MACHINE LEARNING FOR PREDICTING HEMODYNAMIC DETERIORATION OF PATIENTS WITH INTERMEDIATE-RISK PULMONARY EMBOLISM IN INTENSIVE CARE UNIT.

ABSTRACT: Background: Intermediate-risk pulmonary embolism (PE) patients in the intensive care unit (ICU) are at a higher risk of hemodynamic deterioration than those in the general ward. This study aimed to construct a machine learning (ML) model to accurately identify the tendency for hemodynamic deterioration in the ICU patients with intermediate-risk PE. Method: A total of 704 intermediate-risk PE patients from the MIMIC-IV database were retrospectively collected. The primary outcome was defined as hemodynamic deterioration occurring within 30 days after admission to ICU. Four ML algorithms were used to construct models on the basis of all variables from MIMIC IV database with missing values less than 20%. The extreme gradient boosting (XGBoost) model was further simplified for clinical application. The performance of the ML models was evaluated by using the receiver operating characteristic curve, calibration plots, and decision curve analysis. Predictive performance of simplified XGBoost was compared with the simplified Pulmonary Embolism Severity Index score. SHapley Additive explanation (SHAP) was performed on a simplified XGBoost model to calculate the contribution and impact of each feature on the predicted outcome and presents it visually. Results: Among the 704 intermediate-risk PE patients included in this study, 120 patients experienced hemodynamic deterioration within 30 days after admission to the ICU. Simplified XGBoost model demonstrated the best predictive performance with an area under the curve of 0.866 (95% confidence interval, 0.800-0.925), and after recalibrated by isotonic regression, the area under the curve improved to 0.885 (95% confidence interval, 0.822-0.935). Based on the simplified XGBoost model, a web app was developed to identify the tendency for hemodynamic deterioration in ICU patients with intermediate-risk PE. Conclusion: A simplified XGBoost model can accurately predict the occurrence of hemodynamic deterioration for intermediate-risk PE patients in the ICU, assisting clinical workers in providing more personalized management for PE patients in the ICU.

BFGF attenuates aortic valvular interstitial cell calcification by inhibiting endoplasmic reticulum stress-mediated apoptosis.

The potential protective effect of basic fibroblast growth factor (BFGF) on the cardiovascular system has been proposed previously, however, its effect on calcific aortic valve disease (CAVD) and underlying mechanisms have not been elucidated. The valvular interstitial cell (VIC) were isolated from porcine aortic valve leaflets. To investigate the effect of BFGF on osteogenic differentiation of VIC, the osteogenic induced medium (OIM) and BFGF were added. The protein expression level was detected by Western blot, and apoptosis was determined by flow cytometry. The effect of BFGF on CAVD process in vivo was assessed by a rat CAVD model, which was identified by echocardiography and Alizarin red staining. The expression level of BFGF in the aortic valve and serum were significantly upregulated in CAVD patients compared to control group. In addition, exogenous BFGF injection attenuates CAVD process in vivo. The protein markers of osteogenic differentiation, endoplasmic reticulum stress (ERS), and apoptosis were significantly upregulated by culture with OIM. On the contrary, the aforementioned proteins were suppressed after adding 100 ng/mL of BFGF. Inhibition of PI3K/Akt and ERK1/2 pathways by specific inhibitors abolished the protective effect of BFGF. In conclusion, BFGF could alleviate the VIC calcification by inhibiting ERS-mediated apoptosis, which is partly regulated by activation of the PI3K/Akt and ERK1/2 signaling pathways. BFGF may provide a potential avenue for CAVD therapy.

Influences of Cu Doping on the Microstructure, Optical and Resistance Switching Properties of Zinc OxideThin Films.

Copper-doped zinc oxide films (Zn1-xCuxO) (x = 0, 2%, 4%, 6%) were fabricated on conductive substrates using the sol-gel process. The crystal structure, optical and resistive switching properties of Zn1-xCuxO films are studied and discussed. RRAM is made using Zn1-xCuxO as the resistive layer. The results show that the (002) peak intensity and grain size of Zn1-xCuxOfilms increase from 0 to 6%. In addition, PL spectroscopy shows that the oxygen vacancy defect density of Zn1-xCuxO films also increases with the increase in Cu. The improved resistive switching performance of the RRAM device can be attributed to the formation of conductive filaments and the destruction of more oxygen vacancies in the Zn1-xCuxO film. Consequently, the RRAM device exhibits a higher low resistance state to high resistance state ratio and an HRS state of higher resistance value.

