Real world effectiveness of PCSK-9 inhibitors combined with statins versus statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease in China(RWE-PCSK study)

BACKGROUND The efficacy and safety of proprotein convertase subtilisin/kexin type 9(PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease(ASCVD).METHODS This is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention(PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events(MACE) over six months were compared between two groups.A propensity score-matched(PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE.RESULTS In a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol(LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81%(P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group(P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE(hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250).CONCLUSIONS In the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.

Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson’s disease

Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson’s disease,but its specific mechanism of action is still unclear.Stromal cell-derived factor-1 and its receptor,chemokine receptor 4(CXCR4),are important regulators of cell migration.We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson’s disease.A Parkinson’s disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway,and then treated with 5μL of neural stem cell suspension(1.5×104/L)in the right substantia nigra.Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation.Parkinson-like behavior in rats was detected using apomorphine-induced rotation.Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Using quantitative real-time polymerase chain reaction,the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured.In addition,western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4.Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation,increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra,and enhanced the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Injection of AMD3100 inhibited the aforementioned effects.These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson’s disease.This study was approved by the Animal Care and Use Committee of Kunming Medical University,China(approval No.SYXKK2015-0002)on April 1,2014.

Influence of Cy berKnife Prescription Isodose Line on the Discrepancy of Dose Results Calculated by the Ray Tracing and Monte Carlo Algorithms for Head and Lung Plans: A Phantom Study

Incorporation of the Monte Carlo(MC)algorithm in optimizing CyberKnife(CK)plans is cumbersome,and early models unconfigured MC calculations,therefore,this study investigated algorithm-based dose calculation discrepancies by selecting different prescription isodose lines(PIDLs)in head and lung CK plans.CK plans were based on anthropomorphic phantoms.Four shells were set at 2-60 mm from the target,and the constraint doses were adjusted according to the design stratcgy.After optimization,30%-90%PIDL plans were generated by ray tracing(RT).In the evaluation module,CK plans were recalculated using the MC algorithm.Therefore,the dosimetric parameters of different PIDL plans based on the RT and MC algorithms were obtained and analyzed.The discrepancies(mean+SD)were 3.72%+0.31%,3.40%+0.11%,3.47%+0.32%,0.17%+0.11%,0.64%+3.60%,7.73%+1.60%,14.62%+3.21%and 10.10%+1.57%for Djs,Dmeam),Dys,and coverage of the PTV,DGI,V,,V;and V,in the head plans and-6.32%+1.15%,-13.46%+0.98%,-20.63%+2.25%,-34.78%+25.03%,12248%+175.60%,-12.92%+5.41%,3.19%+4.67%and 7.13%+1.56%in the lung plans,respectively.The following parameters were significantly correlated with PIDL:dp98%at the 0.05 level and dpal,dys and dv3 at the 0.01 level for the head plans;dp98e%at the 0.05 level and do1e%,dpmeam,Ccoweange,dool,dvs and dv;at the 0.01 level for the lung plans.RT may be used to calculate the dose in CK head plans,but when the dose of organs at risk is close to the limit,it is necessary to refer to the MC results or to further optimize the CK plan to reduce the dose.For lung plans,the MC algorithm is recommended.For early models without the MC algorithm,a lower PIDL plan is recommended;otherwise,a large PIDL plan risks serious underdosage in the target area.

Energy-spread measurement of triple-pulse electron beams based on the magnetic dispersion principle

The method of energy dispersion in magnetic field is used to analyze the energy spread of the triple-pulse electron beam generated by the Dragon-II linear induction accelerator.A sector magnet is applied for energy analysis of the electron beam,with a bending radius of 300 mm and a deflection angle of 90°.For each pulse,the time-resolved and integral images of the electron position at the output port of beam-bending line are recorded by a streak camera and a CCD camera,respectively.Experimental results demonstrate an energy spread of less than ±2.0%for the electron pulses.The cavity voltage waveforms obtained by different detectors are also analyzed for comparison.

