Prediction model of pressure injury occurrence in diabetic patients during ICU hospitalization--XGBoost machine learning model can be interpreted based on SHAP.

BACKGROUND: The occurrence of pressure injury in patients with diabetes during ICU hospitalization can result in severe complications, including infections and non-healing wounds. AIMS: The aim of this study was to predict the occurrence of pressure injury in ICU patients with diabetes using machine learning models. STUDY DESIGN: In this study, LASSO regression was used for feature screening, XGBoost was employed for machine learning model construction, ROC curve analysis, calibration curve analysis, clinical decision curve analysis, sensitivity, specificity, accuracy, and F1 score were used for evaluating the model's performance. RESULTS: Out of the 503 ICU patients with diabetes included in the study, pressure injury developed in 170 cases, resulting in an incidence rate of 33.8 %. The XGBoost model had a higher AUC for predicting pressure injury in patients with diabetes during ICU hospitalization (train: 0.896, 95 %CI: 0.863 to 0.929; test: 0.835, 95 % CI: 0.761-0.908). The importance of SHAP variables in the model from high to low was: 'Days in ICU', 'Mechanical Ventilation', 'Neutrophil Count', 'Consciousness', 'Glucose', and 'Warming Blanket'. CONCLUSION: The XGBoost machine learning model we constructed has shown high performance in predicting the occurrence of pressure injury in ICU patients with diabetes. Additionally, the SHAP method enables the interpretation of the results provided by the machine learning model. RELEVANCE TO CLINICAL PRACTICE: Improve the ability to predict the early occurrence of pressure injury in diabetic patients in the ICU. This will enable clinicians to intervene early and reduce the occurrence of complications.

Arthroscopic treatment of osteoid osteoma in the posterior proximal tibia: A case report and literature review.

BACKGROUND: Osteoid osteoma (OO) is a benign lesion characterized by an increased fibrous component in the bone marrow, presence of bone-like structures within the medullary cavity, and a surrounding sclerotic bone rim. Reports on OO located in the posterior proximal tibia are rare. CASE SUMMARY: Herein, we report the case of an 18-year-old male, admitted for the evaluation of right knee pain. The right knee pain had started 6 months prior without any apparent cause, which was notably severe at night, affecting sleep, and was exacerbated while climbing stairs or bearing weight. The patient also experienced pain on flexion. Three-dimensional computed tomography and magnetic resonance imaging revealed a nodular lesion beneath the cortical bone of the posterior medial plateau of the right tibia and an abnormal signal focus on the posterior lateral aspect of the right tibial plateau associated with extensive bone marrow edema. A small amount of fluid was present in the right knee joint capsule. The patient subsequently underwent arthroscopic excision of the OO. Postoperatively, there was significant relief of pain, and the knee range of motion returned to normal. CONCLUSION: Although OO in the posterior proximal tibia is a rare occurrence, it can be effectively excised through minimally invasive arthroscopic visualization.

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes.

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway.

Gastric cancer stem cells (GCSCs) contribute to the refractory features of gastric cancer (GC) and are responsible for metastasis, relapse, and drug resistance. The key factors drive GCSC function and affect the clinical outcome of GC patients remain poorly understood. PRSS23 is a novel serine protease that is significantly up-regulated in several types of cancers and cancer stem cells, and related to tumor progression and drug resistance. In this study, we investigated the role of PRSS23 in GCSCs as well as the mechanism by which PRSS23 regulated the GCSC functions. We demonstrated that PRSS23 was critical for sustaining GCSC survival. By screening a collection of human immunodeficiency virus (HIV) protease inhibitors (PIs), we identified tipranavir as a PRSS23-targeting drug, which effectively killed both GCSC and GC cell lines (its IC50 values were 4.7 and 6.4 µM in GCSC1 cells and GCSC2 cells, respectively). Administration of tipranavir (25 mg·kg-1·d-1, i.p., for 8 days) in GCSC-derived xenograft mice markedly inhibited the growth of subcutaneous GCSC tumors without apparent toxicity. In contrast, combined treatment with 5-FU plus cisplatin did not affect the tumor growth but causing significant weight loss. Furthermore, we revealed that tipranavir induced GCSC cell apoptosis by suppressing PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex to activate p38 MAPK, and thereby activating the IL24-mediated Bax/Bak mitochondrial apoptotic pathway. In addition, tipranavir was found to kill other types of cancer cell lines and drug-resistant cell lines. Collectively, this study demonstrates that by targeting both GCSCs and GC cells, tipranavir is a promising anti-cancer drug, and the clinical development of tipranavir or other drugs specifically targeting the PRSS23/MKK3/p38MAPK-IL24 mitochondrial apoptotic pathway may offer an effective approach to combat gastric and other cancers.

Identification and bioactivity evaluation of miliusanes from Miliusa sinensis.