Activation Energy and Bipolar Switching Properties for the Co-Sputtering of ITOX:SiO2 Thin Films on Resistive Random Access Memory Devices.

Activation energy, bipolar resistance switching behavior, and the electrical conduction transport properties of ITOX:SiO2 thin film resistive random access memory (RRAM) devices were observed and discussed. The ITOX:SiO2 thin films were prepared using a co-sputtering deposition method on the TiN/Si substrate. For the RRAM device structure fabrication, an Al/ITOX:SiO2/TiN/Si structure was prepared by using aluminum for the top electrode and a TiN material for the bottom electrode. In addition, grain growth, defect reduction, and RRAM device performance of the ITOX:SiO2 thin film for the various oxygen gas flow conditions were observed and described. Based on the I-V curve measurements of the RRAM devices, the turn on-off ratio and the bipolar resistance switching properties of the Al/ITOX:SiO2/TiN/Si RRAM devices in the set and reset states were also obtained. At low operating voltages and high resistance values, the conductance mechanism exhibits hopping conduction mechanisms for set states. Moreover, at high operating voltages, the conductance mechanism behaves as an ohmic conduction current mechanism. Finally, the Al/ITOX:SiO2/TiN/Si RRAM devices demonstrated memory window properties, bipolar resistance switching behavior, and nonvolatile characteristics for next-generation nonvolatile memory applications.

ENO1 promotes immunosuppression and tumor growth in pancreatic cancer

Background Pancreatic adenocarcinoma (PAAD) is a highly aggressive and malignant cancer type with the highest mortality rate of all major cancers. However, the molecular and tumor immune escape mechanism underlying pancreatic cancer remains largely unclear. α-enolase (ENO1) is a glycolytic enzyme reported to overexpress in a variety of cancer types. This study was undertaken to investigate the functional role and therapeutic potential of ENO1 in pancreatic cancer. Methods We examined the expression levels of ENO1 across a broad spectrum of cancer types from the TCGA database. ENO1-knockout (ENO1-KO) through CRISPR/CAS9 technology in a mouse pancreatic cancer cell line (PAN02) was used to analyze the role of ENO1 on proliferation and colony formation. Flow cytometry and RT-PCR were also applied to analyze T lymphocytes and relevant cytokines. Results In the present study, we identified that ENO1 promoted pancreatic cancer cell proliferation. Our bioinformatics data indicated that ENO1 was significantly overexpressed in pancreatic cancer cell lines and tissues. Survival analyses revealed that ENO1 overexpression implicated poor survival of PAAD patients. Knockout of ENO1 expression repressed the ability of proliferation and colony formation in PAN02. In addition, ENO1-KO significantly decreased tumor growth in mouse models. Further flow cytometry and RT-PCR analysis revealed that ENO1-KO modulates the tumor microenvironment (TME), especially in suppressed Treg cells and inducing anti-tumor cytokine responses. Conclusions Taken together, our data showed that ENO1 was an oncogenic biomarker and might serve as a promising target for immunotherapy of pancreatic cancer (AU)

Bipolar Switching Properties of the Transparent Indium Tin Oxide Thin Film Resistance Random Access Memories.

In this study, the bipolar switching properties and electrical conduction behaviors of the ITO thin films RRAM devices were investigated. For the transparent RRAM devices structure, indium tin oxide thin films were deposited by using the RF magnetron sputtering method on the ITO/glass substrate. For the ITO/ITOX/ITO/glass (MIM) structure, an indium tin oxide thin film top electrode was prepared to form the transparent RRAM devices. From the experimental results, the 102 On/Off memory ratio and bipolar switching cycling properties for set/reset stable states were found and discussed. All transparent RRAM devices exhibited the obvious memory window and low set voltage for the switching times of 120 cycles. The electrical transport mechanisms were dominated by the ohmic contact and space charge limit conduction (SCLC) models for set and reset states. Finally, the transmittances properties of the transparent ITO/ITOX/ITO RRAM devices for the different oxygen growth procedures were about 90% according to the UV-Vis spectrophotometer for the visible wavelength range.

