Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

Objective:To analyze the risk factors of in-hospital mortality in patients with femoral neck fracture and establish a prediction model for in-hospital mortality.Methods:From 2014 to 2023, a total of 4,028,102 hospitalized patients from six directly affiliated hospitals and two co-constructed affiliated hospitals of Peking University were retrospectively analyzed. Among them, 4,744 patients were hospitalized with femoral neck fractures, including 1,486 males and 3,258 females, aged 74±13.3 years (range, 19-103 years). Gender, age, length of hospital stay, hospitalization costs, preoperative comorbidities, treatment methods, anesthesia methods, and in-hospital mortality were extracted from the medical records. According to the presence or absence of in-hospital death, the patients were divided into death group and survival group. The differences in general data and clinical indicators between the two groups were compared, and the indicators with statistically significant differences were included in binary logistic regression analysis to screen the risk factors for in-hospital death in patients with femoral neck fracture. The receiver operating characteristic (ROC) curve for predicting in-hospital mortality of femoral neck fracture was drawn, and the area under the curve (AUC) was calculated.Results:There were 30 cases in the death group and 4,714 cases in the survival group, with a mortality rate of 0.63%. Among the dead patients, 20 had undergone hip replacement, and 10 had received non-surgical treatment. In the death group, age ( t=7.524, P<0.001), length of hospital stay ( t=3.802, P<0.001), hospitalisation cost ( t=3.961, P<0.001), rate of non-surgical treatment ( P<0.001), anaesthesia modality ( P=0.002), dementia ( P=0.045), malignant tumour ( P<0.001), renal insufficiency (χ 2=27.901, P<0.001), hypertension (χ 2=4.155, P=0.042), cerebral infarction (χ 2=8.271, P=0.004), urinary infections ( P=0.043), electrolyte disorders (χ 2=16.660, P<0.001), post-cholecystectomy ( P=0.070), abnormal liver function ( P=0.015), schizophrenia ( P=0.062), myocardial infarction (χ 2=19.057, P<0.001), diabetes mellitus with end-organ damage ( P=0.036), congestive heart failure (χ 2=93.122, P<0.001), and chronic obstructive pulmonary disease (χ 2=27.714, P<0.001) were greater than in the survival group, and the differences were statistically significance ( P<0.10). Bicategory logistic regression analysis showed age ( OR=1.08, P=0.008), non-surgical treatment ( OR=2.87, P=0.017), combined malignancy ( OR=9.35, P<0.001), renal insufficiency ( OR=4.07, P=0.004), hypertension ( OR=4.45, P=0.007), cerebral infarction ( OR=2.42, P=0.040), electrolyte disorders ( OR=4.29, P=0.009), schizophrenia ( OR=41.23, P=0.002), chronic obstructive pulmonary disease ( OR=3.84, P=0.002), and congestive heart failure ( OR=7.08, P<0.001) were the independent risk factors for in-hospital mortality of femoral neck fracture. The AUC and its 95% confidence interval (CI) for the predictive model were 0.908(0.84, 0.97), indicating excellent predictive value. Conclusion:Elderly, non-surgical treatment, malignant tumor, renal insufficiency, hypertension, cerebral infarction, electrolyte disturbance, schizophrenia, chronic obstructive pulmonary disease, congestive heart failure are associated with higher in-hospital mortality in patients with femoral neck fracture.

