Meropenem （MEM） is one of the important drugs for the treatment of severe infections， but the standard dose is often difficult to achieve an effective therapeutic concentration target. This article reviews the related studies on the population pharmacokinetics of MEM in patients with severe infection. It is found that the apparent volume of distribution （Vd） and clearance rate are the most important factors affecting the dose adjustment， and the factors affecting Vd include serum albumin， age， overall weight， shock status， and chest/abdomen/cerebrospinal fluid drainage. The main factors affecting the clearance rate were renal function， renal replacement therapy treatment mode and combination therapy. For adult patients with severe infections in China， MEM is recommended to be administered in an individualized manner based on glomerular filtration rate， with a dosage range of 500 to 1 500 mg given every 4 to 6 hours， and prolonged infusion is preferred. When the minimum inhibitory concentration （MIC） of the pathogenic bacteria reaches 64 mg/L， therapeutic drug monitoring is required. For therapeutic efficacy， it is essential to ensure that the trough concentration remains above the MIC； to prevent drug resistance， it should be maintained above 4×MIC. Regarding safety， it is recommended that the upper limit of the trough concentration be 32 mg/L， and blood sampling for monitoring can be conducted as early as after 1 to 2 doses of administration.

Objective To investigate the antibacterial activity of the antifungal peptide Mt6-21DLeu derived from Musca domestica against Acinetobacter baumannii (AB) and unravel its underlying mechanisms, so as to provide insights into development of novel agents against AB. Methods The minimum inhibitory concentrations (MICs) of Mt6-21DLeu, M. domestica-derived antifungal peptide-1 (MAF-1A), and polymyxin B were determined against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and AB using the broth microdilution assay, and the antibacterial activity of Mt6-21DLeu and polymyxin B was dynamically assessed against AB over 24 hours with time-kill curves. The inhibitory effects of Mt6-21DLeu and polymyxin B on biofilm formation in AB at concentrations of 1/4 × MIC, 1/2 × MIC and MIC, and the eradication effects of Mt6-21DLeu and polymyxin B on mature biofilms in AB at concentrations of MIC, 2 × MIC, and 4 × MIC were evaluated using crystal violet staining. Structural changes in the cell membrane of AB were observed 3 hours post-exposure to Mt6-21DLeu at concentrations of MIC and 2 × MIC using scanning electron microscopy, and alterations in the cell membrane permeability of AB were analyzed 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC and 2 × MIC by means of fluorescence microscopy and propidium iodide (PI) staining. Intracellular reactive oxygen species (ROS) levels in AB were measured 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC, 2 × MIC, and 4 × MIC using flow cytometry. The survival of Caenorhabditis elegans exposed to Mt6-21DLeu at concentrations of MIC, 2 × MIC, and 4 × MIC was monitored for 7 consecutive days, and survival curves were plotted to evaluate the in vivo toxicity of Mt6-21DLeu. In addition, C. elegans infected with AB and treated with Mt6-21DLeu at a concentration of 4 × MIC served as the treatment group, and uninfected C. elegans served as the control group, while infected but untreated C. elegans served as the infection group. The in vivo antibacterial efficacy of Mt6-21DLeu at a concentration of 4 × MIC was evaluated by comparing the survival curves and bacterial load among the three groups. Results The MICs of MAF-1A were all >128 μg/mL against S. aureus, B. subtilis, E. coli, K. pneumoniae, P. aeruginosa, and AB. In contrast, the MICs of Mt6-21DLeu were >128, 32, 8, 8, 16, and 4 μg/mL against these strains, respectively, and the MIC of Mt6-21DLeu against AB was close to that of polymyxin B (2 μg/mL). Time-kill curve analysis showed that both Mt6-21DLeu at concentrations of MIC and 2 × MIC and polymyxin B at a concentration of MIC inhibited AB growth over the 24-hour study period. The biofilm biomass in AB was (52.38 ± 6.92)%, (40.88 ± 9.17)% and (14.77 ± 6.00)% post-exposure with Mt6-21DLeu at concentrations of 1/4 × MIC, 1/2 × MIC and MIC, (61.58 ± 7.35)%, (47.42 ± 5.51)% and (20.85 ± 10.48)% post-treatment with polymyxin B at concentrations of 1/4 × MIC, 1/2 × MIC and MIC, and (100.00 ± 15.92)% in the control group (only bacterial suspension), respectively (F = 68.38, P < 0.001), and pairwise comparisons indicated that Mt6-21DLeu and polymyxin B at all concentrations significantly inhibited biofilm formation as compared to the control group (all P values < 0.001). The mature biofilm biomass in AB was (73.44 ± 11.41)%, (72.56 ± 13.08)% and (49.65 ± 9.23)% post-exposure to Mt6-21DLeu at concentrations of MIC, 2 × MIC, and 4 × MIC, (84.38 ± 8.60)%, (72.31 ± 9.63)% and (58.85 ± 4.96)% post-treatment with polymyxin B at concentrations of MIC, 2 × MIC, and 4 × MIC, and (100.00 ± 6.36)% in the control group (F = 35.63, P < 0.001), and pairwise comparisons revealed that Mt6-21DLeu at all concentrations significantly eradicated biofilm biomass (all P values < 0.05); however, polymyxin B showed no clear-cut eradication effect at a concentration of MIC (P > 0.05). Scanning electron microscopy revealed pore formation and content leakage in the cell membrane of AB 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC and 2 × MIC. Fluorescence microscopy showed that the proportions of PI-stained AB were (24.79 ± 11.51)% and (68.44 ± 15.80)% post-treatment with Mt6-21DLeu at concentrations of MIC and 2 × MIC, and (0.96 ± 0.94)% in the phosphate-buffered saline (PBS) treatment group (F = 105.90, P < 0.001), with the highest proportion of PI-stained AB seen post-treatment with Mt6-21DLeu at a concentration of 2 × MIC (P < 0.05). Flow cytometry revealed that the relative intracellular ROS levels in AB were (652.00 ± 141.90), (694.33 ± 14.19), and (974.33 ± 160.02) 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC, 2 × MIC and 4 × MIC, and (403.67 ± 86.56) in the PBS treatment group, respectively (F = 12.27, P < 0.05), with the highest intracellular ROS level measured following treatment with Mt6-21DLeu at a concentration of 4 × MIC (P < 0.05). Survival curve analysis revealed that Mt6-21DLeu posed no impact on C. elegans survival at concentrations of MIC (χ² = 0.02, P > 0.05), 2 × MIC (χ² = 0.06, P > 0.05) or 4 × MIC (χ² = 0.16, P > 0.05), and there was a significant difference in the survival period of C. elegans among the control group, the infection group, and the treatment group (χ² = 82.66, P < 0.05), with a significantly longer survival period in the treatment group than in the infection group (χ² = 45.00, P < 0.05). In addition, the log-transformed bacterial colony counts in C. elegans were (0.00 ± 0.00), (5.46 ± 0.03), and (3.91 ± 0.47) CFU/mL in the control group, the infection group, and the treatment group, respectively (F = 324.80, P < 0.001), and the log-transformed bacterial colony counts in C. elegans were significantly lower in the treatment group than in the infection group (P < 0.05). Conclusions Mt6-21DLeu exerts potent antibacterial effects through disrupting the cell membrane integrity of AB and promoting intracellular ROS accumulation in AB, and exhibits promising potential for treatment of AB infections both in vivo and in vitro, which may serve as a candidate drug molecule against multidrug-resistant AB infections.

