ObjectiveTo observe the effect of M1 bone marrow-derived macrophages （M1-BMDM） with Wnt5a knockdown on liver fibrosis and regeneration in a rat model of liver cirrhosis， and to investigate its gain-of-function effect compared with unmodified M1-BMDM. MethodsPrimary bone marrow-derived macrophages were isolated from rats and were polarized to M1 phenotype to construct M1-BMDM^Wnt5a-KD cells. A rat model of liver cirrhosis induced by CCl₄/2-AAF was established， and at the end of week 8， rats were randomly divided into model group， M1-BMDM group， M1-BMDM Wnt5a-knockdown empty vector group （M1-BMDM^KD-EV group）， and M1-BMDM Wnt5a-knockdown group （M1-BMDM^Wnt5a-KD group）， with 6 rats in each group. On the first day of week 9， the rats in each group were given a single injection of the corresponding cells via the caudal vein， along with an intraperitoneal injection of a CCR2 inhibitor. Six rats without any treatment were used as normal control group. Samples were collected at the end of week 12 to assess liver histopathology， serum liver function parameters， hepatic stellate cell activation， and the expression levels of mature hepatocyte markers. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the model group， all cell treatment groups had significant alleviation of liver inflammatory response and significant reductions in the activities of alanine aminotransferase and aspartate aminotransferase （AST） in serum （all P<0.01）， and the M1-BMDM^Wnt5a-KD group had a significantly lower serum level of AST than the M1-BMDM group （P<0.05）. The semi-quantitative analysis based on immunohistochemical staining showed that compared with the model group， all cell treatment groups had a significant reduction in the percentage of CD68-positive area （all P<0.05）， and compared with the M1-BMDM^KD-EV group， the M1-BMDM^Wnt5a-KD group had a significant reduction in the percentage of CD68-positive area and a significant increase in the percentage of CD163-positive area （both P<0.05）. Compared with the model group， all cell treatment groups had significant reductions in the mRNA expression levels of CD68 and tumor necrosis factor-α （all P<0.05） and the protein expression level of CD68 （all P<0.01）； compared with the M1-BMDM^KD-EV group， the M1-BMDM^Wnt5a-KD group had significant increases in the protein and mRNA expression levels of CD163 （both P<0.05）， significant reductions in the protein and mRNA expression levels of CD68 （both P<0.05）， and a significant reduction in the protein expression level of tumor necrosis factor-α （P<0.01）. Sirius Red collagen staining and alpha-smooth muscle actin （α-SMA） immunohistochemical staining showed that compared with the model group， all cell treatment groups had significant alleviation of liver collagen deposition and α-SMA-positive area， with the most significant changes in the M1-BMDM^Wnt5a-KD group， and compared with the M1-BMDM^KD-EV group， the M1-BMDM^Wnt5a-KD group had significantly smaller Sirius Red-positive area and α-SMA-positive area and a significantly lower content of hydroxyproline in liver tissue （all P<0.05）. Compared with the M1-BMDM^KD-EV group， the M1-BMDM^Wnt5a-KD group had significant reductions in the protein and mRNA expression levels of α-SMA and the mRNA expression level of COL-I and TGF-β （all P<0.05）. Compared with the model group， all cell treatment groups had a significant increase in the protein expression level of HNF-4α in liver tissue （all P<0.05）， and the M1-BMDM^Wnt5a-KD group had significantly higher protein and mRNA expression levels of HNF-4α and hepatocyte specific antigen than the M1-BMDM^KD-EV group （both P<0.05）. The M1-BMDM^Wnt5a-KD group had a significantly higher serum level of albumin than the M1-BMDM^KD-EV group （P<0.01）. Immunofluorescence co-staining showed that compared with the model group， all cell treatment groups had a significant increase in the number of cells stained positive for HNF and HNF-4α and Ki67 （all P<0.01）， and the M1-BMDM^Wnt5a-KD group had a significantly higher number of such cells than the M1-BMDM^KD-EV group （P<0.05）. ConclusionInhibition of Wnt5a expression enhances the therapeutic effect of M1-BMDM on rats with liver cirrhosis induced by CCl₄/2-AAF， which provides new ideas for enhancing the anti-cirrhotic effect of M1-BMDM through genetic modification.