Objective:To analyze the risk factors of in-hospital mortality in patients with femoral neck fracture and establish a prediction model for in-hospital mortality.Methods:From 2014 to 2023, a total of 4,028,102 hospitalized patients from six directly affiliated hospitals and two co-constructed affiliated hospitals of Peking University were retrospectively analyzed. Among them, 4,744 patients were hospitalized with femoral neck fractures, including 1,486 males and 3,258 females, aged 74±13.3 years (range, 19-103 years). Gender, age, length of hospital stay, hospitalization costs, preoperative comorbidities, treatment methods, anesthesia methods, and in-hospital mortality were extracted from the medical records. According to the presence or absence of in-hospital death, the patients were divided into death group and survival group. The differences in general data and clinical indicators between the two groups were compared, and the indicators with statistically significant differences were included in binary logistic regression analysis to screen the risk factors for in-hospital death in patients with femoral neck fracture. The receiver operating characteristic (ROC) curve for predicting in-hospital mortality of femoral neck fracture was drawn, and the area under the curve (AUC) was calculated.Results:There were 30 cases in the death group and 4,714 cases in the survival group, with a mortality rate of 0.63%. Among the dead patients, 20 had undergone hip replacement, and 10 had received non-surgical treatment. In the death group, age ( t=7.524, P<0.001), length of hospital stay ( t=3.802, P<0.001), hospitalisation cost ( t=3.961, P<0.001), rate of non-surgical treatment ( P<0.001), anaesthesia modality ( P=0.002), dementia ( P=0.045), malignant tumour ( P<0.001), renal insufficiency (χ 2=27.901, P<0.001), hypertension (χ 2=4.155, P=0.042), cerebral infarction (χ 2=8.271, P=0.004), urinary infections ( P=0.043), electrolyte disorders (χ 2=16.660, P<0.001), post-cholecystectomy ( P=0.070), abnormal liver function ( P=0.015), schizophrenia ( P=0.062), myocardial infarction (χ 2=19.057, P<0.001), diabetes mellitus with end-organ damage ( P=0.036), congestive heart failure (χ 2=93.122, P<0.001), and chronic obstructive pulmonary disease (χ 2=27.714, P<0.001) were greater than in the survival group, and the differences were statistically significance ( P<0.10). Bicategory logistic regression analysis showed age ( OR=1.08, P=0.008), non-surgical treatment ( OR=2.87, P=0.017), combined malignancy ( OR=9.35, P<0.001), renal insufficiency ( OR=4.07, P=0.004), hypertension ( OR=4.45, P=0.007), cerebral infarction ( OR=2.42, P=0.040), electrolyte disorders ( OR=4.29, P=0.009), schizophrenia ( OR=41.23, P=0.002), chronic obstructive pulmonary disease ( OR=3.84, P=0.002), and congestive heart failure ( OR=7.08, P<0.001) were the independent risk factors for in-hospital mortality of femoral neck fracture. The AUC and its 95% confidence interval (CI) for the predictive model were 0.908(0.84, 0.97), indicating excellent predictive value. Conclusion:Elderly, non-surgical treatment, malignant tumor, renal insufficiency, hypertension, cerebral infarction, electrolyte disturbance, schizophrenia, chronic obstructive pulmonary disease, congestive heart failure are associated with higher in-hospital mortality in patients with femoral neck fracture.

【Objective】 To investigate the relationship between cerebrospinal fluid exosome-derived miR-630 and the function of brain microvascular endothelial cells （BMECs）. 【Methods】 The subarachnoid hemorrhage endothelial cell model was established to evaluate the effect of hemorrhagic cerebrospinal fluid （BCSF） on BMECs’ proliferation by MTT assay and cell cycle analysis. qRT-PCR and immunofluorescence staining were used to detect the expressions of endothelial cell tight junction protein （ZO-1） and adhesion molecule （ICAM-1 and VCAM-1）. Changes in NOx concentration were detected by radioimmunoassay. The cerebrospinal fluid exosomes in the experimental group （co-incubated with BCSF） and the control group （normal cerebrospinal fluid） were isolated and identified， and differences in the expressions of cerebrospinal fluid exosomal miR-630 between the two groups were compared. BMECs work changes after the intervention with miR-630 analogue were observed. 【Results】 The proliferation of BMECs was significantly inhibited in the experimental group； the mRNA and protein levels of ICAM-1， VCAM-1 and ZO-1 were significantly decreased， and the function of endothelial cells was significantly inhibited （P<0.05）. After the successful separation and identification of cerebrospinal fluid exosomes， the expression of miR-630 was significantly lower in the experimental group than in the control group （P<0.05）. The function of BMECs was significantly improved with miR-630 mimics. 【Conclusion】 The low expression of miR-630 in cerebrospinal fluid exosomes after subarachnoid hemorrhage is closely related to BMECs injury.