First Order Rate Law Analysis for Reset State in Vanadium Oxide Thin Film Resistive Random Access Memory Devices.

In the reset state, the decay reaction mechanism and bipolar switching properties of vanadium oxide thin film RRAM devices for LRS/HRS are investigated and discussed here. To discover the properties of I-V switching curves, the first order rate law behaviors of the reset state between the resistant variety properties and the reaction time were observed. To verify the decay reaction mechanism in the reset state, vanadium oxide thin films from RRAM devices were measured by different constant voltage sampling and exhibited the same decay reaction rate constant. Finally, the electrical conduction transfer mechanism and metallic filament forming model described by I-V switching properties of the RRAM devices were proven and investigated.

Analysis of reasons for screening failure of healthy subjects in clinical trials of orally inhaled drug products / 中国临床药理学与治疗学

AIM: To explore the reasons for screening failure of healthy subjects in clinical trials of orally inhaled drug products (OIDPs). METHODS: Screening data of 1 432 healthy subjects who participated in clinical trials of OIDPs were collected. The main reasons for the screening failure, gender differences in screening failure rate and the correlation between age and screening failure rate were summarized and analyzed. RESULTS: The screening failure rate was 72.4 % and increased with age. The failure rate was slightly higher in females than in males. Besides abnormal vital signs (17.3%), abnormal laboratory test results (16.5%) and withdrawal of consent (7.6%), poor venous condition (13.9%), positive for cigarette test results (12.6%) and failure in inhalation training (7.1%) were also the other three main reasons affecting the screening success rate. Abnormal vital signs and poor venous conditions were the primary screening failure reasons for males and females, respectively. CONCLUSION: The screening success rate could be improved by informing fully and communicating effectively, selecting young subjects with strong understanding abilities, and enhancing the training skills of investigators.

Safety analysis on bioequivalence studies of orally inhaled drug products in healthy Chinese subjects / 中国临床药理学与治疗学

AIM: To investigate the safety of bioequivalence (BE) studies of orally inhaled drug products (OIDPs) conducted by Phase I clinical Research Center of our hospital. METHODS: The safety data were collected from 482 healthy subjects enrolled in 20 OIDPs BE studies in Wuxi People's hospital from 2017 to 2022. The difference of adverse events (AEs) between test preparation and reference preparation were compared, as well as the influence of gender, age, mechanism of drug action and device type on AE were analyzed. RESULTS: A total of 102 cases of AEs were occurred in 77 subjects (16.0%, 77/482), 87 cases of AEs were related to experimental drugs, all AEs were mild or moderate, and no serious adverse events occurred. There was no difference in the incidence of AE between test preparation and reference preparation. In addition, gender, age, mechanism of drug action and device type had no significant effects on AEs. CONCLUSION: In 20 bioequivalence studies of OIDPs, OIDPs were safe and well tolerated in healthy subjects after dosing, and safety features of generic OIDPs and original drug were basically similar.

Role of macrophages in heart failure and traditional Chinese medicine intervention / 中国中药杂志

As the disease with high morbidity and mortality in the world, heart failure affects the development of human society. Due to its complicated pathology and limited treatment options, it is urgent to discover new disease targets and develop new treatment strategies. As innate immune cells accompanied by the evolution of heart failure, macrophages play an important role in cardiac homeostasis and stress. In recent years, the role of macrophages in the heart has attracted more and more attention as a potential target for heart failure intervention, and the research on cardiac macrophages has made important progress. Traditional Chinese medicine(TCM) has significant effects on regulating inflammatory response, treating heart failure, and maintaining homeostasis. In this article, researches on the functions of cardiac macrophages and application of TCM were reviewed from the source and classification of cardiac macrophages and the relationship of macrophages and cardiac inflammation, myocardial fibrosis, cardiac angiogenesis, and cardiac electrical conduction, which provided a basis for further basic research and clinical applications.