Microstructure and mechanical properties of as-cast(CuNi)100-xCox medium-entropy alloys

Microstructure and mechanical properties of non-equiatomic(CuNi)_(100-x)Co_(x)(x=15,20,25 and 30,at.%)medium-entropy alloys(MEAs)prepared by vacuum arc-melting were investigated.Results show that all the as-cast MEAs exhibit dual face-centered cubic(fcc)solid-solution phases with identical lattice constant,showing typical dendrite structure consisting of(Ni,Co)-rich phase in dendrites and Cu-rich phase in inter-dendrites.The positive enthalpy of mixing among Cu and Ni-Co elements is responsible for the segregation of Cu.With the increase of Co content,the volume fraction of(Ni,Co)-rich phase increases while the Cu-rich phase decreases,resulting in an increment of yield strength and a decrement of elongation for the(CuNi)_(100-x)Co_(x) MEAs.Nano-indentation test results show a great difference of microhardness between the two fcc phases of the MEAs.The measured microhardness value of the(Ni,Co)-rich phase is almost twofold as compared to that of the Cu-rich phase in all the(CuNi)_(100-x)Co_(x) MEAs.During the deformation of the MEAs,the Cu-rich phase bears the main plastic strain,whereas the(Ni,Co)-rich phase provides more pronounced strengthening.

Long-term Therapeutic Outcome and Prognostic Factors of Patients with Nasopharyngeal Carcinoma Receiving Intensity-modulated Radiotherapy: An Analysis of 608 Patients from Low-endemic Regions of China

Objective To evaluate the long-term outcome and prognostic factors of patients with nasopharyngeal carcinoma(NPC)from low-endemic regions of China who received definitive intensity-modulated radiation therapy(IMRT).Methods The clinical data from 608 patients with newly-diagnosed non-metastatic NPC who have received initial treatment at our cancer center from January,2008 to December,2013 were retrospectively reviewed.All patients received definitive IMRT,and 87.7%received platinum-based chemotherapy.Results The median follow-up duration was 51 months(follow-up rate,98.5%;range,10–106 months)for the entire cohort.The 5-year overall survival rate was 79.7%.The 5-year local relapse-free survival rate,regional relapse-free survival rate,distant metastasis-free survival rate and progression-free survival rate were 92.4%,93.3%,79.2%and 74.3%,respectively.A total of 153 patients had experienced treatment failure,with distant metastasis as the primary cause in 77.1%(118/153).Patients with T4 or N3 diseases had a significantly poorer prognosis than other subcategories.Stage T4 and N3 were closely associated with distant metastasis,with the metastatic rate of 29.3%and 45.5%,respectively.Conclusion IMRT provides patients with non-metastatic NPC with satisfactory long-term survival.Both T stage and N stage are important prognostic factors for NPC patients.Patients with T4 or N3 diseases have significantly increased distant metastatic rates and poor survival time.

Pinhole imaging to observe spatial jitters of a triple-pulse X-ray source on the Dragon-Ⅱ LIA

In high-energy flash radiography,scattered photons degrade the acquiring image,which limits the resolving power of interfaces and density of dense object.The application of large anti-scatter grid can reduce the scattered photons remarkably,but this requires a stable source position in order to reduce the loss of signal photons in the grid structure.The pinhole imaging technique is applied to observe spatial jitters of a triple-pulse radiographic source of a linear induction accelerator.Numerical simulations are conducted to analyze the imaging performance with the same or close parameters of the pinhole object and experimental alignment.Experiments are carried out to observe spatial jitters of the source between different measurements.Deviations of the source position between different pulses are measured in each experiment.

Effects of DEX on inflammation, oxidative stress and endothelial function in patients with ischemia-reperfusion injury caused by orthopedic tourniquet