The feasibility and safety of intracardiac echocardiography (ICE)-guided catheter ablation for atrial fibrillation (AF) using a minimal/zero-fluoroscopy approach have recently been reported. This approach helps to reduce ionizing radiation exposure and orthopedic complications resulting from using lead aprons. The objectives of this planned prospective, multicenter randomized controlled trial (RCT) (paroxysmal AF (PAF)-ICE trial; ChiCTR2000033624) are to evaluate the efficacy and safety of ICE-guided minimal-fluoroscopy ablation in patients with PAF and the impact on occupational hazards among lab staff.Patients will be randomized in a 1:1 ratio to 2 groups: minimal fluoroscopy group ( n = 216) and traditional approach group ( n = 216). In the minimal fluoroscopy group, an ICE catheter will be used for geometry/anatomic construction, transseptal puncture, catheter tracking, and effusion monitoring. Pulmonary vein isolation (PVI) will be performed using an open-irrigated radiofrequency SmartTouch Surround Flow or SmartTouch catheter (Biosense Webster, Diamond Bar, California, USA), and confirmed by a multipolar Lasso or PentaRay catheter (Biosense Webster). In the traditional approach group, an ICE catheter will not be used. Transseptal puncture will be performed under fluoroscopic guidance, with all geometries constructed by mapping the catheters. The primary efficacy endpoint is freedom from AF recurrence (without antiarrhythmic medications) at 12 months after ablation. Other endpoints include duration of lead apron use, measures of intra-procedural efficiency, and peri-procedural complications. This RCT will evaluate the efficacy and safety of ICE-guided minimal-fluoroscopy ablation in patients with PAF, also evaluate the benefits to lab staff (regarding reducing occupational hazards) related to this "minimal/zero-fluoroscopy" and "leadless" mode.

The feasibility and safety of intracardiac echocardiography (ICE)-guided catheter ablation for atrial fibrillation (AF) using a minimal/zero-fluoroscopy approach have recently been reported. This approach helps to reduce ionizing radiation exposure and orthopedic complications resulting from using lead aprons. The objectives of this planned prospective, multicenter randomized controlled trial (RCT) (paroxysmal AF (PAF)-ICE trial; ChiCTR2000033624) are to evaluate the efficacy and safety of ICE-guided minimal-fluoroscopy ablation in patients with PAF and the impact on occupational hazards among lab staff.Patients will be randomized in a 1:1 ratio to 2 groups: minimal fluoroscopy group ( n = 216) and traditional approach group ( n = 216). In the minimal fluoroscopy group, an ICE catheter will be used for geometry/anatomic construction, transseptal puncture, catheter tracking, and effusion monitoring. Pulmonary vein isolation (PVI) will be performed using an open-irrigated radiofrequency SmartTouch Surround Flow or SmartTouch catheter (Biosense Webster, Diamond Bar, California, USA), and confirmed by a multipolar Lasso or PentaRay catheter (Biosense Webster). In the traditional approach group, an ICE catheter will not be used. Transseptal puncture will be performed under fluoroscopic guidance, with all geometries constructed by mapping the catheters. The primary efficacy endpoint is freedom from AF recurrence (without antiarrhythmic medications) at 12 months after ablation. Other endpoints include duration of lead apron use, measures of intra-procedural efficiency, and peri-procedural complications. This RCT will evaluate the efficacy and safety of ICE-guided minimal-fluoroscopy ablation in patients with PAF, also evaluate the benefits to lab staff (regarding reducing occupational hazards) related to this "minimal/zero-fluoroscopy" and "leadless" mode.

Objective: To explore the therapeutic effect of subcutaneous negative pressure drainage and absorbable suture in preventing postoperative complications of cranioplasty. Methods: The clinical data of 175 cases of skull defect admitted and treated in Department of Neurosurgeryof the Affiliated Hospital of Binzhou Medical University from January 2012 to February 2018 were retrospectively analyzed.According to the different intraoperative treatment methods, 97 cases were treated with thread suture to the galea aponeurotica combined with general drainage(the general drainage group), and 78 cases were treated with absorbable suture to the galea aponeurotica combined with negative pressure drainage(the negative pressure drainage group). The galea aponeurotica were sutured intermittently with both silk thread and absorbable suture, and the drainage tube was placed outside the metal titanium plate under the skin, and removed after 48-72 hours.The postoperative complications of the two groups were compared. Results: The incidence rates of subcutaneous hemorrhage, knotting reaction, infection of incision in the negative pressure drainage group were 1.3%(1/78), 0.0%(0/78), and 0.0%(0/78), respectively, which were significantly lower than those in the average drainage group[11.3%(11/97), 20.6%(20/97), 7.2%(7/97)], the differences were statistically significant(χ²=6.85, 18.16, 4.13, all P<0.05). Conclusion The application of absorbable suture suturing galea aponeurotica and subcutaneous negative pressure drainage in skull repair can significantly reduce and prevent postoperative complications of cranioplasty.

