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.

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*

Objective:To investigate the predictive value of preoperative aspartate aminotransferase to alanine aminotransferase ratio (AAR) for early recurrence after radical resection of single small hepatocellular carcinoma.Methods:A retrospective cohort study was conducted to analyze the clinical data of 137 patients who underwent radical resection of liver cancer at the General Hospital of Ningxia Medical University from January 2017 to July 2021. These patients were categorized into a recurrence group ( n = 72) and a non-recurrence group ( n = 65) based on early postoperative recurrence. Univariate and multivariate logistic regression analyses were conducted in the training cohort to identify independent risk factors for early recurrence of small hepatocellular carcinomas. Subsequently, the AARs were grouped, and patients with similar propensity scores estimated by the logistic model were matched 1:1 using the Propensity Score Match method with a caliper value of 0.02 to eliminate confounders. Logistic regression analysis was then repeated to assess the predictive value of the matched AAR for postoperative recurrence in patients with single small hepatocellular carcinoma. Results:Univariate analysis revealed that age ( χ2 = 4.22, P = 0.040), the ratio of fibrinogen to albumin ( χ2 = 8.26, P = 0.004), and the AAR ( χ2 = 5.83, P = 0.016) were significantly associated with early recurrence of small liver cancer after radical resection. Multivariate logistic regression analysis further identified age ( P = 0.042), the ratio of fibrinogen to albumin ( P = 0.024), and the AAR ( P = 0.018) as independent risk factors for early recurrence of single small hepatocellular carcinoma following radical surgery. After excluding confounding factors using the Propensity Score Match method, 25 patient pairs were successfully matched. Post-matching logistic regression analysis revealed that an AAR > 0.74 ( P = 0.005) and age > 60 years ( P = 0.024) were independent risk factors for early recurrence in patients with single small hepatocellular carcinoma following radical resection. Conclusion:Preoperative AAR is an independent risk factor for early recurrence in patients with single small hepatocellular carcinoma following surgery, demonstrating excellent predictive value.

Objective:To investigate the predictive values of clinical test indexes and imaging indexes for early postoperative recurrence of hepatitis B virus (HBV)-related small hepatocellular carcinoma.Methods:Clinical case data of 163 patients with HBV-related small hepatocellular carcinoma undergoing radical hepatectomy at the Department of Hepatobiliary Surgery in the General Hospital of Ningxia Medical University from January 2017 to August 2021 were retrospectively collected. The patients were categorized into 87 cases in an early recurrence group and 76 cases in a non-early recurrence group according to whether or not they had recurrence within 2 years after surgery. After excluding the covariance of various indicators, independent risk factors for postoperative tumor recurrence were established using univariate analysis and multivariate logistic regression analysis. A clinical prediction model was constructed and presented visually in a nomogram diagram, and the predictive ability of the nomogram diagram model was evaluated using receiver operating characteristic curves as well as calibration curves. Cox regression analysis was used to determine the relationship between independent risk factors and time to recurrence.Results:Univariate analysis showed that in the early recurrence group, the number and proportion of patients with preoperative gamma-glutamyl transferase to lymphocyte count ratio (GLR) > 35.79 [41.38% (36/87)], tumor multiplicity [25.29% (22/87)], the presence of peritumoral edema [45.98% (40/87)], intratumoral small arterial clusters [50.58% (44/87)], and age ≥ 60 years [74.71% (65/87)] were significantly higher than those in the non-early recurrence group ( χ2 = 5.73, 3.78, 3.97, 3.73, 3.75, all P < 0.05). Multivariate logistic regression analysis showed that GLR > 35.79 and the presence of peritumoral edema were independent risk factors for early recurrence after radical hepatectomy of HBV-related small hepatocellular carcinomas [odds ratio ( OR) = 2.22, 1.99, 95% confidence interval ( CI): 1.10-4.59, 1.00-3.99, P < 0.05]. The nomogram diagram prediction model was established, with a C index of 0.70 (95% CI: 0.60-0.79) in the receiver operating characteristic curve and a Brier Score of 0.22 in the calibration curve, which demonstrated good model differentiation and accuracy. Cox regression analysis showed that a GLR > 35.79 and the presence of peritumoral edema were risk factors affecting the time to recurrence after resection of HBV-associated small hepatocellular carcinomas. Conclusion:GLR > 35.79 and the presence of peritumoral edema are independent risk factors for early recurrence after radical hepatectomy of HBV-related small hepatocellular carcinoma. The constructed clinical prediction model has good predictive efficacy.