Objective: To investigate the effects of dexmedetomidine on inflammation, oxidative stress and endothelial function in patients with ischemia-reperfusion injury caused by orthopedic tourniquet. Methods: According to random data table method, a total of 120 patients who were scheduled for lower limb surgery from August 2016 to April 2017 were divided into observation group and the control group, 60 cases in each group. Both groups were treated with subarachnoid block combined with epidural anesthesia, the observation group was given intravenous injection of DEX 10 min before the tourniquet (load dose 1 μg/kg), follwed by the maintenance dose of 0.5 μg/(kg?h) until the end of surgery;the control group were given intravenous injection of the same speed, equal volume of saline. The levels of inflammatory factors (IL-8, TNF-α), oxidative stress (SOD, MDA) and vascular endothelial function (ET-1, NO) were detected before tourniquet inflation (T0), 10 min (T1) , 60 min (T2) and 120 min (T3) after tourniquet release. Results: The levels of IL-8, TNF-α, SOD, MDA, ET-1 and NO in the control group and the observation group at time T0 were not statistically significant. Compared with T0, the levels of IL-8, TNF-α, MDA and ET-1 were significantly higher and the levels of SOD and NO were significantly lower in the two groups at T1, T2, T3 after tourniquet release, the difference was statistically significant. In addition, the levels of IL-8, TNF-α, MDA and ET-1 in the observation group were significantly lower than those in the control group and the levels of SOD and NO were significantly higher than those in the control group at T1, T2 and T3 after the tourniquet, the difference was significant. Conclusion: During the course of orthopedic surgery, DEX can alleviate the inflammatory response, oxidative stress and endothelial dysfunction induced by ischemia-reperfusion injury (I-R) caused by tourniquet, which is beneficial to the patient's postoperative recovery and has important clinical value.

Correlation of Th17 cell function with the inflammatory response and apoptosis in the course of prostatitis

Objective: To study the correlation of Th17 cell function with the inflammatory response and apoptosis in the course of prostatitis. Methods: A total of 128 patients with chronic prostatitis who were treated in our hospital between January 2015 and December 2016 were collected, and 50 healthy men who received physical examination in our hospital during the same period were selected as normal control group. The differences in Th17 cell ratio and IL-17 levels in peripheral blood, inflammatory factor levels in serum, and apoptosis gene expression in prostatic fluid were compared between the two groups. Pearson test was used to assess the correlation of Th17 cell function in peripheral blood with inflammation and apoptosis in patients with chronic prostatitis. Results: Th17 cell ratio and IL-17 level in peripheral blood of observation group were higher than those of normal control group;inflammatory factors IL-1β, IL-2, IL-8, TNF-α and M-CSF levels in serum were higher than those of normal control group;apoptosis gene BAX mRNA in prostatic fluid was higher than that of control group while anti-apoptosis genes Bcl-2, livin and hPEBP4 mRNA expression were lower than those of normal control group. Pearson test showed that Th17 cell ratio and IL-17 level in peripheral blood of patients with chronic prostatitis were positively correlated with IL-1β, IL-2, IL-8, TNF-α and M-CSF levels in serum as well as BAX mRNA expression in prostatic fluid, and negatively correlated with Bcl-2, livin and hPEBP4 mRNA expression in prostatic fluid. Conclusion: There is Th17 cell hyperfunction in patients with chronic prostatitis, and it is an important cause of the systemic inflammatory response and prostate cell apoptosis aggravation.

Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome

Background and Aims:The results of basic research implicate the vascular endothelial growth factor(VEGF)family as a potential target of hepatopulmonary syndrome(HPS).However,the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS.Therefore,we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies.Methods:Clinically,patients with chronic liver disease from two medical centers were enrolled and examined for HPS.Patients were divided into HPS,intrapulmonary vascular dilation[positive contrast-enhanced echocardiography(CEE)and normal oxygenation]and CEE-negative groups.Baseline information and perioperative clinical data were compared between HPS and non-HPS patients.Serum levels of VEGF family members and their receptors were measured.In parallel,HPS rats were established by common bile duct ligation.Liver,lung and serum samples were collected for the evaluation of pathophysiologic changes,as well as the expression levels of the above factors.Results:In HPS rats,all VEGF family members and their receptors underwent significant changes;however,only soluble VEGFR1(sFlt-1)and the sFlt-1/placental growth factor(PLGF)ratio were changed in almost the same manner as those in HPS patients.Furthermore,through feature selection and internal and external validation,sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients.Conclusions:Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

Conformational Behavior of Single Circular Semiflexible Polyelectrolyte in the Presence of Multivalent Counterions

Langevin dynamics simulations are employed to explore the effects of chain stiffness and electrostatic interaction(EI) on the conformational behavior of a circular semiflexible polyelectrolyte(CSPE) in presence of trivalent counterions.We investigate the effect of bending energy b and the dimensionless Bjerrum length A on the conformational behavior of the CSPE with a fixed chain length.The competition among the EIs,chain stiffness and entropy of the system leads to rich conformations for the CSPE.As the b is less than or equal to 50,The shape of the CSPE changes from a oblate ring to a rod at small A,then to a toroid at intermediate A,and finally to a globule at very large A.However,the globular conformation is not observed for large b.In addition,we find that the number of torus ring increases with A increase,while decreases with b increase.This study should be helpful in gaining insight into the conformational behaviour of charged biopolymer.

