PURPOSE: Septic shock is associated with high mortality and poor outcomes among sepsis patients with coagulopathy. Although traditional statistical methods or machine learning (ML) algorithms have been proposed to predict septic shock, these potential approaches have never been systematically compared. The present work aimed to develop and compare models to predict septic shock among patients with sepsis. METHODS: It is a retrospective cohort study based on 484 patients with sepsis who were admitted to our intensive care units between May 2018 and November 2022. Patients from the 908th Hospital of Chinese PLA Logistical Support Force and Nanchang Hongdu Hospital of Traditional Chinese Medicine were respectively allocated to training (n=311) and validation (n=173) sets. All clinical and laboratory data of sepsis patients characterized by comprehensive coagulation indexes were collected. We developed 5 models based on ML algorithms and 1 model based on a traditional statistical method to predict septic shock in the training cohort. The performance of all models was assessed using the area under the receiver operating characteristic curve and calibration plots. Decision curve analysis was used to evaluate the net benefit of the models. The validation set was applied to verify the predictive accuracy of the models. This study also used Shapley additive explanations method to assess variable importance and explain the prediction made by a ML algorithm. RESULTS: Among all patients, 37.2% experienced septic shock. The characteristic curves of the 6 models ranged from 0.833 to 0.962 and 0.630 to 0.744 in the training and validation sets, respectively. The model with the best prediction performance was based on the support vector machine (SVM) algorithm, which was constructed by age, tissue plasminogen activator-inhibitor complex, prothrombin time, international normalized ratio, white blood cells, and platelet counts. The SVM model showed good calibration and discrimination and a greater net benefit in decision curve analysis. CONCLUSION The SVM algorithm may be superior to other ML and traditional statistical algorithms for predicting septic shock. Physicians can better understand the reliability of the predictive model by Shapley additive explanations value analysis.
Humans ; Shock, Septic/blood* ; Machine Learning ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Sepsis/complications* ; ROC Curve ; Cohort Studies ; Adult ; Intensive Care Units ; Algorithms ; Blood Coagulation ; Critical Illness

(+)-Borneol, the main component of "Natural Borneol" in the Chinese Pharmacopoeia, is a high-end spice and precious medicine. Plant extraction cannot meet the increasing demand for (+)-borneol, while microbial biosynthesis offers a sustainable supply route. However, its production was extremely low compared with other monoterpenes, even with extensively optimizing the mevalonate pathway. We found that the key challenge is the complex and unusual dephosphorylation reaction of bornyl diphosphate (BPP), which suffers the side-reaction and the competition from the cellular dephosphorylation process, especially lipid metabolism, thus limiting (+)-borneol synthesis. Here, we systematically optimized the dephosphorylation process by identifying, characterizing phosphatases, and balancing cellular dephosphorylation metabolism. For the first time, we identified two endogenous phosphatases and seven heterologous phosphatases, which significantly increased (+)-borneol production by up to 152%. By engineering BPP dephosphorylation and optimizing the MVA pathway, the production of (+)-borneol was increased by 33.8-fold, which enabled the production of 753 mg/L under fed-batch fermentation in shake flasks, so far the highest reported in the literature. This study showed that rewiring dephosphorylation metabolism was essential for high-level production of (+)-borneol in Saccharomyces cerevisiae, and balancing cellular dephosphorylation is also helpful for efficient biosynthesis of other terpenoids since all whose biosynthesis involves the dephosphorylation procedure.

Dysregulated RNA splicing is a well-recognized characteristic of colorectal cancer (CRC); however, its intricacies remain obscure, partly due to challenges in profiling full-length transcript variants at the single-cell level. Here, we employ high-depth long-read scRNA-seq to define the full-length transcriptome of colorectal epithelial cells in 12 CRC patients, revealing extensive isoform diversities and splicing alterations. Cancer cells exhibited increased transcript complexity, with widespread 3'-UTR shortening and reduced intron retention. Distinct splicing regulation patterns were observed between intrinsic-consensus molecular subtypes (iCMS), with iCMS3 displaying even higher splicing factor activities and more pronounced 3'-UTR shortening. Furthermore, we revealed substantial shifts in isoform usage that result in alterations of protein sequences from the same gene with distinct carcinogenic effects during tumorigenesis of CRC. Allele-specific expression analysis revealed dominant mutant allele expression in key oncogenes and tumor suppressors. Moreover, mutated PPIG was linked to widespread splicing dysregulation, and functional validation experiments confirmed its critical role in modulating RNA splicing and tumor-associated processes. Our findings highlight the transcriptomic plasticity in CRC and suggest novel candidate targets for splicing-based therapeutic strategies.
Humans ; Colorectal Neoplasms/metabolism* ; RNA Isoforms/metabolism* ; Single-Cell Analysis ; RNA Splicing ; Gene Expression Regulation, Neoplastic ; RNA, Neoplasm/metabolism* ; Transcriptome