In this study, we used next-generation sequencing methods to screen 300 individuals for BRCA1 and BRCA2. A novel mutation (c.849dupT) in BRCA2 was identified in a female patient and her unaffected brothers. This mutation leads to the truncation of BRCA2 functional domains. Moreover, BRCA2 mRNA expression levels in mutation carriers are significantly reduced compared to noncarriers. Immunofluorescence and western blot assays showed that this mutation resulted in reduced BRCA2 protein expression. Thus, we identified a novel mutation that damaged the function and expression of BRCA2 in a family with breast cancer history. The pedigree analysis suggested that this mutation is strongly associated with familial breast cancer. Genetic counsellors suggest that mutation carriers in this family undergo routine screening for breast cancer, as well as other malignancies, such as prostate and ovarian cancer. The effects of this BRCA2 mutation on drug resistance should be taken into consideration during treatment.
Blotting, Western ; BRCA2 Protein ; Breast Neoplasms* ; Breast* ; Drug Resistance ; Female ; Fluorescent Antibody Technique ; Genes, BRCA2 ; High-Throughput Nucleotide Sequencing ; Humans ; Mass Screening ; Nonsense Mediated mRNA Decay* ; Ovarian Neoplasms ; Pedigree ; Prostate ; RNA, Messenger ; Siblings

Objective To investigate the thawing modes on stability of coagulation control products after frozen,looking for a new theoretical basis for cost control and the quality and safety of laboratory.Methods Using ACL TOP 700 automated co-agulation analyzer and supporting the same batch of reagents and quality control materials conduct of the study:after daily QC,recycled the remaining control materials immediately and dispensed into two EP tubes and frozen at-40℃,respectively thawed by room-temperature and 37℃water bath after 24 hours,and examined together with the date of quality control ma-terial,got 20 pairs of data for analysis the financial impact of two alternate ways on coagulation QC parameters.Results For the room-temperature thawing group,FIB high value increasedby an average 0.23 g/L (t=4.026 9,P<0.05);TT normal value average reduction of 0.46 s (t=-3.813 8,P<0.05),TT high value reduced by an average 0.41s (t=-3.972 8,P<0.05);D-Dimer low-value increased by an average of 14.75 ng/ml FEU (t=2.281 6,P<0.05),while APTT,PT normal and high value,FIB normal value,D-Dimer high value were no significant difference after thawing (P>0.05).For the 37℃water bath group,both normal and high value of APTT,PT,FIB,TT and D-Dimer were no significant difference after tha-wing (P>0.05).Conclusion The commercialization of coagulation control materials can be for the second QC,just follow the principle of rapid after melting and timely detection,other laboratories can be used as a reference.

Objective To investigate the diagnostic value of D-dimer age-adjusted threshold in elderly patients with Pulmonary thromboembolism(PTE).Methods Collected patients older than 50 years of suspected PTE,who visited Yan′an People′s Hospital and the Hospital Affiliated to Yan′an University from June 2015 to September 2016,using the revised Geneva criteria for clinical probability assessment firstly.The low-risk group was excluded from the study;the patients with moderate-to-high risk were performed D-dimer detection and CTPA.All patients determined both by D-dimer age-adjusted thresholds and traditional thresholds,comparing the diagnostic efficacy of the two methods subsequently.Results 163 patients were diagnosed with PTE by CTPA among the 549 subjects,the positive rate was 29.69％.The diagnostic sensitivity of plasma D-dimer was 83.44％,78.53％,the specificity was 17.88％,31.61％ respectively,the missed diagnosis rate was 16.56％,21.47％,respectively.The misdiagnosis rates were 82.12％ and 68.39％,respectively,and the Younden index was 0.013 2 and 0.101 4 respectively.All subjects were divided into four groups according to age:50-60 years,60-70 years,70-80 years,and equal or greater than 80 years age group.Compared with the traditional threshold,the misdiagnosis rates of the four groups of age-adjusted thresholds decreased by 4.00％,15.70％,21.36％ and 17.39％,respectively and the specificity was increased by 1.23,1.65,2.56 and 3.00 times,respectively.Conclusion The diagnostic accuracy of the age-corrected threshold is higher than the traditional threshold;combined with clinical practice,the optimal threshold is determined by the ROC curve,the clinician can serve as a reference.