Carbide dissolution and austenite grain growth behavior of a new ultrahigh-strength stainless steel

The isothermal grain growth behavior for a new ultrahigh-strength stainless steel (UHSSS) is investigated in temperature range from 900 to 1150 ℃ and holding time range from 0 to 20 min. In the temperature range from 1000 to 1050 ℃, a bimodal grain size distribution was induced by different austenite grain growth rates which resulted from the weakened pin-ning effect by the partial dissolution of M6C particles along austenite grain boundaries. Further raising heating temperatures, M6C particles almost dissolved and the bimodal grain size distribution phenomenon became weakened, indicating that the austenite grain coarsening temperature of the new UHSSS was close to 1050 ℃. According to the present experimental results, a pragmatic mathematical model based on the Arrhenius equations was developed to predict the austenite grain growth process, which elaborated the influence of heating temperature, holding time and initial grain size on the austenite grain growth. Predictions for the new UHSSS presented a good agreement with experimental results.

Atomic-scale characterization of multiple precipitating species in a precipitation-hardened martensitic stainless steel

Multiple precipitating species in a 2.2 GPa grade precipitation-hardened martensitic stainless steel with balanced ductility were characterized at atomic scale by atom probe tomography.The results indicated that the clustering of solute atoms was promoted with progressive aging treatments.(Cr,Mo)-rich carbide(M_(2)C)precipitated at the linear dislocations in the as-aged steels.Obvious segregation of Cr,Mo,and C at phase boundaries favored the precipitation of carbide and caused the formation of Cr-lean domains.Spinodal decomposition of martensitic matrix during aging led to the substantial precipitation of fine Cr-rich(α′Cr)phase.Compared with the first aging treated samples,a synergistic enhancement of both strength and ductility of the secondary aging treated(SAT)samples was primarily ascribed to the enhanced precipitation of Cr-rich phase.Additionally,Ni-rich filmy reversed austenite precipitated at the lath boundary,which was beneficial to the ductility of SAT samples.

A Simple and Quick Screening Method for Intrapulmonary Vascular Dilation in Cirrhotic Patients Based on Machine Learning

Background and Aims:Screening for hepatopulmonary syndrome in cirrhotic patients is limited due to the need to perform contrast enhanced echocardiography(CEE)and arterial blood gas(ABG)analysis.We aimed to develop a simple and quick method to screen for the presence of intrapulmonary vascular dilation(IPVD)using noninvasive and easily available variables with machine learning(ML)algorithms.Methods:Cirrhotic patients were enrolled from our hospital.All eligible patients underwent CEE,ABG analysis and physical examination.We developed a twostep model based on three ML algorithms,namely,adaptive boosting(termed AdaBoost),gradient boosting decision tree(termed GBDT)and eXtreme gradient boosting(termed Xgboost).Noninvasive variables were input in the first step(the NI model),and for the second step(the NIBG model),a combination of noninvasive variables and ABG results were used.Model performance was determined by the area under the curve of receiver operating characteristics(AUCROCs),precision,recall,F1-score and accuracy.Results:A total of 193 cirrhotic patients were ultimately analyzed.The AUCROCs of the NI and NIBG models were 0.850(0.738–0.962)and 0.867(0.760–0.973),respectively,and both had an accuracy of 87.2%.For both negative and positive cases,the recall values of the NI and NIBG models were both 0.867(0.760–0.973)and 0.875(0.771–0.979),respectively,and the precisions were 0.813(0.690–0.935)and 0.913(0.825–1.000),respectively.Conclusions:We developed a two-step model based on ML using noninvasive variables and ABG results to screen for the presence of IPVD in cirrhotic patients.This model may partly solve the problem of limited access to CEE and ABG by a large numbers of cirrhotic patients.