Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder characterized by recurrent episodes of subcutaneous and submucosal edema, which can be life-threatening in severe cases. Lanadelumab, a recombinant human monoclonal antibody against kallikrein, has been recommended as a first-line option for long-term prophylaxis of HAE. This paper analyzed the clinical data of four patients with HAE diagnosed and treated with lanadelumab for long-term prophylaxis in our department since 2020. It also reviewed relevant literature, summarizing the clinical manifestations of HAE, as well as the efficacy and safety of lanadelumab in treating HAE, to provide therapeutic references for clinicians.

Poor water solubility is the primary obstacle preventing the development of many pharmacologically active compounds into oral preparations. Self-nanoemulsifying drug delivery systems(SNEDDS) have become a widely used strategy to enhance the oral bioavailability of poorly soluble drugs by inducing a supersaturated state, thereby improving their apparent solubility and dissolution rate. However, the supersaturated solutions formed in SNEDDS are thermodynamically unstable systems with solubility levels exceeding the crystalline equilibrium solubility, making them prone to drug precipitation in the gastrointestinal tract and ultimately hindering drug absorption. Therefore, maintaining a stable supersaturated state is crucial for the effective delivery of poorly soluble drugs. Incorporating polymers as precipitation inhibitors(PPIs) into the formulation of supersaturated self-nanoemulsifying drug delivery systems(S-SNEDDS) can inhibit drug aggregation and crystallization, thus maintaining a stable supersaturated state. This has emerged as a novel preparation strategy and a key focus in SNEDDS research. This review explores the preparation design of SNEDDS and the technical challenges involved, with a particular focus on polymer-based S-SNEDDS for enhancing the solubility and oral bioavailability of poorly soluble drugs. It further elucidates the mechanisms by which polymers participate in transmembrane transport, summarizes the principles by which polymers sustain a supersaturated state, and discusses strategies for enhancing drug absorption. Altogether, this review provides a structured framework for the development of S-SNEDDS preparations with stable quality and reduced development risk, and offers a theoretical reference for the application of S-SNEDDS technology in improving the oral bioavailability of poorly soluble drugs.
Solubility ; Administration, Oral ; Polymers/chemistry* ; Drug Delivery Systems/methods* ; Humans ; Emulsions/chemistry* ; Biological Availability ; Animals ; Pharmaceutical Preparations/administration & dosage*

PURPOSE: To investigate the pathological changes of the synovium in mice with post-traumatic osteoarthritis (PTOA) treated with 4-octyl itaconate (4-OI) and evaluate the therapeutic effects of 4-OI. METHODS: In the phenotypic validation experiment, the mice were randomly divided into 3 groups: wild-type (WT) group, sham group, and destabilization of the medial meniscus (DMM) group. Through MRI, micro-CT, and histological analysis, it was determined that the DMM surgery induced a mouse PTOA model with significant signs of synovitis. At 12 weeks post-DMM surgery, synovial tissues from the DMM group and WT group mice were collected for ribonucleic acid sequencing analysis. In the 4-OI treatment experiment, mice were randomly divided into the sham group, DMM group, DMM + 4-OI (50 mg/kg) group, and DMM + 4-OI (100 mg/kg) group. Von Frey tests and open field tests were conducted at intervals during the 12 weeks following the DMM surgery. After 12 weeks of surgery, the efficacy of 4-OI treatment on PTOA in mice was evaluated using MRI, micro-CT, histological analysis, and