OBJECTIVE: To construct a prediction model for the clinical effect of eye acupuncture combined with rehabilitation therapy on ischemic stroke based on interpretable machine learning. METHODS: From January 1st, 2020 to October 1st, 2024, the clinical data of 470 patients with ischemic stroke were collected in the the Second Department of Encephalopathy Rehabilitation of the Affiliated Hospital of Liaoning University of TCM. The modified Barthel index (MBI) score before and after treatment was used to divide the patients into an effect group (291 cases) and a non-effect group (179 cases). Random forest and recursive feature elimination with cross-validation were combined to screen the predictors of the therapeutic effect of patients. Seven representative machine learning models with different principles were established according to the screening results. The predictive effect of the best model was evaluated by receiver operating characteristics (ROC), calibration, and clinical decision-making (DCA) curves. Finally, the Shapley additive explanation (SHAP) framework was used to interpret the prediction results of the best model. RESULT: ①All the machine learning models presented the area under curve (AUC) to be above 85%. Of these models, the random forest model showed the best prediction ability, with AUC of 0.96 and the precision of 0.87. ②The prediction probability of calibration curve and the actual probability showed a good prediction consistency. ③The net benefit rate of DCA curve in the range of 0.1 to 1.0 was higher than the risk threshold, indicating a good effect of model. ④SHAP explained the characteristic values of variables that affected the prediction effect of the model, meaning, more days of treatment, lower MBI score before treatment, lower level of fibrinogen, shorter days of onset and younger age. These values demonstrated the better effect of eye acupuncture rehabilitation therapy. CONCLUSION The rehabilitation effect prediction model constructed in this study presents a good performance, which is conductive to assisting doctors in formulating targeted personalized rehabilitation programs, and identifying the benefit groups of eye acupuncture combined with rehabilitation therapy and finding the advantageous groups with clinical effect. It provides more ideas for the treatment of ischemic stroke with eye acupuncture combined with rehabilitation therapy.
Humans ; Acupuncture Therapy ; Machine Learning ; Male ; Female ; Middle Aged ; Ischemic Stroke/rehabilitation* ; Aged ; Stroke Rehabilitation ; Adult ; Eye