OBJECTIVE: To compare the efficacy and safety of intravenous colistin sulfate combined with nebulized inhalation versus intravenous monotherapy for pulmonary infections caused by carbapenem-resistant organism (CRO). METHODS: A multicenter retrospective cohort study was conducted. Clinical data were collected from patients admitted to the intensive care unit (ICU) of 10 tertiary class-A hospitals in Henan Province between July 2021 and May 2023, who received colistin sulfate for CRO pulmonary infections. Data included baseline characteristics, inflammatory markers [white blood cell count (WBC), neutrophil count (NEU), procalcitonin (PCT), C-reactive protein (CRP)], renal function indicators [serum creatinine (SCr), blood urea nitrogen (BUN)], life support measures, anti-infection regimens, clinical efficacy, microbiological clearance rate, and prognostic outcomes. Patients were divided into two groups: intravenous group (colistin sulfate monotherapy via intravenous infusion) and combination group ((intravenous infusion combined with nebulized inhalation of colistin sulfate). Changes in parameters before and after treatment were analyzed. RESULTS: A total of 137 patients with CRO pulmonary infections were enrolled, including 89 in the intravenous group and 48 in the combination group. Baseline characteristics, life support measures, daily colistin dose, and combination regimens (most commonly colistin sulfate plus carbapenems in both groups) showed no significant differences between two groups. The combination group exhibited higher clinical efficacy [77.1% (37/48) vs. 59.6% (52/89)] and microbiological clearance rate [60.4% (29/48) vs. 39.3% (35/89)], both P < 0.05. Pre-treatment inflammatory and renal parameters showed no significant differences between two groups. Post-treatment, the combination group showed significantly lower WBC and CRP [WBC (×10⁹/L): 8.2±0.5 vs. 10.9±0.6, CRP (mg/L): 14.0 (5.7, 26.6) vs. 52.1 (24.4, 109.6), both P < 0.05], whereas NEU, PCT, SCr, and BUN levels showed no significant between two groups. ICU length of stay was shorter in the combination group [days: 16 (10, 25) vs. 21 (14, 29), P < 0.05], although mechanical ventilation duration and total hospitalization showed no significant differences between two groups. CONCLUSIONS Intravenous colistin sulfate combined with nebulized inhalation improved clinical efficacy and microbiological clearance in CRO pulmonary infections with an acceptable safety profile.
Humans ; Colistin/therapeutic use* ; Retrospective Studies ; Administration, Inhalation ; Anti-Bacterial Agents/therapeutic use* ; Carbapenems/pharmacology* ; Male ; Female ; Middle Aged ; Gram-Negative Bacteria/drug effects* ; Aged ; Treatment Outcome ; Respiratory Tract Infections/drug therapy*