The 2-(2-phenylethyl)chromones were separated from agarwood of Aquilaria agallocha Roxb. and their anti-KRAS mutant non-small cell lung cancer (NSCLC) activities were evaluated. 2-(2-Phenyethyl)chromones in agarwood were separated and purified by silica gel, RP-18 reverse phase silica gel, MCI gel CH20P, Diol, and semi preparative HPLC chromatography techniques, while the structures of the compounds were identified by extensive spectroscopic analysis, such as 1D and 2D NMR and ESI-MS. The cell counting kit 8 (CCK-8) assay was used to screen the anti-tumor activity of the isolated monomeric compounds on three KRAS-mutant NSCLC cells. The cell proliferation, cloning formation, adhesion ability, and cell cycle arrest activity of compound 8 were analyzed. Molecular docking and Western blot experiments were used to study the mechanism of compound 8. The in vivo anti-tumor activity of the compound 8 was evaluated by zebrafish cell derived xenograft (CDX) model. Nineteen known 2-(2-phenylethyl)chromones were isolated from the ethyl acetate extract of agarwood. On A549 (KRAS G12S) cells, compounds 8, 10, and 19 showed good inhibitory activity, on H23 (KRAS G12C) cells, compounds 7, 8, and 19 showed good inhibitory activity, and on H358 (KRAS G12C) cells, compounds 8, 10, and 16 showed good inhibitory activity. Compound 8 had the best inhibitory activity in all three cell lines. It effectively inhibited cell proliferation, clone formation, adhesion ability, and arrested the H23 cell cycle at G2/M phase. Compound 8 could also inhibit the expression of c-Met and its downstream signaling pathways, effectively inhibiting tumor growth in zebrafish CDX model. In conclusion, among the nineteen known 2-(2-phenylethyl)chromones, compound 8 had the best activity and significantly inhibited the proliferation of KRAS-mutant NSCLC cells by arresting the cells in the G2/M phase.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Abstract Allergic diseases can occur in all systems of the body, covering the whole life cycle, from children to adults and to old age, can be lifelong onset and even fatal in severe cases. Children account for the largest proportion of the victims of allergic disease, Children s allergies start from scratch, ranging from mild to severe, from less to more, from single to multiple systems and systemic performance, so the prevention and treatment of allergic diseases in children is of great importance, which can not only prevent high risk allergic conditions from developing into allergic diseases, but also further block the process of allergy. At present, there is no consensus on the management system of allergic children in kindergartens and primary schools. The "Consensus on Allergy Management and Prevention in Kindergartens and Primary Schools", which includes the organizational structure, system construction and management of allergic children, provides evidence informed recommendations for the long term comprehensive management of allergic children in kindergartens and primary schools, and provides a basis for the establishment of the prevention system for allergic children.

Objective: To investigate the safety and efficacy of troxatabine in advanced or relapsed malignant tumors resistant to standard therapy in China. Methods: This is a phase Ⅰ prospective study. During dose escalation, patients in Cancer Hospital, Chinese Academy of Medical Sciences received a single-dose intravenous infusion of troxacitabine. The planned dosing groups were 1.8, 3.6, 4.8, 6.4 and 8.0 mg/m(2) on days 1 and 8 every 3 weeks. The data of all patients were collected for safety analyses. Safety and tolerability were evaluated by monitoring adverse events. Results: Nineteen patients were enrolled from April 2018 to May 2019. The major adverse events were fatigue (89.5%, 17/19), leukopenia (84.2%, 16/19) and neutropenia (78.9%, 15/19). The dose limiting toxicity was neutropenia. The maximum tolerated dose was 6.4 mg/m(2). The best effect was stable disease (43.8%). The half-life of elimination phase from 15.91 hours to 76.63 hours in each dose group. Conclusions: The toxicity of troxacitabine is well tolerant. We recommend that the dose for Phase Ⅱ clinical trial should be 6.4 mg/m(2).
Humans ; Antineoplastic Agents/adverse effects* ; Maximum Tolerated Dose ; Neoplasms/drug therapy* ; Neutropenia/chemically induced* ; Prospective Studies