quantitative real-time polymerase chain reaction. Finally, we utilized network pharmacology analysis to predict the mechanism of 4-OI in treating PTOA synovitis and conducted preliminary validation. Statistical analysis was performed using one-way ANOVA and the Kruskal-Wallis test. Difference was considered statistically significant at p < 0.05. RESULTS: The DMM surgery effectively induced a PTOA mouse model, which displayed significant symptoms of synovitis. These symptoms included a notable increase in both the number of calcified tissues and osteophytes (p < 0.001), an enlargement of the calcified meniscus and synovial tissue volume (p < 0.001), and thickening of the synovial lining layer attributable to M1 macrophage accumulation (p = 0.035). Additionally, we observed elevated histological scores for synovitis (p < 0.001). Treatment with 4-OI inhibited the thickening of M1 macrophages in the synovial lining layer of PTOA mice (p < 0.001) and reduced fibrosis in the synovial stroma (p = 0.004). Furthermore, it reduced the histological scores of knee synovitis in PTOA mice (p = 0.006) and improved the inflammatory microenvironment associated with synovitis. Consequently, this treatment alleviated pain in PTOA mice (p < 0.001) and reduced spontaneous activity (p = 0.003). Bioinformatics and network pharmacology analyses indicated that 4-OI may exert its therapeutic effects by inhibiting the differentiation of synovial Th17 cells. Specifically, compared to the lipopolysaccharide stimulation group, 4-OI reduced the levels of positive regulatory factors of Th17 cell differentiation (IL-1: p < 0.001, IL-6: p < 0.001), key effector molecules (IL-17A: p < 0.001, IL-17F: p = 0.004), and downstream effector molecules in the IL-17 signaling pathway (CCL2: p < 0.001, MMP13: p < 0.001). CONCLUSION 4-OI is effective in inhibiting synovitis in PTOA, thereby alleviating the associated painful symptoms.
Animals ; Synovitis/etiology* ; Mice ; Osteoarthritis/etiology* ; Disease Models, Animal ; Male ; Succinates/pharmacology* ; Mice, Inbred C57BL ; X-Ray Microtomography

To investigate the impact of preoperative serum follicle-stimulating hormone (FSH) levels on the probability of testicular sperm retrieval, we conducted a study of nonobstructive azoospermic (NOA) men with different testicular volumes (TVs) who underwent microdissection testicular sperm extraction (micro-TESE). A total of 177 NOA patients undergoing micro-TESE for the first time from April 2019 to November 2022 in Shenzhen Zhongshan Obstetrics and Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital, Shenzhen, China) were retrospectively reviewed. The subjects were divided into four groups based on average TV quartiles. Serum hormone levels in each TV group were compared between positive and negative sperm retrieval subgroups. Overall sperm retrieval rate was 57.6%. FSH levels (median [interquartile range]) were higher in the positive sperm retrieval subgroup compared with the negative outcome subgroup when average TV was <5 ml (first quartile [Q1: TV <3 ml]: 43.32 [17.92] IU l -1 vs 32.95 [18.56] IU l -1 , P = 0.048; second quartile [Q2: 3 ml ≤ TV <5 ml]: 31.31 [15.37] IU l -1 vs 25.59 [18.40] IU l -1 , P = 0.042). Elevated serum FSH levels were associated with successful micro-TESE sperm retrieval in NOA men whose average TVs were <5 ml (adjusted odds ratio [OR]: 1.06 per unit increase; 95% confidence interval [CI]: 1.01-1.11; P = 0.011). In men with TVs ≥5 ml, larger TVs were associated with lower odds of sperm retrieval (adjusted OR: 0.84 per 1 ml increase; 95% CI: 0.71-0.98; P = 0.029). In conclusion, elevated serum FSH levels were associated with positive sperm retrieval in micro-TESE in NOA men with TVs <5 ml. In men with TV ≥5 ml, increases in average TVs were associated with lower odds of sperm retrieval.