Ras homolog gene family member A(RhoA)is a small GTPase protein.Rho-associated coiled-coil forming protein kinase(ROCK)can be activated during the occurrence and development of ischemic stroke.RhoA/ROCK signaling pathway is an important regulatory factor in the pathological process of ischemic stroke,and regulation of this signaling pathway has become a research focus in promoting neuronal recovery and improving cerebral ischemia/reperfusion injury after ischemic stroke.However,only Fasudil is currently available as a RhoA/ROCK inhibitor.The rest is still in the stage of research and development or clinical trials,and has broad research prospects.In this paper,the regulatory role and mechanism of RhoA/ROCK signaling pathway in ischemic stroke were analyzed,and the application of inhibitors and regulatory drugs were described,aiming to provide new ideas for the prevention and treatment of ischemic stroke.

OBJECTIVE: To investigate the effectiveness of sacroiliac screw implantation assisted by three-dimensional (3D) printed faceted honeycomb guide plate in the treatment of posterior pelvic ring fracture. METHODS: The clinical data of 40 patients with posterior pelvic ring fractures treated with sacroiliac screw implantation between December 2019 and December 2022 were retrospectively analyzed. Among them, 18 cases were treated with sacroiliac screws fixation assisted by 3D printed faceted honeycomb guide plate (guide plate group), and 22 cases were treated with sacroiliac screws percutaneously fixation under fluoroscopy (conventional group). There was no significant difference in baseline data ( P>0.05) such as gender, age, time from injury to operation, and Dennis classification between the two groups. The implantation time, frequency of C-arm X-ray fluoroscopy, frequency of guide pin adjustment of each sacroiliac screw, and postoperative complications and bone healing were recorded. Majeed score was used to evaluate the functional recovery at 6 months after operation, and CT was used to observe whether the screw penetrated the bone cortex. The deviation between the virtual position and the actual position of the screw tip, the sacral foramen, and the screw entry point was measured on the sagittal CT images of the guide plate group. RESULTS: The number of screws implanted in S ₁ and S ₂ vertebral bodies was 14 and 16 respectively in the guide plate group, and 17 and 18 respectively in the conventional group. The implantation time of each sacroiliac screw, the frequency of C-arm X-ray fluoroscopy, and the frequency of guide pin adjustment in S ₁, S ₂, and all vertebrae in the guide plate group were significantly less than those in the conventional group ( P<0.05). Patients in both groups were followed up 8-48 months, with an average of 19.7 months. There was no incision infection, screw displacement, or internal fixation loosening in both groups. Callus growth was observed in all patients at 12 weeks after operation, and bone healing was achieved in all patients. The healing time ranged from 12 to 24 weeks, with an average of 15.7 weeks. No sacroiliac screw penetrated the bone cortex in the guide plate group; 2 patients in the conventional group had sacroiliac screws penetrating the bone cortex without damaging blood vessels or nerves. In the guide plate group, the deviation between the virtual position and the actual position of the screw tip, the sacral foramen, and the screw entry point were (2.91±1.01), (2.10±0.74), and (1.67±0.70) mm, respectively, with an average deviation of (2.19±1.22) mm. There was no significant difference in Majeed function evaluation between the two groups at 6 months after operation ( P>0.05). CONCLUSION The application of 3D printed faceted honeycomb guide plate in sacroiliac screw implantation for posterior pelvic ring fracture can shorten the screw implantation time, reduce the frequency of fluoroscopy and guide pin adjustment, and reduce the risk of screw penetration through the bone cortex.
Humans ; Fracture Fixation, Internal/instrumentation* ; Bone Screws ; Printing, Three-Dimensional ; Bone Plates ; Fractures, Bone/surgery* ; Pelvic Bones/surgery* ; Retrospective Studies ; Treatment Outcome ; Male ; Female ; Middle Aged ; Adult