Role of glutathione transferase in nonalcoholic fatty liver disease: An analysis based on gene expression profile / 临床肝胆病杂志

Objective To investigate the role of glutathione transferase in nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet using the RNA-Seq technique in combination with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of differentially expressed genes. Methods A total of 14 male C57BL/6J mice were divided into control group with 6 mice and model group with 8 mice by random sampling. The mice in the control group were fed with normal diet, and those in the model group were fed with high-fat diet for 7 consecutive weeks to establish a model of NAFLD. Kits were used to measure the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the level of triglyceride (TG), and HE staining and oil red staining were used to observe liver pathology and deposition of lipid droplets. Liver tissue RNA was extracted for RNA-Seq, and genes with a fold change of ≥2.0 and a P value of 0.05). Compared with the control group, the model group had a significantly higher serum level of TG (2.02±0.50 mmol/L vs 1.00±0.29 mmol/L, t =-4.45, P =0.001). HE staining showed diffuse steatosis and ballooning degeneration in the model group, and oil red staining showed that the model group had a significant increase in orange-red lipid droplets in the cytoplasm of hepatocytes and a significantly higher grade of hepatocyte steatosis than the control group (1.88±0.64 vs 1.00±0.00, t =-3.86, P =0.006). RNA-seq results showed a total of 1367 differentially expressed genes between the two groups, among which there were 608 upregulated genes and 759 downregulated genes, and there were 17 differentially expressed GST genes between the two groups. The top 10 GST genes in terms of fold change were validated, and compared with the control group, the model group had downregulated expression of GSTa2, GSTa3, GSTa4, GSTm1, GSTm2, GSTm3, GSTm4, GSTp1, and GSTo1 and upregulated expression of GSTk1. The results of qRT-PCR were consistent with the results of sequencing. Conclusion GST affects lipid metabolism by participating in various biological processes such as steroid metabolism, fatty acid metabolism, and cholesterol metabolism and is closely associated with the pathogenesis of NAFLD.

Accuracy of calculating mechanical power of ventilation by one commonly used equation.

Gattinoni's equation, [Formula: see text], now commonly used to calculate the mechanical power (MP) of ventilation. However, it calculates only inspiratory MP. In addition, the inclusion of PEEP in Gattinoni's equation raises debate because PEEP does not produce net displacement or contribute to MP. Measuring the area within the pressure-volume loop accurately reflects the MP received in a whole ventilation cycle and the MP thus obtained is not influenced by PEEP. The MP of 25 invasively ventilated patients were calculated by Gattinoni's equation and measured by integration of the areas within the pressure-volume loops of the ventilation cycles. The MP obtained from both methods were compared. The effects of PEEPs on MP were also evaluated. We found that the MP obtained from both methods were correlated by R2 = 0.75 and 0.66 at PEEP 5 and 10 cmH2O, respectively. The biases of the two methods were 3.13 (2.03 to 4.23) J/min (P < 0.0001) and - 1.23 (- 2.22 to - 0.24) J/min (P = 0.02) at PEEP 5 and 10 cmH2O, respectively. These P values suggested that both methods were significantly incongruent. When the tidal volume used was 6 ml/Kg, the MP by Gattinoni's equation at PEEP 5 and 10 cmH2O were significantly different (4.51 vs 7.21 J/min, P < 0.001), but the MP by PV loop area was not influenced by PEEPs (6.46 vs 6.47 J/min, P = 0.331). Similar results were observed across all tidal volumes. We conclude that the Gattinoni's equation is not accurate in calculating the MP of a whole ventilatory cycle and is significantly influenced by PEEP, which theoretically does not contribute to MP.

Microsurgical techniques and one-stage surgical treatment of chronic osteomyelitis——concept and clinical application / 中华显微外科杂志

Chronic osteomyelitis is a serious clinical problem with repeated courses and high disability rate, which seriously affects the physical and mental health of patients. Through continuous learning and summary in the process of using traditional therapies, the innovative improvements and changes had made in the treatment of osteomyelitis: Radical debridement of lesions was performed by applying the basic principles of modern bone tumor surgery. The application of microsurgical technique to transfer composite tissue flap can provide guarantee for tissue defect repair and wound closure without tension. Combined with bone grafting, local antibiotics and bone fixation, an one-stage operation has significantly improve the therapeutic effect of chronic complex osteomyelitis.