Humans ; Male ; Azoospermia/surgery* ; Sperm Retrieval/statistics & numerical data* ; Adult ; Follicle Stimulating Hormone/blood* ; Retrospective Studies ; Testis/pathology* ; Microdissection ; Organ Size

OBJECTIVE: To investigate the effectiveness of Xuanshen Yishen Decoction (XYD) in the treatment of hypertension. METHODS: Hospital electronic medical records from 2019-2023 were utilized to emulate a randomized pragmatic clinical trial. Hypertensive participants were eligible if they were aged ⩾40 years with baseline systolic blood pressure (BP) ⩾140 mm Hg. Patients treated with XYD plus antihypertensive regimen were assigned to the treatment group, whereas those who followed only antihypertensive regimen were assigned to the control group. The primary outcome assessed was the attainment rate of intensive BP control at discharge, with the secondary outcome focusing on the 6-month all-cause readmission rate. RESULTS: The study included 3,302 patients, comprising 2,943 individuals in the control group and 359 in the treatment group. Compared with the control group, a higher proportion in the treatment group achieved the target BP for intensive BP control [8.09% vs. 17.5%; odds ratio (OR)=2.29, 95% confidence interval (CI)=1.68 to 3.13; P<0.001], particularly in individuals with high homocysteine levels (OR=3.13; 95% CI=1.72 to 5.71; P<0.001; P for interaction=0.041). Furthermore, the 6-month all-cause readmission rate in the treatment group was lower than in the control group (hazard ratio=0.58; 95% CI=0.36 to 0.91; P=0.019), and the robustness of the results was confirmed by sensitivity analyse. CONCLUSIONS XYD could be a complementary therapy for intensive BP control. Our study offers real-world evidence and guides the choice of complementary and alternative therapies. (Registration No. ChiCTR2400086589).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Antihypertensive Agents/pharmacology* ; Blood Pressure/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Hypertension/physiopathology* ; Patient Readmission ; Treatment Outcome

Objective To explore the efficacy of single and combined parameters from 4 non-Gaussian diffusion models for differentiating breast imaging reporting and data system(BI-RADS)MRI category 4 benign and malignant breast tumors.Methods A total of 161 BI-RADS MRI category 4 breast lesions from 159 patients were retrospectively enrolled.Based on pathological results,the lesions were divided into malignant group(n=132)and benign group(n=29).The apparent diffusion coefficient(ADC)values were calculated from diffusion weighted imaging(DWI)sequences.Multi-b-value diffusion imaging data were acquired and fitted using 4 non-Gaussian models to obtain respective parameters,including diffusion kurtosis imaging(DKI),stretched exponential model(SEM),continuous-time random walk(CTRW)and fractional order calculus(FROC)model.Univariable and multivariable logistic regression analyses were employed to identify the diffusion quantitative indicators useful for differentiating benign and malignant BI-RADS MRI category 4 breast tumors.Receiver operating characteristic(ROC)curves were drawn,and the optimal threshold was determined using Youden index.The differentiating performance of ADC value,single parameter and their combination from non-Gaussian diffusion models were assessed and compared according to the area under the curve(AUC)of ROC curves,as well as the sensitivity,specificity and accuracy under the optimal thresholds.Results In malignant group,αCTRW,KDKI and μFROC values were higher,while ADC,DCTRW,DFROC,DDCSEM,αSEM and DDKI values were lower than those in benign group(all P＜0.05).Multivariable logistic regression analysis identified DCTRW and αCTRW values as independent factors for differentiating benign and malignant BI-RADS MRI category 4 breast tumors(both P＜0.05),and a combined model was then constructed.The AUC of the combined model was higher than that of each single parameter including ADC,DCTRW and αCTRW values(all P＜0.05).Conclusion The combined model of DCTRW and αCTRW had better efficacy than each single parameter for differentiating benign and malignant BI-RADS MRI category 4 breast tumors.

Objective:To investigate the clinical value of a fully autonomous ultrasound robot in splenic ultrasound imaging.Methods:A retrospective study was conducted by enrolling 56 adult volunteers from the Third Medical Center of the Chinese PLA General Hospital between February 1-8，2024 as research subjects.A senior physician sequentially performed splenic ultrasound examinations using both the fully autonomous ultrasound robot and a matched portable ultrasound device. The acquired images were randomly coded and scored via a double-blind method by 3 physicians. The differences of the image quality scores and high-quality image proportions between the two groups were compared. Examination durations were recorded and compared between the two groups.Results:Both modalities successfully acquired splenic images in all 56 volunteers. No statistically significant differences were observed in image quality scores among the 3 physicians：（3.52 ± 1.31）points vs.（3.83 ± 1.23）points，（2.77 ± 1.23）points vs.（3.17 ± 1.17）points，and（3.48 ± 0.97）points vs.（3.79 ± 0.94）points（all P>0.05）. The numbers of images scoring ≥ 3 points showed no significant differences：45（80.36%） vs. 50（89.29%），30（53.57%） vs. 38（67.86%），and 48（85.71%） vs. 52（92.86%）（all P>0.05）. The fully autonomous ultrasound robot required significantly longer examination time［（60.86 ± 50.55）s vs.（7.95 ± 4.35）s， t=6.88， P＜0.01］. Conclusions:The fully autonomous ultrasound robot demonstrates comparable image quality and clinically acceptable image proportions to conventional portable ultrasound in splenic examinations. These findings suggest its potential equivalence to operator-dependent ultrasound for splenic imaging，supporting its feasibility as an alternative ultrasound modality despite longer procedural duration.