OBJECTIVE: To identify specific Chinese medicines (CMs) that may benefit patients with gastroesophageal reflux disease (GERD), and explore the action mechanism. METHODS: Domestic and foreign literature on the treatment of GERD with CMs was searched and selected from China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and PubMed from October 1, 2011 to October 1, 2021. Data from all eligible articles were extracted to establish the database of CMs for GERD. Apriori algorithm of data mining techniques was used to analyze the rules of herbs selection and core Chinese medicine formulas were identified. A system pharmacology approach was used to explore the action mechanism of these medicines. RESULTS: A total of 278 prescriptions for GERD were analyzed, including 192 CMs. Results of Apriori algorithm indicated that Evodiae Fructus and Coptidis Rhizoma were the highest confidence combination. A total of 32 active ingredients and 66 targets were screened for the treatment of GERD. Enrichment analysis showed that the mechanisms of action mainly involved pathways in cancer, fluid shear stress and atherosclerosis, advanced glycation end product (AGE), the receptor for AGE signaling pathway in diabetic complications, bladder cancer, and rheumatoid arthritis. CONCLUSION Evodiae Fructus and Coptidis Rhizoma are the core drugs in the treatment of GERD and the potential mechanism of action of these medicines includes potential target and pathways.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional ; Network Pharmacology ; Data Mining ; Gastroesophageal Reflux/drug therapy*

OBJECTIVE: To analyze the composition and metabolites of gut microbiota in septic rats by fecal 16s rRNA sequencing and untargeted metabolomics, and to preliminarily explore the effect and potential mechanism of gut microbiota and its metabolites on inflammatory response and multiple organ damage in sepsis. METHODS: Ten males healthy male Wistar rats were randomly divided into a sham operated group (Sham group) and sepsis model group (CLP group) using a random number table method, with 5 rats in each group. A rat sepsis model was established by cecal ligation and perforation (CLP) method. The animals were sacrificed 24 hours after modeling, the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in peripheral blood were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to observe the pathological changes of lung and kidney tissues, and the pathological scores were evaluated. Fecal samples were collected, and 16s rRNA high-throughput sequencing and non-targeted metabolomics were used to screen microbiota, metabolites and potential signal pathways that may play an important role in disease outcomes. Spearman correlation analysis was conducted to jointly analyze the gut microbiota and non-targeted metabolism. RESULTS: Compared with the Sham group, the degree of pathological damage to lung and kidney tissues in the CLP group was significantly increased (lung tissue score: 3.60±0.80 vs. 0.00±0.00, kidney tissue score: 2.40±0.80 vs. 0.00±0.00, both P < 0.01), the level of IL-6 and TNF-α in peripheral blood significantly increased [TNF-α (ng/L): 248.12±55.98 vs. 143.28±36.57, IL-6 (ng/L): 260.26±39.47 vs. 116.01±26.43, both P < 0.05], the species diversity of intestinal flora of rats in the CLP group was significantly reduced, the relative abundance of Morganella, Bacteroides and Escherichia-Shigella were significantly increased, and the relative abundance of Lachnospiraceae NK4A136, Ruminococcus, Romboutsia and Roseburia were significantly reduced. In addition, the biosynthesis and bile secretion of phenylalanine, tyrosine, and tryptophan in the gut microbiota of the CLP group were significantly increased, while the biosynthesis of secondary bile acids was significantly reduced. There was a significant correlation between differential metabolites and differential microbiota. CONCLUSIONS Sepsis can cause significant changes in the characteristics of gut microbiota and fecal metabolites in rats, which provides a basis for translational research to seek new targets for the treatment of sepsis.
Rats ; Male ; Animals ; Tumor Necrosis Factor-alpha ; RNA, Ribosomal, 16S ; Gastrointestinal Microbiome ; Interleukin-6 ; Rats, Wistar ; Sepsis

Objective: This study’s objective is to assess the efficacy and safety of Pulsed Magnetic Therapy System (PMTS) in improving insomnia disorder. Methods: Participants with insomnia disorder were randomly assigned to receive either PMTS or sham treatment for four weeks (n= 153; PMTS: 76, sham: 77). Primary outcomes are the Insomnia Severity Index (ISI) scores at week 0 (baseline), 1, 2, 3, 4 (treatment), and 5 (follow-up). Secondary outcomes are the Pittsburgh Sleep Quality Index at baseline and week 4, and weekly sleep diary-derived values for sleep latency, sleep efficiency, real sleep time, waking after sleep onset, and sleep duration. Results: The ISI scores of the PMTS group and the sham group were 7.13±0.50, 11.07±0.51 at week 4, respectively. There was a significant group×time interaction for ISI (F3.214, 485.271=24.25, p<0.001, ηp 2=0.138). Only the PMTS group experienced continuous improvement throughout the study; in contrast, the sham group only experienced a modest improvement after the first week of therapy. At the end of the treatment and one week after it, the response of the PMTS group were 69.7% (95% confidence interval [CI]: 58.6%–79.0%), 75.0% (95% CI: 64.1%–83.4%), respectively, which were higher than the response of the sham group (p<0.001). For each of the secondary outcomes, similar group×time interactions were discovered. The effects of the treatment persisted for at least a week. Conclusion PMTS is safe and effective in improving insomnia disorders.