Objective:To investigate the effects of continuous renal replacement therapy (CRRT) on plasma concentration, clinical efficacy and safety of colistin sulfate.Methods:Clinical data of patients received with colistin sulfate were retrospectively analyzed from our group's previous clinical registration study, which was a prospective, multicenter observation study on the efficacy and pharmacokinetic characteristics of colistin sulfate in patients with severe infection in intensive care unit (ICU). According to whether patients received blood purification treatment, they were divided into CRRT group and non-CRRT group. Baseline data (gender, age, whether complicated with diabetes, chronic nervous system disease, etc), general data (infection of pathogens and sites, steady-state trough concentration, steady-state peak concentration, clinical efficacy, 28-day all-cause mortality, etc) and adverse event (renal injury, nervous system, skin pigmentation, etc) were collected from the two groups.Results:A total of 90 patients were enrolled, including 22 patients in the CRRT group and 68 patients in the non-CRRT group. ① There was no significant difference in gender, age, basic diseases, liver function, infection of pathogens and sites, colistin sulfate dose between the two groups. Compared with the non-CRRT group, the acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) and sequential organ failure assessment (SOFA) were higher in the CRRT group [APACHE Ⅱ: 21.77±8.26 vs. 18.01±6.34, P < 0.05; SOFA: 8.5 (7.8, 11.0) vs. 6.0 (4.0, 9.0), P < 0.01], serum creatinine level was higher [μmol/L: 162.0 (119.5, 210.5) vs. 72.0 (52.0, 117.0), P < 0.01]. ② Plasma concentration: there was no significant difference in steady-state trough concentration between CRRT group and non-CRRT group (mg/L: 0.58±0.30 vs. 0.64±0.25, P = 0.328), nor was there significant difference in steady-state peak concentration (mg/L: 1.02±0.37 vs. 1.18±0.45, P = 0.133). ③ Clinical efficacy: there was no significant difference in clinical response rate between CRRT group and non-CRRT group [68.2% (15/22) vs. 80.9% (55/68), P = 0.213]. ④ Safety: acute kidney injury occurred in 2 patients (2.9%) in the non-CRRT group. No obvious neurological symptoms and skin pigmentation were found in the two groups. Conclusions:CRRT had little effect on the elimination of colistin sulfate. Routine blood concentration monitoring (TDM) is warranted in patients received with CRRT.

OBJECTIVE Alzheimer disease(AD)is a neurodegenerative disease with clinical hallmarks of pro-gressive cognitive impairment.Synergistic effects of Aβ-tau cascade reaction are tightly implicated in AD patholo-gy,and microglial NLRP3 inflammasome activation drives neuronal tauopathy through microglia and neurons cross-talk.However,the underlying mechanism of how Aβ medi-ates NLRP3 inflammasome remains unclear.Shab related potassium channel member 1(Kv2.1)as a voltage gated po-tassium channel widely distributed in the central nervous system and plays an important role in regulating the out-ward potassium flow in neurons and glial cells.In current work,we aimed to explore the underlying mechanism of Kv2.1 in regulating Aβ/NLRP3 inflammasome/tau axis by using a determined Kv2.1 inhibitor drofenine(Dfe).METHODS Cell-based assays including Western blot-ting and immunofluorescence staining against primary microglia or neurons were carried out to expound the role of Kv2.1 channel in NLRP3 inflammasome activa-tion and subsequent neuronal tau hyperphosphorylation.For animal studies,new object recognition,Y-maze and Morris water maze were performed to evaluate the ame-lioration of Kv2.1 inhibition through either Kv2.1 inhibitor Dfe treatment or adeno-associated virus AAV-ePHP-si-Kv2.1injectionon5×FADADmodel mice.Assays of histol-ogy and immunostaining of tissue sections and Western blotting of brain tissues were performed to verify the con-clusion of cellular assays.RESULTS We reported that oligomeric Aβ(o-Aβ)bound to microglial Kv2.1 and pro-moted Kv2.1-dependent potassium leakage to activate NLRP3 inflammasome through JNK/NF-κB pathway sub-sequently resulting in neuronal tauopathy.Treatment of either Kv2.1 inhibitor Dfe or AAV-ePHP-si-Kv2.1 for brain-specific Kv2.1 knockdown deprived o-A β of its capability in inducing microglial NLRP3 inflammasome activation and neuronal tau hyperphosphorylation,while improved the cognitive impairment of 5×FAD AD model mice.CONCLUSION Our results have highly addressed that Kv2.1 channel is required for o-Aβ driving NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Kv2.1 inhibition is a prom-ising therapeutical strategy for AD and Dfe as a Kv2.1 inhibitor shows potential in the treatment of this disease.