Objective:To investigate the efficacy of anatomical resection (AR) in the early stages of treating solitary hepatocellular carcinoma (HCC) combined with liver cirrhosis with a diameter of ≤5 cm in comparison to different surgical methods of preferential hepatic parenchymal preservation (non-anatomical liver resection, NAR).Methods:The clinical data of 1 390 cases with solitary HCC combined with liver cirrhosis at an early stage who underwent liver resection at Mengchao Hepatobiliary Hospital of Fujian Medical University and six other medical centers from September 2013 to May 2019 were retrospectively analyzed. Patients were divided into the AR group (486 cases) and the NAR group (904 cases) and the wide surgical margin (WSM) group (745 cases) and the narrow surgical margin (NSM) group (645 cases) according to whether they received AR and the width of the surgical margin (1 cm). The basic information of the patients, preoperative evaluation index data, and postoperative follow-up (follow-up every 3 months) were collected. The Kaplan-Meier method was used to plot the survival curve.The log-rank test was used to compare the difference in survival between the two groups. The Cox proportional hazards regression model was used to analyze the factors affecting the prognosis. Propensity score matching (PSM) was applied to reduce intergroup bias.Results:The overall survival (OS) rates for all patients at 1, 3, and 5 years were 95.5%, 79.9%, and 63.5%, respectively. The recurrence-free survival (RFS) rates were 81.5%, 59.0%, and 43.7%, respectively. There was a statistically significant difference in RFS rate between the AR group and the NAR group prior to PSM, but no statistically significant difference in OS rate (RFS rate: 47.0% vs. 41.9%, P<0.05; OS rate: 64.4% vs. 62.9%, P>0.05). The postoperative RFS rate and OS rate were significantly superior in the WSM group than those of the NSM group (RFS rate: 47.8% vs. 37.2%, P<0.001; OS rate: 69.0% vs. 57.3%, P<0.001). There was no statistically significant difference in OS rate and RFS rate between the AR group and the NAR group following PSM (RFS: 46.3% vs. 45.1%, P>0.05; OS rate: 64.0% vs. 64.3%, P>0.05).The 5-year OS and RFS rates in the WSM group were 66.8% and 60.2%, respectively. The 5-year OS and RFS rates for the NSM group were 48.7% and 41.4%, respectively, with a statistically significant difference ( P<0.05). Cox multivariate analysis indicated that serum albumin, tumor diameter, microvascular invasion, and surgical margin were independent prognostic factors affecting OS and RFS. The Child-Pugh grade and satellite lesions were independent prognostic factors affecting OS. Conclusion:Anatomical liver resection is not an independent risk factor for prognosis, but the state of the resection margin determines the prognosis of patients with solitary HCC combined with cirrhosis. Therefore, hepatic resection margins should be prioritized in such patients.

