CLP group (TNF-α:95.37 ±12.68 vs.186.35 ±20.43 pg/mL,t =12.29,P＜0.01;IL-6:354.27±46.27vs.763.25±85.23pg/mL,t=14.45,P＜0.01;MDA:16.27±3.14vs.29.36±3.27 nmol/mgprot,t=9.831,P＜0.01;SOD:55.35 ±6.23vs.35.75±6.53 U/mgprot,t=5.522,P ＜0.01).Conclusions Allicin could inhibit local inflammation and oxidative stress in the intestine and exerts protective effect on intestinal mucosal barrier of septic rats.

The previous investigation has proved that their existed pharmacokinetic difference between the different crystal forms of the polymorphic drugs after oral administration. However, no systemic investigations have been made on the change of this pharmacokinetic difference, resulted either from the physiological or from the pathological factors. In this paper, we used polymorphic nimodipine (Nim) as a model drug and investigated the effect of age difference (2- and 9-month old) on the pharmacokinetics after oral delivery in rats. As the results shown, for L-form of Nim (L-Nim), the AUCin 2-month-old rats was 343.68±47.15 ng·h/mL, which is 23.36% higher than that in 9-month-old rats. For H-form of Nim (H-Nim), the AUCin 2-month-old rats was 140.91±19.47 ng·h/mL, which is 54.64% higher than that in 9-month-old rats. The AUCratio between H-Nim and L-Nim was 2.44 in 2-month-old rats and 3.06 in 9-month-old rats. Since age difference could result in unparallelled change of the absorption and bioavailability of the polymorphic drugs, the results in this experiment are of value for further investigation of crystal form selection in clinical trials and rational clinical application of the polymorphic drugs.

To evaluate the safety and efficiency of citrate anticoagulant-based continuous blood purification in patients at high risk of bleeding. 
 Methods: One hundred and fifty-two patients at high risk of bleeding were divided into local citrate group (group A, n=68) and heparin group (group B, n=84). Clotting function, change of pH, ionized sodium, bicarbonate ion, ionized calcium, activated clotting time (ACT) and complications were monitored before and during treatment. 
 Results: Compared to the group A, the incidence of clotting in filter and chamber, the degree of bleeding or fresh bleeding were significantly reduced in the group B (P<0.05). ACT of post-filter at 4, 8 and 12 h during the treatment in the group A was significantly extended compared with that without treatment (P<0.05), while there was no significant change in group B (P>0.05). The pH value, the levels of ionized sodium, bicarbonate ion and ionized calcium during the treatment were maintained in normal range in both group A and group B.
 Conclusion: Local citrate-based continuous blood purification can achieve effective anticoagulation and decrease the incidence of bleeding. It is an ideal choice for patients at high risk of bleeding.
Anticoagulants ; pharmacology ; Bicarbonates ; blood ; Blood Coagulation ; drug effects ; Blood Coagulation Tests ; Calcium ; blood ; Citrates ; Citric Acid ; therapeutic use ; Female ; Hemodiafiltration ; adverse effects ; methods ; Hemofiltration ; Hemorrhage ; etiology ; prevention & control ; Heparin ; therapeutic use ; Humans ; Intensive Care Units ; Male ; Reference Values ; Renal Dialysis ; Sodium ; blood ; Treatment Outcome