Osteoporosis （OP） is a systemic metabolic bone disease. Amid population aging， OP has become a major health problem for the middle-aged and the elderly in China. Aging， iron load， and estrogen deficiency break the balance between oxidation and antioxidant systems， and the increase of reactive oxygen species mediates oxidative stress to damage DNA， lipids， proteins and other macromolecules， thus accelerating cell apoptosis and inducing OP， obesity， and neurodegenerative disorders. It has been found that oxidative stress is of great significance in the pathogenesis of OP. Oxidative stress regulates the signaling pathways， cytokines， and proteins related to the mesenchymal stem cells， osteoblasts， and osteoclasts， thereby weakening the osteogenic differentiation of mesenchymal stem cells， inhibiting osteoblast mineralization， and promoting the activation， proliferation， and maturation of osteoclasts. As a result， the dynamic imbalance between bone resorption and bone formation occurs， influencing bone remodeling and promoting the progression of OP. At the moment， anti-bone resorption drugs， bone formation-promoting drugs， and hormones are mainly used in clinical settings in western medicine. However， due to the long treatment cycle and the occurrence of serious gastrointestinal reactions， hypocalcemia， osteonecrosis， and others， patients show poor compliance and thus the effect is not as expected. Traditional Chinese medicine （TCM） demonstrates remarkable effect on OP attributing to the multi-pathway and multi-target characteristics. With low price and few adverse reactions， TCM is widely applied in clinical practice in comparison with western medicine. TCM has unique advantages in the treatment of OP by regulating oxidative stress. It exerts the therapeutic effect on OP by modulating different signaling pathways， providing new mindset for the treatment of this disease. Therefore， through literature research， this study summarized the research on mechanism of oxidative stress in OP and the treatment by TCM， which is expected to lay a foundation for further research.

【Objective】 To identify and propose blood transfusion suggestions for 3 children suspected to have red blood cell T polyagglutination. 【Methods】 According to the RBC reactions with phytohemagglutinin, adult serum and cord blood serum, aggregation test with polybrene reagent and MN antigen phenotype test were carried out on 3 children to confirm the presence of T polyagglutination. The donor serum with negative or weak reactions was selected by minor cross matching for the 3 children who needed therapeutic plasma exchange(TPE). 【Results】 Three cases of RBC T polyagglutination were caused by bacterial infection, with transient appearance of MN antigen; the samples were reactive to peanut agglutinin, soybean agglutinin, adult serum but nonreactive to cord blood serum, and didn′t aggregate after adding polybrene reagent. After receiving timely TPE, the T polyagglutination gradually disappeared. 【Conclusion】 Some bacteria, such as Streptococcus pneumoniae, may cause polyagglutination of red blood cells. The patients with suspected T polyagglutination should be diagnosed in time. For T polyagglutination patients, the minor matched plasma should be used for avoiding the random plasma with anti-T antibody transfusion.

Objective:To screen out the potential key genes of sepsis-associated acute kidney injury (AKI), and provide theoretical and experimental evidence for the treatment of sepsis-associated AKI.Methods:① Bioinformatics analysis: two gene expression datasets (GSE30718 and GSE53773) were downloaded for bioinformatics analysis from the Gene Expression Omnibus (GEO). These two datasets recorded mRNA microarray data from kidney biopsies before and after kidney transplantation, and a subset of patients developed AKI after kidney transplantation. Differential analysis was conducted, and the genes with the same differential expression and a higher area under the receiver operator characteristic curve (AUC) in both databases were used as the target gene for subsequent cell experiments. ② Cell validation experiment: human proximal renal tubular cells HK2 were cultured in vitro, and lipopolysaccharide (LPS) was used for establishing LPS-HK2 cell model (LPS 10 mg/L for 6 hours, LPS model group), and the blank control group was set. Then, small interfering RNA (siRNA) technology was used to knock down the target gene obtained by bioinformatics analysis in LPS-HK2 cells (gene knockdown group), and a gene negative control group was set. The real-time fluorescent quantitative reverse transcription-polymerase chain reaction (RT-qPCR) technique was used to detect the expression of the target gene in HK2 cells. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory factors in the cell supernatants. Western blotting was used to detect the expressions of key apoptosis proteins. Results:① Results of bioinformatics analysis: 325 genes in the two datasets showed the same expression trend, of which 144 were significantly down-regulated and 181 were significantly up-regulated, while the expression difference of secretory leukocyte protease inhibitor (SLPI) in the two datasets was both statistically significant. Further receiver operator characteristic curve (ROC curve) analysis confirmed that the SLPI expression in GSE30718 and GSE53773 datasets had a high diagnostic efficiency for AKI, with AUC of 0.83 and 0.92, respectively. Therefore, SLPI was selected as the target gene for subsequent cell validation experiment. ② Cell validation experiment: the RT-qPCR analysis showed that the expression of SLPI in LPS-HK2 cells of the LPS model group was significantly higher than that of the blank control group (2 -ΔΔCT: 1.80±0.14 vs. 1.00±0.11, P < 0.01), and the change trend was the same with the results of bioinformatics analysis. Furthermore, knockdown SLPI gene analysis showed that the levels of inflammatory factors in LPS-HK2 cells supernatants in the gene knockdown group were significantly higher than those in the negative control group [Interleukin-6 (IL-6, ng/L): 509.58±27.08 vs. 253.87±75.83, IL-1β (ng/L): 490.99±49.52 vs. 239.67±26.97, tumor necrosis factor-α (TNF-α, ng/L): 755.22±48.66 vs. 502.06±10.92, all P < 0.01]. The above results indicated that SLPI could inhibit the inflammatory response of HK2 cells induced by LPS. The expressions of key apoptosis proteins Bax and caspase-3 in LPS-HK2 cells in the gene knockdown group were significantly higher than those in the negative control group [Bax protein (Bax/GAPDH): 1.38±0.12 vs. 1.00±0.10, caspase-3 protein (caspase-3/GAPDH): 1.44±0.15 vs. 1.00±0.11, both P < 0.05], and Bcl-2 expression was significantly decreased (Bcl-2/GAPDH: 0.83±0.08 vs. 1.00±0.05, P < 0.05), the above results indicated that SLPI could inhibit the apoptosis of cells in the inflammatory response. Conclusion:SLPI can inhibit the inflammatory response and apoptosis of HK2 cells induced by LPS, which may be involved in the protective mechanism of renal tubular cells in the response to sepsis, and is a potential target for the treatment of sepsis-associated AKI.

