Background::While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD.Methods::We evaluated phenotypic associations using data from the United Kingdom Biobank ( N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: Ncase/ Ncontrol = 74,124/824,006; T2DM adjusted for BMI [T2DM adjBMI]: Ncase/ Ncontrol = 50,409/523,897) and for CAD ( Ncase/ Ncontrol = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM ( Ncase/ Ncontrol = 180,834/1,159,055). Results::Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DM→CAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01–2.24; CAD→T2DM: HR = 1.72, 95% CI: 1.63–1.81). A positive overall genetic correlation between T2DM and CAD was observed ( rg = 0.39, P = 1.43 × 10 -75), which was largely independent of BMI (T2DM adjBMI–CAD: rg = 0.31, P = 1.20 × 10 –36). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DM→CAD: odds ratio [OR] = 1.13, 95% CI: 1.11-1.16; CAD→T2DM: OR = 1.12, 95% CI: 1.07-1.18), which was confirmed in multiancestry individuals (T2DM→CAD: OR = 1.13, 95% CI: 1.10-1.16; CAD→T2DM: OR = 1.08, 95% CI: 1.04-1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9-83.4%) and 90.4% (95% CI: 29.3-151.5%), respectively. Conclusion::Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.

Polyphyllin Ⅰ(PPⅠ)and polyphyllin Ⅱ(PⅡ)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPⅠ and PⅡ exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepa-totoxicity of PPⅡ and PⅡwas associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the choles-terol synthesis,selected as the potential targets,were confirmed by the molecular docking,the over-expression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPⅠ could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPⅠ-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.

Smart manufacturing still remains critical challenges for pharmaceutical manufacturing. Here, an original data-driven engineering framework was proposed to tackle the challenges. Firstly, from sporadic indicators to five kinds of systematic quality characteristics, nearly 2,000,000 real-world data points were successively characterized from Ginkgo Folium tablet manufacturing. Then, from simplex to the multivariate system, the digital process capability diagnosis strategy was proposed by multivariate C_pk integrated Bootstrap-t. The C_pk of Ginkgo Folium extracts, granules, and tablets were discovered, which was 0.59, 0.42, and 0.78, respectively, indicating a relatively weak process capability, especially in granulating. Furthermore, the quality traceability was discovered from unit to end-to-end analysis, which decreased from 2.17 to 1.73. This further proved that attention should be paid to granulating to improve the quality characteristic. In conclusion, this paper provided a data-driven engineering strategy empowering industrial innovation to face the challenge of smart pharmaceutical manufacturing.

Oligoasthenospermia is the primary cause of infertility. However, there are still enormous challenges in the screening of critical candidates and targets of oligoasthenospermia owing to its complex mechanism. In this study, stem cell factor (SCF), c-kit, and transient receptor potential vanilloid 1 (TRPV1) biosensors were successfully established and applied to studying apoptosis and autophagy mechanisms. Interestingly, the detection limit reached 2.787 × 10^-15 g/L, and the quantitative limit reached 1.0 × 10^-13 g/L. Furthermore, biosensors were used to investigate the interplay between autophagy and apoptosis. Schisandrin A is an excellent candidate to form a system with c-kit similar to SCF/c-kit with a detection constant (K_D) of 5.701 × 10^-11 mol/L, whereas it had no affinity for SCF. In addition, it also inhibited autophagy in oligoasthenospermia through antagonizing TRPV1 with a K_D of up to 4.181 × 10^-10 mol/L. In addition, in vivo and in vitro experiments were highly consistent with the biosensor. In summary, high-potency schisandrin A and two potential targets were identified, through which schisandrin A could reverse the apoptosis caused by excessive autophagy during oligoasthenospermia. Our study provides promising insights into the discovery of effective compounds and potential targets via a well-established in vitro-in vivo strategy.