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

OBJECTIVES: To analyze bone mass distribution and the factors affecting bone mass in a general Chinese Han cohort undergoing physical examinations at our center. METHODS: We retrospectively collected the data of bone mineral density (BMD) measurements from 30 599 healthy Han Chinese adults (age≥20 years) who underwent dual-energy X-ray absorptiometry scans at our hospital from July, 2013 to July, 2023. Basic parameters including height, body weight, and gender were recorded, and descriptive statistics and correlation analyses were performed using R software. RESULTS: In this cohort, the male individuals had a mean peak BMD of 1.00±0.12 g/cm² in the lumbar vertebrae, 0.94±0.14 g/cm² in the femoral neck, and 0.99±0.13 g/cm² in the total hip, significantly higher than the values in the female individuals [0.99±0.12 g/cm² in the lumbar vertebrae (P=0.022), 0.79±0.11 g/cm² in the femoral neck (P<0.001), and 0.88±0.11 g/cm² in the total hip (P<0.001)]. In the overall cohort, the BMD values of the lumbar spine and femur decreased with age after reaching their peak levels. There was a positive correlation between BMD value and body mass index (BMI) in both male and female individuals. The 2013-2014 period recorded the lowest BMD values in the lumbar, hip, and femoral neck, which tended to increase steadily in the following years (2015-2023). CONCLUSIONS Our data suggest that the BMD values vary among different populations, and future multi-center studies using more accurate BMD detection technology are warranted to capture the variation patterns of BMD with demographic characteristics of specific populations.
Humans ; Bone Density ; Absorptiometry, Photon ; Male ; Female ; Retrospective Studies ; Osteoporosis/diagnostic imaging* ; Adult ; Middle Aged ; Lumbar Vertebrae/diagnostic imaging* ; China/epidemiology* ; Femur Neck/diagnostic imaging* ; Aged ; Beijing/epidemiology* ; Young Adult

A UHPLC-Q-Orbitrap/MS method was developed to identify the related substances in apixaban tablets. Complete separation was accomplished with a Waters Xbridge C18 (250 mm×4.6 mm, 5 μm) column by linear gradient elution using a mobile phase consisting of 30 mmol/L ammonium acetate buffer solution (pH 4.50) and acetonitrile. The related substances were successfully characterized through the accurate mass and elemental composition of the parent ions and their product ions determined by electrospray positive ionization high-resolution Q-Orbitrap/MS methods. Under the established analytical condition, apixaban and its related substances were well separated, and 30 related substances were detected and identified by hyphenated techniques in apixaban tablets and their stressed samples. Among them, 11 were known impurities and the rest 19 were unknown related substances identified for the first time in this study. The results obtained are valuable for apixaban manufacturing process optimization and quality control.

ObjectivesTo analyze the trends in mortality and disease burden of colorectal cancer (CRC) among the registered residents in Danyang City, Jiangsu Province, from 2013 to 2023, and to provide a scientific basis for developing CRC prevention and control strategies. MethodsMortality surveillance data on CRC among the registered residents in Danyang City from 2013 to 2023 were collected and analyzed. Crude mortality rate (CMR), age-standardized mortality rate (ASMR), years of life lost (YLL) due to premature death, and YLL rate were calculated. The annual percentage change (APC) and average annual percent change (AAPC) of CMR, ASMR and YLL rate were calculated with Joinpoint Regression Program 4.9.0.1. ResultsA total of 1 920 deaths from colorectal cancer were recorded in Danyang City during 2013‒2023, with an average annual CMR of 21.75/100 000, which showed an upward trend (APC=6.47%, 95%CI: 4.21%‒8.79%, P<0.001), with higher CMR observed in males than that in females. The overall ASMR by Chinese standard population was 12.10/100 000, with no obvious temporal trends (APC=1.37%, P=0.364). ASMR increased with age, particularly after 45 years. The total YLL due to CRC was 34 711 person-years, with an average YLL rate of 3.93‰. The YLL rate showed a significant upward trend from 2013 to 2023 (APC=4.96%, 95%CI: 4.08%‒18.16%, P<0.001) in Danyang City. ConclusionThe mortality rate of colorectal cancer in Danyang City is relatively high and has shown a rising trend, resulting in an increasing disease burden on the residents year by year. Continued efforts to strengthen CRC prevention and control are needed, particularly targeting males and the elderly population.