Objective:To screen preoperative microvascular invasion (MVI)-related indicators in patients with hepatocellular carcinoma by machine learning, and to construct a predictive model for predicting MVI and evaluate it.Methods:The clinical data of hepatocellular carcinoma patients who underwent radical resection from January 2018 to March 2023 in General Hospital of Ningxia Medical University were retrospectively analyzed. A total of 437 patients were enrolled, including 325 males and 112 females, aged (56.3±13.6) years. The 437 patients were divided into a training set ( n=305) and a test set ( n=132) by computer-generated random numbers on a 7∶3 basis; the training set was used to construct the predictive model as well as to internally validate it by the five-fold cross-validation method, and the test set was used to externally validate the model. Two machine learning Boruta algorithm and LASSO regression, were used to screen MVI characteristic variables and construct multifactorial logistic regression prediction models. Receiver operating characteristic (ROC) curve, calibration curves, and decision curve were evaluated for predictive modeling, applying Shapley's additive explanatory analysis (SHAP) of the significance of key variables. Results:The intersection (5 variables) of 8 characteristic variables selected by Boruta algorithm and 8 variables selected by LASSO regression were selected: aspartate aminotransferase/lymphocyte ratio (ALR), tumor margin, intratumbral necrosis, tumor number and tumor maximum diameter, and the logistic regression model was constructed. The area under ROC curve for predicting the MVI were 0.77 (95% CI: 0.70-0.82) (training set), 0.76 (95% CI: 0.63-0.87) (validation set), and 0.84 (95% CI: 0.78-0.91) (test set). The prediction results of calibration curve logistic regression model were close to those of reagent, and the analysis of decision curve indicates that the model had good clinical application value. According to the mean absolute SHAP value, the order of importance was tumor margin, tumor maximum diameter, tumor number, ALR, and intratumoral necrosis. Conclusion:Tumor margin, tumor maximum diameter, tumor number, ALR and intratumoral necrosis were independent influencing factors for hepatocellular carcinoma associated with MVI, and the logistic regression model based on these factors was effective in predicting MVI.

Objective: To study the effect of nonthermal argon atmospheric pressure plasma (NTAPP) treatment on the bonding strength between dentine and self-etch adhesive and the wettability of dentine surfaces under different treatment times. Methods: The plasma jet was operated at an input power of 9 W. Argon was used as the operating gas at a flow rate of 5 L/min. The dentin surface was exposed to the plasma jet (n=6) for various times (0, 5, 10, 15, 20 s). After a one-step self-etch adhesive (S3 Bond) was applied to the treated dentine surface, microtensile bonding specimens were made, and the microtensile bonding strength was tested. Then, the dentine surface contact angles were measured after NTAPP treatment for 5, 10, 15, and 20 s with the same gas flow rate and input power described above. Results: Along with the NTAPP treatment time, the dentin immediate bonding strength was significantly increased. The 15 s group showed significantly elevated bonding strength (31.82±2.80 MPa) in contrast to the other groups. The contact angles of each experimental group significantly decreased compared with the contact angles of the negative control group (75.57°±1.45°). The contact angles decreased the most to 33.56°±2.14° with NTAPP treatment for 15 s, and its wettability was the highest. Conclusion NTAPP treatment can significantly increase the wettability of the dentin surface and improve the adhesive strength of the adhesive interface with self-etching adhesive, which is also related to the treatment time.

Solitary fibrous tumor is a rare mesenchymal tumor associated with NAB2-STAT6 fusion gene, which is rarely seen in kidney. A 16-year-old boy was hospitalized because of left back pain for more than 3 years. Abdominal CT/MRI identified a huge space-occupying lesion in the left kidney. Laparoscopic radical left nephrectomy was performed initially. Nevertheless, laparoscopic-to-open procedure was adopted due to the huge size of the tumor. The pathological diagnosis was renal solitary fibrous tumor. The symptoms of the patient disappeared and no recurrence was observed at the 2-month follow-up after the surgery.