Objective:This study aimed to evaluate the efficacy and safety of daratumumab as a maintenance treatment after autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with newly diagnosed multiple myeloma (NDMM) .Methods:The clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between May 1, 2022 and June 30, 2023 were retrospectively analyzed.Results:Fifteen patients (11 males and 4 females) with a median age of 58 (41-72) years were included. Thirteen patients did not receive daratumumab during induction therapy and auto-HSCT, 6 patients had renal impairment, and nine patients had high-risk cytogenetics. The median infusion of daratumumab was 12 (6-17) times, and the median duration of maintenance was 6 (1.5-12) months. The treatment efficacy was evaluated in all 15 patients, and daratumumab maintenance therapy increased the rate of stringent complete response from 40% to 60%. The renal response rate and median estimated glomerular filtration rate of six patients with RI-NDMM were also improved. During daratumumab maintenance therapy, the most common hematological grade 3 adverse event (AE) was lymphopenia [4 of 15 patients (26.67%) ], whereas the most common nonhematologic AEs were infusion-related reactions [7 of 15 patients (46.67%) ] and grade 3 pneumonia [5 of 15 patients (33.33%) ]. The five patients with pneumonia were daratumumab naive [5 of 13 patients (38.46%) ], with a median of 8 (6-10) infusions. Among them, the chest computed tomography of three patients showed interstitial infiltrates, and treatment with methylprednisolone was effective. With a median follow-up of 12 months, the 1-year overall survival rate was 93.33%, and only one patient died (which was not related to daratumumab treatment) .Conclusions:Daratumumab was safe and effective as a maintenance agent for post-auto-HSCT patients with NDMM, and AEs were controllable. The most common nonhematologic AE was grade 3 pneumonia, and a less dose-intense maintenance regimen for the first 8 weeks could reduce the incidence of pneumonia.

Objective: The aim of the present study was to investigate the survival rate and its prognostic factors for patients with biliary tract cancer, and then a prognostic risk prediction model was constructed to predict the survival probability of patients. Methods: A total of 14 005 patients with biliary tract cancer (including gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater cancer), who were diagnosed between 2010 and 2015 in the US National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) were included in the development cohort. The prognostic risk factors of biliary tract cancer were investigated using multivariate Cox regression models. The predictive nomograms were then constructed to predict the overall survival probability of 1, 3, and 5 years, and the predictive discrimination and calibration ability of the nomograms were further evaluated. Meanwhile, 11 953 patients who were diagnosed during 2004 to 2009 from SEER Program were then selected to validate the external predictive accuracy of the prediction models. Results: The 1, 3 and 5-year cumulative survival rates of patients with biliary tract cancer were 41.9%, 20.4% and 15.3%, respectively, in the development cohort. Age greater than 50 years, African Americans and Native Americans and Alaska Natives, higher T, N and M stage and poor histological differentiation grade were risk factors for death, while married status, Asia-Pacific Islanders, insured status and surgery on primary site were protective factors. Gender was not significantly associated with the overall survival. The C statistic of the prediction model was 0.73 (95%CI: 0.72-0.74), and the calibration curve showed that the interaction curves of predictive and actual survival rates of 1, 3 and 5 years were close to the 45 degree diagonal. Results in the validation cohort were similar with those in the construction cohort, with a C statistic of 0.70 (95%CI: 0.69-0.72), indicating high external applicability of the prediction model. Findings from gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater cancer are in consistent with the overall biliary tract cancer. Conclusions The survival rate of patients with biliary tract cancer is relatively poor, and the survival prediction model based on prognostic factors has high prediction accuracy. In the future, this prognostic prediction model could be applied to clinical practice to guide individualized treatment for patients with biliary tract cancer.

Objective Evaluation of the effect of manual reduction with small external fixation on the treatment of elderly Barton fractures.Methods A total of 244 elderly patients with Barton fractures were divided into conservative group (n=126) and operation group (n=118) according to random number table. The conservative group was treated by with manual reduction with small external fixation, and the operation group was treated with open reduction and internal fixation. The complications of the patients, the time of fracture healing, hospitalization time and treatment cost were recorded.The wrist function was evaluated by PRWE wrist score system and Wrightington wrist function score system.The clinical efficacy was evaluated by Gartland-Werley Colles fracture evaluation method.Results The excellent and good effect rate was 91.3% (115/126) in the conservative group and 97.5% (115/118) in the operation group. There was no significant difference between the two groups(χ2=0.857,P=0.354). One year, 6 months, 3 months and 6 weeks after treatment, in the conservative group, the PRWE score (10.4 ± 7.9, 19.1 ± 8.0, 40.5 ± 7.8, 55.7 ± 8.1vs. 80.8 ± 8.2,F=113.665), wrightington score (8.2 ± 3.7, 13.2 ± 4.0, 21.4 ± 3.9, 26.3 ± 4.2vs. 30.1 ± 4.2,F=121.348) were significantly lower than those before treatment (P<0.01). And in the operation group, the PRWE score (10.2 ± 7.8, 15.0 ± 8.0, 26.5 ± 8.0, 44.7 ± 8.2vs. 79.6 ± 8.6,F=81.411), Wrightington score (8.1 ± 3.8, 12.1 ± 4.0, 16.5 ± 4.0, 20.6 ± 4.3vs. 29.8 ± 4.6,F=69.113) were significantly lower than those before treatment (P<0.01). But there was no significant difference in PRWE score and Wrightington scores between the two groups after treatment (t=0.149, 0.104,P=0.881, 0.917, respectively). In the conservative group, the hospitalization time (5.28 ± 2.10 dvs. 12.8 ± 2.21d,t=25.260) was significantly shorter than that of the control group (P<0.01), and the treatment cost (3.26 ± 0.93 thousandvs. 28.66 ± 1.04 thousand,t=200.369) was significantly lower than that in the control group (P<0.01). The overall incidence of complication was 8.7% (11/126) in the conservative group and 17.8% in the surgery group (21/118). There was significant difference between the two groups(χ2=4.396,P=0.036).Conclusions The manual reduction with small splint external fixation was simple, low cost, small trauma, short hospitalization time, and less complications.