AIM: To study the effects of trigliptin succinate on gut microbiota of type 2 diabetic mice. METHODS: 16S rRNA high-throughput sequencing method was used to sequence the intestinal flora of mice in the healthy group, the T2DM group, the trigliptin succinate group and the sitagliptin phosphate group. QIME was used to filter the data, classify and annotate the species. Alpha diversity index and Beta diversity index of the samples were analyzed.The richness and diversity of bacteria in the four groups were compared. RESULTS: The gut microbiota structure of mice in the healthy group, the T2DM group, the trigliptin succinate group and the setagliptin phosphate group were significantly different. The results showed that the ratio of Firmicutes to Bacteroidetes was decreased compared with that in the healthy group. Cyanobacteria, Verrucomicrobia and Tenericutes had significant differences (P< 0.05). Potential biomarkers for T2DM group were Bacilli, Lactobacillales, Lactococcus and Streptococcaceae. Candidate biomarkers of trigliptin succinate group may be Bacteroidia, Bacteroidetes, Bacteroidales, Prevotella, Paraprevotellaceae, Parabacteroides, Porphyromonadaceae; The candidate biomarkers of sitagliptin phosphate group may be Lactobacillus, Lactobacillaceae and Helicobacter. CONCLUSION: The intestinal flora of mice in the trigliptin succinate group was significantly different from that in the healthy group and the T2DM group. Using trigliptin succinate to improve the intestinal flora of mice might achieve the hypoglycemic effect by improving the intestinal flora.

Objective:To investigate the clinical effect of hearing aid combined with cognitive rehabilitation training in the treatment of dementia with hearing loss.Methods:Forty-six cases of dementia patients with hearing loss in Dalian Municipal Central Hospital Affiliated of Dalian Medical University from September 2019 to September 2020 were divided into two groups by random number table method. The treatment group received cognitive rehabilitation training assisted by sound amplifier, while the control group only received cognitive rehabilitation training for 7 weeks. Before and after treatment, questionnaires were used to evaluate the training effect of patients, including MMSE, HAMA, HAMD and ADL, and satisfaction questionnaire was used to evaluate the satisfaction of caregivers.Results:After treatment, the MMSE score of the treatment group was significantly higher than that of the control group: (20.22 ± 3.38) scores vs. (19.89 ± 3.10) scores ( P<0.05), and HAMA and HAMD were significantly lower than those of the control group: (11.43 ± 5.07) scores vs. (11.83 ± 4.79) scores, (8.39±3.37) scores vs. (9.67 ± 5.34) scores ( P<0.05); there was no difference in activities of daily living between the treatment group and the control group ( P>0.05); the caregiver satisfaction of the treatment group was significantly improved, compared with that of the control group ( P<0.05). Conclusions:Hearing assisted cognitive training can improve the cognitive function of patients with hearing-impaired dementia, promote mental and emotional stability, and improve the feelings of caregivers; we emphasize the importance of hearing evaluation for the elderly with dementia, and the importance of cognitive rehabilitation training with hearing assistance.