Specialty system of special physical education at master's level based on World Health Organization rehabilitation competency framework / 中国康复理论与实践

@#Objective To explore the specialty system of special physical education at master's level.Methods Professional competency for special physical education was developed using the World Health Organization Rehabilitation Competency Framework (RCF), and was applied to the exploration of theoretical structure and methodological system for the construction of special physical education program at master's level.Results Based on the RCF, a competency framework for special physical education teachers was constructed, involving in five areas: practice, professionalism, learning and development, management and leadership, and research. The proficiency of competencies and activities should attain the corresponding level. The construction of special physical education program should be built to highlight the characteristics of RCF and focus on the training of competency in four areas: education objectives, instructional methods, the curriculum of the program and instructional assessment.Conclusion A competency-based program at the master's level in special physical education has been constructed using the RCF. The program uses the RCF to specify professional competency standards for special physical education teachers, and this can be transformed into the content of the competency-based program for special physical education at the master's level. The RCF is used to construct a competency-based special physical education system, which can be used to specify the educational objectives, instructional modalities, specialized core curriculum, and content and methods of instructional assessment in the design of a special physical education program at the master's level.

Interpretation of Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions / 中国中药杂志

Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions,a series of group standards,were proposed by Professor ZHANG Bing from Research Center for Pharmacovigilance and Rational Use of Traditional Chinese Medicine,and underwent centralized management by Chinese Association of Chinese Medicine. They were officially released on July 23 and implemented on July 31,2021. The series of group standards consist of six sections,including general principles,adverse drug events,contraindications,precautions,application for special populations,and warnings. The section of general principles is comprised of holistic and programmatic expressions,which explain the general technical requirements for revising the marketed Chinese patent medicine instructions. The other five sections focus on information collection,screening,transformation,and illustration of specific items,forming a standardized revision technical process. This series of standards is the result of multiple rounds of research and the suggestions of more than 200 experts in different professional fields of " medicine-pharmacy-management-law-enterprise" have been gathered therein to reach a consensus. With the purposes of establishing standardized technical specifications for the revision of safety information in the marketed Chinese patent medicine instructions,guiding marketing authorization holders in revising the instructions,filling the gaps in the research of Chinese patent medicine instructions,promoting the deve-lopment of pharmaceutical care and academic research,and encouraging the rational and safe medication of Chinese patent medicine,the series of group standards is of great significance.

Series of group standards of Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions / 中国中药杂志

Drug instructions,the statutory and technical documents recording effectiveness and safety information,are an important basis for guiding doctors,pharmacists,and patients to use drugs rationally,and their scientificity,standardization,and accuracy directly affect the medication safety of the public. The sections of adverse drug events,contraindications,precautions,warnings,and application for specific populations in drug instructions directly express safety information and measures for rational use of drugs. In the drug life cycle,marketing authorization holders( MAHs) need to update safety information in the instructions promptly to ensure the safety and effectiveness of clinical drug medication. At present,revising instructions is an important measure to control drug risks. In the drug life cycle,in order to standardize the revision of safety information in the instructions by MAHs and eliminate inexact terms such as " unclear",the Technical Specifications for Revision of Safety Information in Marketed Chinese Patent Medicine Instructions,a series of group standards,have been established under the guidance of Standardization Department,China Association of Chinese Medicine. Therefore,on the basis of the existing rules and regulations,the standardized technical procedures for revising instructions came into being to help clinical safe and rational medication of drugs,and implement the strategy of " Healthy China".

Application of interatrial shunt device in patients with severe pulmonary hypertension / 中国胸心血管外科临床杂志

@#Pulmonary arterial hypertension (PAH) is a severe, progressive disease leading to right ventricular failure and finally death. Lung transplantation is recommended for PAH patients who do not respond to targeted drug combination therapy or World Health Organization functional class (WHO FC) Ⅲ or Ⅳ. However, only 3% of PAH patients can recieve the lung transplantation. A novel implantable interatrial shunt device (ISD) can create a relatively fixed right-to-left shunt established by balloon atrial septostomy (BAS). The device may decompress the right sided chambers, facilitate left heart filling, improve organ perfusion and reduce the likelihood of syncope, acute pulmonary hypertensive crisis and death. The systemic oxygen transport improves despite hypoxemia. Implantation is simple, feasible and safe, and the X-ray time and operation time are short. There is no severe complication or thrombosis during the mid-term follow-up of the clinical studies and the device remained patent. The syncope symptoms, six-minute walk distance, cardiac index and systemic oxygen transport improve significantly in the patients. ISD may be currently the last alternative treatment to improve symptoms and prolong survival in currently drug-resistant patients with severe PAH.