Objective To observe the effect of Chinese herbal fumigation combined with CPM promote the function recovery after Postoperative Patellar Fracture. Methods Eighty patients with patellar fracture were randomly divided into treatment group (40 cases) and control group (40 cases). The control group was treated with CPM. The treatment group was treated with Chinese Herbal Fumigation and CPM. After 8th weeks, the clinical curative effect, knee range of motion and KSS knee score were observed and compared. Results The effect rate of the treatment group was 87.5% (35/40), and the control group was 65.0% (26/40). The difference was statistically significant (χ2=5.591, P<0.01). After treatment, the range of motion of knee joint (138.38°± 7.82°vs. 0.29°± 7.83°, t=10.338), KSS knee function score (88.38 ± 9.52 vs. 3.46 ± 9.36, t=2.330) of the treatment group were higher than those in the control group (P<0.01 or P<0.05). Conclusions The Chinese medicine fumigation combined with CPM functional exercise could accelerate the recovery of knee function and reduce the complications of fracture after patellar fracture.

AIM To investigate the effects of Sanqi Huayu Oral Liquid (Notoginseng Radix et Rhizoma,Corydalis Rhizoma) on femoral shaft comminuted fracture caused by trauma in perioperative period of high-risk groups.METHODS One hundred and twenty patients meeting the inclusion criteria were randomly and equally divided into treatment group and control group.The control group was treated by low molecular weight heparin calcium injection,while the treatment group was additionally given Sanqi Huayu Oral Liquid.Two groups' levels of serum IL-6,TNF-α and D-D were detected on pre-operation and the 1 st,3rd,7th after operation,respectively.Additionally,the adverse drug reactions were also observed.RESULTS There were no statistically significant differences in the levels of serum IL-6,TNF-α and D-D between the two groups before operation.The first day after operation,the levels of serum IL-6,TNF-α and D-D between the two groups showed increasing trends,which had similar elevated levels without statistically significant differences.The third day after operation,the levels of serum IL-6,TNF-α and D-D between the two groups presented downward trends,but those in the treatment group were decreased more markedly with statistically significant differences.Furthermore,the seventh day after operation,the levels of serum IL-6,TNF-α and D-D between the two groups were lower than those before the operation,and these indices in the treatment group were lower than those in the control group with statistically significant differences.CONCLUSION Sanqi Huayu Oral Liquid can not only effectively reduce the levels of serum IL-6,TNF-α and D-D in perioperative period of high-risk groups,but also prevent the formation of deep vein thrombosis.

Objective To analyze the clinically isolated bacterial distribution and drug resistance characteristics in the our hospital during 2016 to provide the pathogenic drug resistance monitoring data for rational bacterial drugs use in clinic.Methods The clinicaly submitted samples were performed the pathogenic bacterial isolation according to the routine method.The isolated pathogens were identified by the Vitek2-Compact system and the drug susceptibility test was performed by adopting the MIC and KB methods.The results were statistically analyzed by adopting the WHONET5.6 software.Results A total of 2 214 non-repeat strains of bacteria were isolated in 2016,including 1 614 strains of Gram-negative bacilli,accounting for 72.9％,600 strains of Gram-positive bacteria,accounting for 27.1 ％.The top five isolated bacteria were Klebsiella pneumoniae,Escherichia coli,Pseudomonas aeruginosa,Acinetobacter baumannii and Staphylococcus aureus.The detection rates of ESBLs producing Escherichia coli and Klebsiella pneumoniae were 51.8％ and 27.6％ respectively.The detection rates of methicillin-resistant Staphylococcus aureus (MRSA) was 26.5％.No vancomycin or linezolid resistant staphylococcal strains were found.Conclusion The main isolated pathogens in our hospital are dominated by Gram-negative bacteria.Hospital should strengthen reasonable and standardized use of antibacterial drugs to reduce the generation of drug resistant bacterial strains.