OBJECTIVES: This study aimed to explore the expression of lysosomal-associated membrane protein 5 (LAMP5) and microRNA (miR)-302a-3p in oral squamous cell carcinoma (OSCC) and their functional mechanism on the invasion and metastasis of OSCC. METHODS: The expression of LAMP5 in OSCC and its sensitivity as a prognostic indicator were analyzed on the basis of The Cancer Genome Atlas database. Western blot, quantitative reverse transcription polymerase chain reaction, and cell immunocytochemistry were used to detect the expression of LAMP5 in OSCC tissues and cells. The effect of LAMP5 on the proliferation, migration, and invasion of OSCC cells was evaluated through cell counting kit-8, immunocytochemistry, migration, and invasion assays, respectively. The miRNA targeting prediction websites were used to predict the miR that regulates LAMP5 and verify the targeted regulatory effect of miR-302a-3p on LAMP5. The effect of LAMP5 knockdown on OSCC tumor growth was evaluated in a nude mouse tumorigenesis model. RESULTS: LAMP5 was highly expressed in OSCC tissues and cells. It showed high sensitivity in the early diagnosis of OSCC. LAMP5 knockdown significantly inhibited the proliferation, migration, and invasion of OSCC cells, whereas LAMP5 overexpression increased these cell activities. The expression of LAMP5 was regulated by miR-302a-3p. In vivo, LAMP5 knockdown significantly inhibited the growth of OSCC tumor. CONCLUSIONS LAMP5 promotes the malignant progression of OSCC by enhancing the proliferation, migration, and invasion of OSCC cells. The expression of LAMP5 is negatively regulated by miR-302a-3p.
MicroRNAs/metabolism* ; Mouth Neoplasms/metabolism* ; Humans ; Animals ; Carcinoma, Squamous Cell/genetics* ; Neoplasm Invasiveness ; Cell Proliferation ; Mice, Nude ; Cell Movement ; Lysosomal Membrane Proteins/genetics* ; Mice ; Cell Line, Tumor ; Neoplasm Metastasis

Objective To explore the impact of neurally adjusted ventilatory assist(NAVA)mode on the weaning outcomes of patients with severe cerebrovascular disease who have weaning difficulty from mechanical ventilation.Methods Patients with severe cerebrovascular disease who had weaning difficulty from mechanical ventilation and were admitted to the Intensive Care Unit(ICU)of Neurosurgery Departement,the First Affiliated Hospital of Wannan Medical College(Yijishan Hospital of Wannan Medical College)from November 2019 to November 2021 were prospectively and consecutively included.They were randomly divided into the NAVA group and the pressure support ventilation(PSV)group using a random number table,with 28 patients in each group.Baseline and clinical data of the two groups were collected,including gender,age,main diagnosis,past medical history(hypertension,stroke,respiratory diseases,diabetes,coronary heart disease),body mass index,acute physiology and chronic health evaluation(APACHE)Ⅱ score,Glasgow coma scale(GCS)score,types of difficult weaning(failure of the first spontaneous breathing trial[SBT],re-intubation within 48 h after the first weaning attempt),and mechanical ventilation time before randomization.SBT and weaning-related indicators after randomization were collected,including respiratory mechanics and parameters before SBT implementation after randomization(peak airway pressure,expiratory tidal volume,positive end-expiratory pressure,inspired oxygen concentration,minute ventilation,mean airway pressure,diaphragmatic electrical activity signal value,neural ventilation efficiency,neural mechanical efficiency),basic vital signs(mean arterial pressure,respiratory heart rate)before weaning after passing SBT,blood routine(white blood cells,hemoglobin)and biochemical tests(albumin,creatinine,troponin,B-type natriuretic peptide)within 48 h before weaning,and arterial blood gas within 30 min before weaning(pH,partial pressure of carbon dioxide,partial pressure of oxygen,bicarbonate ion,oxygenation index).The primary outcome measures included the time required for successful weaning from randomization to day 28(if the patient died or failed to wean successfully before day 28 after randomization,the time required for weaning was defined as 28 d),total mechanical ventilation time after randomization,total weaning success rate from randomization to day 28,total weaning-free time at 7,14,and 28 d after randomization,survival time at 28 d and 90 d after randomization,ICU length of