Miliusanes are a class of anticancer lead molecules belonging to meroterpenoids with an 18-carbon skeleton isolated from Miliusa plants. A phytochemical study of the plant M. sinensis was carried out to discover new miliusanes with diverse structural features in order to better understand their structure-activity relationship. As a result, 20 compounds including 12 new ones (7-14 and 17-20) belonging to two sub-classes of miliusanes were isolated and identified from the twigs and leaves of this plant. Their structures, including absolute configurations, were determined by spectroscopic analyses and electronic circular dichroism. The absolute stereochemistry of miliusane structures has also been confirmed for the first time through the single crystal X-ray diffraction analysis of miliusol (1). Bioactivity evaluation showed that some of the miliusane isolates potently inhibit cell growth of several human derived cancer cell lines with IC50 values ranging from 0.52 to 23.5 µM. Compound 11 demonstrated more potent cytotoxic activity than the known miliusol (1) in stomach cancer cells though its structure contains an unconjugated 1, 4-diketone system, which added a new structure-activity feature to miliusanes. The preliminary mechanism of action studies revealed that they could be a class of dual cell migration inhibitor and senescence inducer.

Tough and stretchable all-κ-carrageenan hydrogel based on the cooperative effects between chain conformation transition and stepwise mechanical training.

The traditional κ-carrageenan (κCG)-based hydrogel obtained from hot water can rupture easily under mechanical loading. To address this vulnerability, here we presented a robust all-κCG hydrogel without employing the second synthetic network. By simply regulating the polymer chains from random coil to stiff chain conformation in NaOH/urea solvent system via the freeze-thawing process, the as-prepared hydrogel with homogeneous structure can display an enhanced stretchability from 42.1 to 156 %, while maintaining the similar fracture stress. Moreover, upon the stepwise mechanical training and subsequent incubation in KCl aqueous solution, more helical segments of κCG were aligned and involved into the association domains, thus leading to the increment in both the crystallinity and anisotropy. Consequently, a fast self-strengthening behavior occurred, and a more stretchable (fracture strain up to 396 %), strong (stress âˆ¼ 0.55 MPa) and tough (∼1.52 MJ m-3) κCG hydrogel was obtained. In comparison to the traditional one, the fracture strain and toughness are increased by 8.5 and 11.5 times, respectively. In addition, this κCG hydrogel can demonstrate good recovery and shape-memory behaviors under medium deformation. Hence, this tough all-κCG hydrogel is expected to be tailored into the biomaterials as the wearable device, artificial tendon, and cartilage in the future.

Improved Domain Adaptation Network Based on Wasserstein Distance for Motor Imagery EEG Classification.

Motor Imagery (MI) paradigm is critical in neural rehabilitation and gaming. Advances in brain-computer interface (BCI) technology have facilitated the detection of MI from electroencephalogram (EEG). Previous studies have proposed various EEG-based classification algorithms to identify the MI, however, the performance of prior models was limited due to the cross-subject heterogeneity in EEG data and the shortage of EEG data for training. Therefore, inspired by generative adversarial network (GAN), this study aims to propose an improved domain adaption network based on Wasserstein distance, which utilizes existing labeled data from multiple subjects (source domain) to improve the performance of MI classification on a single subject (target domain). Specifically, our proposed framework consists of three components, including a feature extractor, a domain discriminator, and a classifier. The feature extractor employs an attention mechanism and a variance layer to improve the discrimination of features extracted from different MI classes. Next, the domain discriminator adopts the Wasserstein matrix to measure the distance between source domain and target domain, and aligns the data distributions of source and target domain via adversarial learning strategy. Finally, the classifier uses the knowledge acquired from the source domain to predict the labels in the target domain. The proposed EEG-based MI classification framework was evaluated by two open-source datasets, the BCI Competition IV Datasets 2a and 2b. Our results demonstrated that the proposed framework could enhance the performance of EEG-based MI detection, achieving better classification results compared with several state-of-the-art algorithms. In conclusion, this study is promising in helping the neural rehabilitation of different neuropsychiatric diseases.

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions.

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.

Clinical Characteristics and Outcomes of Chronic Kidney Disease in People Living with HIV in a Resource-Limited Center of Central China.