Objective: To investigate the environmental contamination of norovirus in nurseries and primary/secondary schools, so as to provide a scientific basis for effective prevention and control measures. Methods: A total of 483 external environmental samples were collected from 34 cluster outbreaks of norovirus gastroenteritis in kindergartens and primary/secondary schools in Linhai City from 2021 to 2024. Pathogen detection was conducted using a rapid nucleic acid extraction kit and realtime fluorescence RT-PCR, and the results were analyzed using the χ2 test or Fishers exact test. Results: Among the collected external environmental samples, the total positive rate of surface contamination was 13.66%. The positive rates in kindergartens and primary/secondary schools were 12.20% and 15.82%, respectively. In kindergartens, the five surfaces with the highest detection rates were desks/chairs (23.33%), toilet stool troughs (20.69%), urinal troughs (12.00%), washbasins/sinks (11.11%), and toilet mops (9.38%). In primary/secondary schools, the top five were toilet stool troughs (38.30%), urinal troughs (23.53%), toilet door handles (13.04%), toilet mops (12.50%), and drinking cups (11.11%). The difference in positive detection rates among different external environments in primary/secondary schools was statistically significant (Fishers exact probability test, P<0.01). The positive detection rate in sanitary toilets was higher than that in classroom environments (χ2=17.38), while the positive detection rate in classroom environments of kindergartens was higher than that in primary/secondary schools (χ2=5.42)(P<0.05). Conclusions Norovirus exhibits a high contamination rate in nurseries and schools, particularly in restroom areas. Strengthening sanitation and disinfection in highrisk environments, and improving hygiene awareness among children and staff, are essential for the effective prevent and control of norovirus.

Objective:To compare the mydriatic effects of a combination of 1% tropicamide and 2.5% phenylephrine with a 0.5% tropicamide and 0.5% phenylephrine combination in patients with type 2 diabetes.Methods:A randomized, double-blind, controlled trial was conducted.Ninety Chinese patients (90 eyes) with dark irises and type 2 diabetes who needed mydriasis examination at the Fundus Disease Clinic of Tianjin Medical University Eye Hospital from June to September 2024 were included.The subjects were divided into control group (30 patients 30 eyes), high concentration group (30 patients 30 eyes) and half-dilution group (30 patients 30 eyes) using the random number table method, which received 2 drops of a mixture of 0.5% tropicamide and 0.5% phenylephrine, 2 drops of a mixture of 1% tropicamide and 2.5% phenylephrine, 1 drop of a mixture of 1% tropicamide and 2.5% phenylephrine+ 1 drop of saline respectively.The pupil diameter of the patients was measured with a pupillometer 40 minutes before and after instillation.The study adhered to the Declaration of Helsinki and the study protocol was approved by the Ethics Committee of Tianjin Medical University Eye Hospital (No.2024KY-16).Written informed consent was obtained from all participants.Results:The proportions of patients whose pupil diameters reached 7 mm 40 minutes after the initial administration in the control group, high-concentration group, and half-dilution group were 56.7%(17/30), 86.7%(26/30) and 66.7%(20/30), respectively, with a statistically significant overall difference ( χ2=6.667, P=0.036).The proportion of patients in the high-concentration group whose pupil diameter reached 7 mm 40 minutes after the initial administration was higher than that in the control group, and the difference was statistically significant ( P<0.05).The pupil diameters 40 minutes after the initial administration in the control group, the high-concentration group and the half-dilution group were (7.01±0.86), (7.64±0.61) and (7.49±1.15)mm, respectively, with a statistically significant overall difference ( F=4.019, P=0.021), and the pupil diameter of the high-concentration group was significantly higher than that of the control group ( P=0.024).Changes in pupil diameter 40 minutes after the initial administration in the control group, high-concentration group and half-dilution group were (3.23±0.81), (3.82±0.60) and (3.62±0.75)mm, respectively, with a statistically significant overall difference ( F=5.121, P=0.008), and the change in pupil diameter in the high-concentration group was higher than that in the control group ( P=0.007). Conclusions:The combination of 1% tropicamide and 2.5% phenylephrine has better pupil dilation than the combination of 0.5% tropicamide and 0.5% phenylephrine.It is recommended that pupil dilation be performed with a high-concentration mydriatic drug prior to outpatient fundus examination for diabetic patients.