stay,total hospital length of stay,and cumulative weaning success rate from randomization to day 28 in both groups.The secondary outcome measures included tracheotomy rate after randomization,ICU mortality rate,mortality rate at 28 d and 90 d after randomization,incidence of mechanical ventilation-related complications(ventilator-associated pneumonia,acute respiratory distress syndrome,pneumothorax,pleural effusion)during mechanical ventilation after randomization,and cumulative survival rate at 90 d after randomization.The human-machine coordination within 24 h after randomization was recorded in both groups including the number and index of ineffective triggering,false triggering,double triggering,premature switching from inspiration to expiration,delayed switching from inspiration to expiration,and triggering delay,as well as the total asynchrony index,with one record every 8 h,each record lasting for 1 min,for a total of 3 min.Results A total of 56 patients with severe cerebrovascular disease who had weaning difficulty from mechanical ventilation were included,with 28 patients in each of the PSV group and the NAVA group.There were no statistically significant differences between the two groups in terms of gender,age,main diagnosis,past medical history,body mass index,APACHE Ⅱ score,GCS score,types of difficult weaning,mechanical ventilation time before randomization,indicators before SBT implementation after randomization and after SBT before weaning(all P＞0.05).(1)The time required for successful weaning from randomization to day 28(9.00[7.00,15.50]d vs.15.50[10.25,22.75]d)and total mechanical ventilation time after randomization(8.50[7.00,12.75]d vs.13.50[10.00,20.00]d)were both lower in the NAVA group than those in the PSV group(all P＜0.05).The cumulative weaning success rate of the NAVA group was higher than that of the PSV group at 28 d after randomization(P=0.039),but there was no statistically significant difference in the total weaning success rate between the two groups from randomization to the day 28(92.9％[26/28]vs.85.7％[24/28],P=0.669).The NAVA group had longer periods without mechanical ventilation within 14 d(5.00[0.00,7.00]d vs.0.00[0.00,3.75]d)and within 28 d(18.00[9.25,20.75]d vs.10.50[0.25,17.75]d)after randomization compared with the PSV group(all P＜0.05),but there was no statistically significant difference in the period without mechanical ventilation within 7 d after randomization between the two groups(P=0.159).The ICU stay of the NAVA group was shorter than that of the PSV group(9.00[6.25,16.75]d vs.14.00[10.25,22.50]d,P=0.015),but there were no statistically significant difference in the total hospital stay and survival time within 28 d and 90 d after randomization between the two groups(all P＞0.05).(2)There was no statistically significant difference between the two groups in tracheotomy rate,ICU mortality rate,mortality rate at 28 d and 90 d after randomization,complications during mechanical ventilation after randomization,and cumulative survival rate at 90 d after randomization(all P＞0.05).(3)In terms of human-machine coordination,the NAVA group had lower frequencies and indices of false triggering(frequency:0.00[0.00,0.00]time/min vs.0.00[0.00,0.58]time/min;index:0.00[0.00,0.00]vs.0.00[0.00,0.02]),ineffective triggering(frequency:0.00[0.00,0.33]time/min vs.1.00[0.33,2.17]time/min;index:0.00[0.00,0.02]vs.0.05[0.02,0.09]),premature switching(frequency:0.00[0.00,0.33]time/min vs.0.33[0.33,1.00]time/min;index:0.00[0.00,0.01]vs.0.02[0.02,0.05]),delayed switching(frequency:0.00[0.00,0.00]time/min rs.1.17[0.00,5.67]time/min;index:0.00[0.00,0.00]rs.0.06[0.00,0.29]),and delayed triggering(frequency:0.00[0.00,0.58]time/min vs.0.67[0.33,1.67]time/min;index:0.00[0.00,0.02]vs.0.05[0.02,0.10])compared with the PSV group(all P＜0.01).The NAVA group had higher frequencies and indices of double triggering(frequency:1.17[0.33,2.00]time/min vs.0.00[0.00,0.00]time/min;index:0.06[0.02,0.11]vs.0.00[0.00,0.00];all P＜0.01),but the total asynchrony index of the NAVA group was lower than that of the PSV group(0.08[0.04,0.14]vs.0.24[0.19,0.51],P＜0.01).Conclusion The NAVA mode can shorten the weaning and mechanical ventilation time of patients with severe cerebrovascular disease who have weaning difficulty from mechanical ventilation,improve human-machine coordination,and has potential advantages in increasing the weaning success rate.