Application and progress of pharmacodynamics study in bioequivalence evaluation of orally inhaled drug products / 中国临床药理学与治疗学

Orally inhaled drug products (OIDPs) play a great role in the pharmacological treatment of chronic obstructive pulmonary disease (COPD) and asthma. There is an unmet clinical need for OIDPs. Pharmacodynamics-Bioequivalence studies (PD-BE) are recommended by several national guidelines as important research methods for bioequivalence study of OIDPs. It can effectively bridge the gap between in vitro studies and PK-BE studies in evaluating the efficacy and safety consistency of generic drugs with the original drugs. There are two research methods for PD-BE, using a diastolic model or an excitation model. The different methods use different metrics to evaluate efficacy. The more commonly used metrics include Forced Expiratory Volume in the First Second (FEV1), Specific Airway Conductance (sGaw), Peripheral Airway Resistance (R5-20), and stimulant concentration/dose (PC20/PD20). PD-BE studies using FEV1 as an efficacy metric is also recommended by the FDA (Food and Drug Administration), EMA (European Medicines Agency) and NMPA (National Medical Products Administration) guidelines and is widely accepted by investigators. In such PD-BE studies, the trial protocols for different OIDPs drugs are relatively consistent in terms of trial design, trial data processing, and equivalence evaluation criteria, while there are detailed differences in terms of target population, single/multiple dosing, dose administration, and collection site design. This paper reviews the progress of PD-BE studies in the bioequivalence evaluation of OIDPs by combining national guidelines and PD-BE-related studies of OIDPs published in the last five years, with a view to providing important theoretical information for PD-BE studies of OIDPs.

Protective effects of Wuwei Xiaodu Drink against chronic osteomyelitis through Foxp3+CD25+CD4+ Treg cells via the IL-2/STAT5 signaling pathway / 中国天然药物

To explore the effectiveness and safety of a Chinese medicinal decoction Wuwei Xiaodu Drink (WWXDD) in inhibiting chronic osteomyelitis via regulatory T cells signaling. The effective constitutes of WWXDD and osteomyelitis related genes were screened. Target proteins were cross-validated using the Venny database. GO function and KEGG pathway analysis were performed for target proteins, while pharmacological network was constructed. The bone properties were analyzed by HE staining and the concentrations of immune factors were measured by ELISA. The expression of CTLA-4 and Foxp3 mRNA and STAT5, p-STAT5, CTLA-4 and Foxp3 protein were detected using Real-time PCR and Western blot, respectively. FACS was used to analyze the percentages of cells. A total of 117 genes overlapped between 785 target genes of the active compounds of WWXDD and 912 osteomyelitis related genes. Inflammation-related genes, including IL-6, TNFα, IL-1β and IL-2 showed high connection degree in the drug-compound-disease-target network. GO function and KEGG pathway analysis revealed that 117 intersection genes mainly enriched in virus infection related pathways, immune related pathways and chemokine signaling pathway. Furthermore, the development of chronic osteomyelitis was suppressed in model rats after treatment with WWXDD. Meanwhile, the concentrations of IL-2 and CD4+CD25+Foxp3 Treg percentages together with the levels of p-STAT5, CTLA-4 and Foxp3 were also down-regulated. Furthermore, IL-2 and WWXDD drug-containing serum exhibited opposite effects on regulating IL-2, IL-10, TGF-β1, Foxp3, CTLA4 and STAT5. In addition, a STAT5 phosphorylation inhibitor suppressed the expression of Foxp3 and CTLA-4. WWXDD can treat chronic osteomyelitis through suppressing the main regulating factors of Tregs and interfere its immunodepression. Our results bring a new solution for chronic osteomyelitis.