Clinical management and optimal treatment are essential to improving outcomes for people living with HIV (PLWH). We assessed trends and outcomes of chronic kidney disease (CKD) in PLWH in a resource-limited center of central China. All PLWH who were followed up in a tertiary referral center in Wuhan, China, from July 2016 to June 2021 were evaluated. CKD was defined as glomerular filtration rate (GFR) <60 mL/min/1.73 m2 during two consecutive measurements 3 months apart. Baseline characteristics of the participants were extracted from the hospital medical records. The prevalence rate and associated risk factors of CKD were analyzed. A total of 863 PLWH with normal kidney function at baseline were analyzed. The median age was 33 (interquartile ranges: 26-49) years, and 778 (90.2%) were male and 85 (9.8%) were female. Among them, 50 (5.8%) had their GFR falling below 60 mL/min/1.73 m2 after a median of 54 months. Adjusted multivariate logistic regression revealed older age [adjusted odds ratio (aOR) = 1.04, 95% confidence interval (95% CI): 1.01-1.07], female sex (aOR = 3.17, 95% CI: 1.14-8.84), lower body weight (aOR = 0.95, 95% CI: 0.91-1.00), lower hemoglobin (aOR = 3.54, 95% CI: 1.51-8.30), longer duration of antiretroviral therapy exposure (aOR = 1.02, 95% CI: 1.00-1.04), and a baseline GFR between 60 and 90 mL/min/1.73 m2 (aOR = 3.89, 95% CI: 1.21-12.46) were associated with the development of CKD. Our findings showed that CKD is not infrequent in PLWH with a combination of traditional and HIV-specific risk factors for kidney disease, highlighting the suboptimal monitoring and treatment options of CKD in PLWH in resource-limited settings. Scalable monitoring strategy to improve care for this population is warranted.

PgtE Enzyme of Salmonella enterica Shares the Similar Biological Roles to Plasminogen Activator (Pla) in Interacting With DEC-205 (CD205), and Enhancing Host Dissemination and Infectivity by Yersinia pestis.

Yersinia pestis, the cause of plague, is a newly evolved Gram-negative bacterium. Through the acquisition of the plasminogen activator (Pla), Y. pestis gained the means to rapidly disseminate throughout its mammalian hosts. It was suggested that Y. pestis utilizes Pla to interact with the DEC-205 (CD205) receptor on antigen-presenting cells (APCs) to initiate host dissemination and infection. However, the evolutionary origin of Pla has not been fully elucidated. The PgtE enzyme of Salmonella enterica, involved in host dissemination, shows sequence similarity with the Y. pestis Pla. In this study, we demonstrated that both Escherichia coli K-12 and Y. pestis bacteria expressing the PgtE-protein were able to interact with primary alveolar macrophages and DEC-205-transfected CHO cells. The interaction between PgtE-expressing bacteria and DEC-205-expressing transfectants could be inhibited by the application of an anti-DEC-205 antibody. Moreover, PgtE-expressing Y. pestis partially re-gained the ability to promote host dissemination and infection. In conclusion, the DEC-205-PgtE interaction plays a role in promoting the dissemination and infection of Y. pestis, suggesting that Pla and the PgtE of S. enterica might share a common evolutionary origin.

RUNX3-mediated circDYRK1A inhibits glutamine metabolism in gastric cancer by up-regulating microRNA-889-3p-dependent FBXO4.

BACKGROUND: Targeting glutamine metabolism is previously indicated as a potential and attractive strategy for gastric cancer (GC) therapy. However, the underlying mechanisms responsible for the modification of glutamine metabolism in GC cells have not been fully elucidated. Accordingly, the current study sought to investigate the physiological mechanisms of RUNX3-mediated circDYRK1A in glutamine metabolism of GC. METHODS: Firstly, GC tissues and adjacent normal tissues were obtained from 50 GC patients to determine circDYRK1A expression in GC tissues. Next, the binding affinity among RUNX3, circDYRK1A, miR-889-3p, and FBXO4 was detected to clarify the mechanistic basis. Moreover, GC cells were subjected to ectopic expression and knockdown manipulations of circDYRK1A, miR-889-3p, and/or FBXO4 to assay GC cell malignant phenotypes, levels of glutamine, glutamic acid, and α-KG in cell supernatant and glutamine metabolism-related proteins (GLS and GDH). Finally, nude mice were xenografted with GC cells to explore the in vivo effects of circDYRK1A on the tumorigenicity and apoptosis. RESULTS: circDYRK1A was found to be poorly expressed in GC tissues. RUNX3 was validated to bind to the circDYRK1A promoter, and circDYRK1A functioned as a miR-889-3p sponge to up-regulate FBXO4 expression. Moreover, RUNX3-upregulated circDYRK1A reduced levels of glutamine, glutamic acid, and α-KG, and protein levels of GLS and GDH, and further diminished malignant phenotypes in vitro. Furthermore, in vivo experimentation substantiated that circDYRK1A inhibited the tumorigenicity and augmented the apoptosis in GC. CONCLUSION: In conclusion, these findings highlighted the significance and mechanism of RUNX3-mediated circDYRK1A in suppressing glutamine metabolism in GC via the miR-889-3p/FBXO4 axis.

Antitumour effect of odoroside A and its derivative on human leukaemia cells through the ROS/JNK pathway.

Oleandrigenin-3-O-ß-D-diginoside (a derivative of odoroside A), isolated and purified by our group, has seldom been explored for its pharmacological activity. This study aimed at clarifying the mechanisms towards the leukaemia-suppressive role of odoroside A (compound #1) and its derivative, oleandrigenin-3-O-ß-D-diginoside (compound #2) isolated from Nerium oleander. Viability and nuclear morphology change were assessed by CCK-8 assay and fluorescence microscope, respectively. Then, the cell apoptosis and autophagy induced by the compounds were detected by flow cytometry and Western blot. Xenograft model of nude mice was also applied to measure the leukaemia-suppressive effects of compound #2 in vivo. The result displayed that compound #1 and compound #2 inhibited the proliferation of HL60 and K562 cells and stronger effects were found in HL60 than K562 cells. Both of the compounds induced a dose-dependent apoptosis and autophagy in HL60 cells, where compound #2 was more potent than compound #1. Compound #2 also demonstrated a time-dependent apoptosis and autophagy in HL60 cells. Furthermore, ROS generation and JNK phosphorylation occurred in a dose-dependent manner in the cells treated with compound #2. Mitochondria also played critical role, proved by the decrease of Bcl-2, the release of cyto c to cytosol and the activation of caspase-3 and caspase-9. Moreover, the antitumour effects of compound #2 were validated in the nude mouse xenograft model in vivo. Odoroside A and its derivative inhibited the growth of leukaemia by inducing apoptosis and autophagy through the activation of ROS/JNK pathway. These results suggest that the compounds can serve as potential antitumour agents against leukaemia, especially acute myeloid leukaemia (AML).

Convergent Synthesis of (R)-Silodosin via Decarboxylative Cross-Coupling.

A new approach to Silodosin capitalizing on a radical retrosynthetic strategy to dissect the molecule into two halves is reported. Using a reductive decarboxylative cross-coupling, a simple indoline can be coupled to a chiral pool-derived fragment to arrive at the target in only seven steps (LLS). This route avoids the use of resolution strategies or asymmetric hydrogenation that requires a subsequent Curtius rearrangement to install a key amino functionality.

MHC class II in renal tubules plays an essential role in renal fibrosis.

Immunomodulation is considered a potential therapeutic approach for chronic kidney disease (CKD). Although it has been previously reported that CD4+ T cells contribute to the development of renal fibrosis, the role of MHC class II (MHCII) in the development of renal fibrosis remains largely unknown. The present study reports that the expression of MHCII molecules in renal cortical tubules is upregulated in mouse renal fibrosis models generated by unilateral ureter obstruction (UUO) and folic acid (FA). Proximal tubule epithelial cells (PTECs) are functional antigen-presenting cells that promote the proliferation of CD4+ T cells in an MHCII-dependent manner. PTECs from mice with renal fibrosis had a stronger ability to induce T cell proliferation and cytokine production than control cells. Global or renal tubule-specific ablation of H2-Ab1 significantly alleviated renal fibrosis following UUO or FA treatment. Renal expression of profibrotic genes showed a consistent reduction in H2-Ab1 gene-deficient mouse lines. Moreover, there was a marked increase in renal tissue CD4+ T cells after UUO or FA treatment and a significant decrease following renal tubule-specific ablation of H2-Ab1. Furthermore, renal tubule-specific H2-Ab1 gene knockout mice exhibited higher proportions of regulatory T cells (Tregs) and lower proportions of Th2 cells in the UUO- or FA-treated kidneys. Finally, Immunohistochemistry (IHC) studies showed increased renal expression of MHCII and the profibrotic gene α smooth muscle actin (α-SMA) in CKD patients. Together, our human and mouse data demonstrate that renal tubular MHCII plays an important role in the pathogenesis of renal fibrosis.

Distinct Patterns of Host Adherence by Neisseria gonorrhoeae Isolated from Experimental Gonorrhea.

Neisseria gonorrhoeae (N. gonorrhoeae, gonococci, or GC), the etiologic agent of gonorrhea, is a human-obligate bacterial pathogen. The GC surface contains pili that mediate the adherence to host cells. Studies have shown that GC pili, coded by pilin genes, undergo remarkable changes during human experimental gonorrhea, possibly generated by DNA phase variation during infection. The question that arises is whether the changes in pilins can alter the adherence capacity of N. gonorrhoeae to host cells. In this study, six variants initially isolated from male volunteers infected with one single clone of GC were examined for their adherence patterns with human Chang conjunctiva cells. In this study, we showed that the variants showed distinct adherence patterns to this cell line under light microscopy and scanning electron microscopy. Moreover, two reisolates showed higher adherence capacities than that of the input strain. The results provide an additional example as to how the pilus variation may play a role in the pathogenesis of N. gonorrhoeae.

Berberine Attenuates Cerebral Ischemia-Reperfusion Injury Induced Neuronal Apoptosis by Down-Regulating the CNPY2 Signaling Pathway.

Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect.