The impact of female sex hormones on cardiovascular disease:from mechanisms to hormone therapy

Cardiovascular disease remains the leading cause of mortality in women,yet it has not raised the awareness from the public.The pathogenesis of cardiovascular disease differs significantly between females and males concerning the effect of sex hormones.Estrogen and progestogen impact cardiovascular system through genomic and non-genomic effects.Before menopause,cardiovascular protective effects of estrogens have been well described.Progestogens were often used in combination with estrogens in hormone therapy.Fluctuations in sex hormone levels,particularly estrogen deficiency,were considered the specific risk factor in women’s cardiovascular disease.However,considerable heterogeneity in the impact of hormone therapy was observed in clinical trials.The heterogeneity is likely closely associated with factors such as the initial time,administration route,dosage,and formulation of hormone therapy.This review will delve into the pathogenesis and hormone therapy,summarizing the effect of female sex hormones on hypertension,pre-eclampsia,coronary heart disease,heart failure with preserved ejection fraction,and cardiovascular risk factors specific to women.

Single-cell transcriptome profiling of sepsis identifies HLA-DR^(low)S100A^(high)monocytes with immunosuppressive function

Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.

A new approach for flow simulation in complex hydraulic fracture morphology and its application:Fracture connection element method

Efficient flow simulation and optimization methods of hydraulic fracture morphology in unconventional reservoirs are effective ways to enhance oil/gas recovery.Based on the connection element method(CEM)and distribution of stimulated reservoir volume,the complex hydraulic fracture morphology was accurately described using heterogeneous node connection system.Then a new fracture connection element method(FCEM)for fluid flow in stimulated unconventional reservoirs with complex hydraulic fracture morphology was proposed.In the proposed FCEM,the arrangement of dense nodes in the stimulated area and sparse nodes in the unstimulated area ensures the calculation accuracy and efficiency.The key parameter,transmissibility,was also modified according to the strong heterogeneity of stimulated reservoirs.The finite difference and semi-analytical tracking were used to accurately solve the pressure and saturation distribution between nodes.The FCEM is validated by comparing with traditional numerical simulation method,and the results show that the bottom hole pressure simulated by the FCEM is consistent with the results from traditional numerical simulation method,and the matching rate is larger than 95%.The proposed FCEM was also used in the optimization of fracturing parameters by coupling the hydraulic fracture propagation method and intelligent optimization algorithm.The integrated intelligent optimization approach for multi-parameters,such as perforation number,perforation location,and displacement in hydraulic fracturing is proposed.The proposed approach was applied in a shale gas reservoir,and the result shows that the optimized perforation location and morphology distribution are related to the distribution of porosity/permeability.When the perforation location and displacement are optimized with the same fracture number,NPV increases by 70.58%,which greatly improves the economic benefits of unconventional reservoirs.This work provides a new way for flow simulation and optimization of hydraulic fracture morphology of multi-fractured horizontal wells in unconventional reservoirs.

Diagnostic accuracy of a deep learning approach to calculate FFR from coronary CT angiography

Background The computational fluid dynamics(CFD)approach has been frequently applied to compute the fractional flow reserve(FFR)using computed tomography angiography(CTA).This technique is efficient.We developed the DEEPVESSEL-FFR platform using the emerging deep learning technique to calculate the FFR value out of CTA images in five minutes.This study is to evaluate the DEEPVESSEL-FFR platform using the emerging deep learning technique to calculate the FFR value from CTA images as an efficient method.Methods A single-center,prospective study was conducted and 63 patients were enrolled for the evaluation of the diagnostic performance of DEEPVESSEL-FFR.Automatic quantification method for the three-dimensional coronary arterial geometry and the deep learning based prediction of FFR were developed to assess the ischemic risk of the stenotic coronary arteries.Diagnostic performance of the DEEPVESSEL-FFR was assessed by using wire-based FFR as reference standard.The primary evaluation factor was defined by using the area under receiver-operation characteristics curve(AUC)analysis.Results For per-patient level,taking the cut-off value<0.8 referring to the FFR measurement,DEEPVESSEL-FFR presented higher diagnostic performance in determining ischemia-related lesions with area under the curve of 0.928 compare to CTA stenotic severity 0.664.DEEPVESSEL-FFR correlated with FFR(R=0.686,P<0.001),with a mean di&ference of-0.006士0.0091(P=0.619).The secondary evaluation factors,indicating per vessel accuracy,sensitivity,specificity,positive predictive value,and negative predictive value were 87.3%,97.14%,75%,82.93%,and 95.45%,respectively.Conclusion DEEPVESSEL-FFR is a novel method that allows efficient assessment of the functional significance of coronary stenosis.

New predictors of in-stent restenosis in patients with diabetes mellitus undergoing percutaneous coronary intervention with drug-eluting stent

Background Percutaneous coronary intervention （PCI） had become the major therapeutic procedure for coronary artery disease （CAD）, but the high rate of in-stent restenosis （ISR） still remained an unsolved clinical problem in clinical practice. Increasing evidences suggested that diabetes mellitus （DM） was a major risk factor for ISR, but the risk predictors of ISR in CAD patients with DM had not been well characterized. The aim of this study was to investigate the clinical and angiographic characteristic predictors significantly associated with the occurrence of ISR in diabetic patients following coronary stenting with drug-eluting stent （DES）. Methods A total of 920 patients with diabetes who diagnosed CAD and underwent coronary DES implantation at Beijing Anzhen Hospital in China were consecutively enrolled from January 2012 to December 2012. Of these, 440 patients underwent the second angiography within ≥ 6 months due to the progression of treated target lesions. Finally, 368 of these patients who met the inclusion and exclusion criteria were followed up by angiography after baseline PCI. According to whether ISR was detected at follow-up angiography, patients were divided into the ISR group （n = 74） and the non-ISR group （n = 294）. The independent predictors of ISR in patients with DM were explored by multivariate Cox＇s proportional hazards regression models. Results A total of 368 patients （260 women and 108 men） with a mean ages of 58.71 ± 10.25 years were finally enrolled in this study. Of these, ISR occurred in 74/368 diabetic patients （20.11%） by follow-up angiography. Univariate analysis showed that most baseline characteristics of the ISR and non-ISR group were similar. Patients in the ISR group had significantly higher serum very low density lipoprotein cholesterol （VLDL-C）, triglyceride （TG） and uric acid （UA） levels, more numbers of target vessel lesions, higher prevalence of multi-vessel disease, higher SYNTAX score, higher rate of previous but lower rate of drinking compared with patients in the non-ISR group. The independent predictors of ISR in patients with DM after DES implantation included VLDL-C （HR = 1.85, 95% CI： 1.24-2.77, P = 0.002）, UA （per 50 μmol/L increments, HR = 1.19, 95% CI： 1.05 1.34, P = 0.006）, SYNTAX score （per 5 increments, HR = 1.34, 95% CI： 1.03-1.74, P = 0.031） and the history ofPCI （HR = 3.43, 95% CI： 1.57-7.80, P = 0.003） by the multivariate Cox＇s proportional hazards regression analysis. Conclusions The increased serum VLDL-C and UA level, higher SYNTAX score and the history of previous PCI were independent predictors of ISR in patients with DM after coronary DES implantation. It provided new evidence for physi- cians to take measures to lower the risk oflSR for the better management of diabetic patients after PCI.

Elevated IL-37 levels in the plasma of patients with severe coronary arterycalcification

Background Coronary artery calcification （CAC） is a predictor of cardiovascular events and plaque burden and is closely associatedwith chronic inflammation. Intedeukin （IL）-37 is a newly discovered member of the IL-1 family and is considered an anti-inflammatorycytokine. Our recent study on mice indicated that IL-37 could attenuate atherosclerosis and vascular calcification, which suggests that IL-37could be associated with the development of atherosclerosis and related diseases. The aim of this study was to investigate if IL-37 plays arole in the progression of CAC in patients. Methods Two hundred participants with suspected cardiovascular disease were recruited. Thelevels of plasma IL-37, osteoprotegerin （OPG）, hypersensitive C-reactive protein （hsCRP） together with other biochemical parameters weremeasured, and a coronary calcium assessment was carried out by multi-detector row CT. A score of 〈 10 AU （Agatston units） denotes anabsence of CAC, a score of 11-100 AU denotes mild CAC, 101-400 denotes moderate CAC, and 〉 400 AU denotes severe CAC. ResultsOur initial data showed that there were no apparent differences in plasma IL-37 levels among patients with or without mild or moderate CAC.However, IL-37 levels were significantly increased in patients with severe CAC （P 〈 0.001）. Similar results were observed for plasma OPGand hsCRP levels. When IL-37 levels in patients with severe calcification were compared with that in all of the other non-severe CAC groups,it became apparent that there was a significant positive correlation between IL-37 level and severe CAC （r = 0.360, P 〈 0.001; OR = 1.033）using Spearrnan＇s correlation and binary logistic regression analysis. Conclusions This study demonstrates that the anti-inflammatory cy-tokine IL-37 is associated with high coronary calcium levels, suggesting that IL-37 expression may be caused by the activation ofinf/amma-tion and that IL-37 might become a predictor of severe CAC in the future, which requires further investigation.

Obstructive sleep apnea is associated with severity and long-term prognosis of acute coronary syndrome

Background Obstructive sleep apnea （OSA） is a common disease in patients with acute coronary syndrome （ACS） and associated with an increased risk of fatal and nonfatal cardiovascular events. However, most patients in previous study were treated with bare metal stents and the sample sizes were relatively low. The goal of this study was to evaluate the influence of OSA on the severity and prognosis of patients admitted for ACS. Methods In this prospective cohort study, we enrolled patients with ACS who were hospitalized for coronary angiogram/percutaneous coronary intervention and undergone polysomnography. We divided the patients into two groups： moderate to severe OSA group [apnea-hypopnea index （AHI） 〉 15 events/h] and control group （AHI ≤ 15 events/h）. They were followed up for up 32 months. Then, we compared the ACS severity and long-term major adverse cardiovascular events （MACE） in patients with different severity of OSA. Results Five hundred and twenty nine patients were included in the final analysis, with 76% of them being men and an average age of 59 ＋ 10 years. The overall mean AHI is 29 ± 19 events/h, 70.5% of them （373/529） being with moderate to severe OSA and 29.5% （156/529） assign into control group. Compared with controls, patients with moderate or severe OSA exhibited a higher prevalence of hypertension as well as higher body mass index, SYNTAX score, Epworth score and length of hospitalization. With a median follow-up duration of 30 months, accumulative rate of MACE was also higher in patients with moderate or severe OSA than that in the control group （8.6% vs. 3.2%, P = 0.028）. After adjusting for baseline confounders by cox regression model, moderate to severe OSA was an independent risk factor of long-term MACE （P = 0.047, HR = 1.618, 95% CI： 1.069-3.869）. Conclusions The results of this study demonstrate that moderate or severe OSA is correlated with disease severity and associated with worse long-term prognosis in ACS patients. The results raising the possibility that early diagnose and interventions of OSA could improve long-term outcomes in ACS patients.

A deep-learning-based prediction method of the estimated ultimate recovery(EUR)of shale gas wells

The estimated ultimate recovery(EUR)of shale gas wells is influenced by many factors,and the accurate prediction still faces certain challenges.As an artificial intelligence algorithm,deep learning yields notable advantages in nonlinear regression.Therefore,it is feasible to predict the EUR of shale gas wells based on a deep-learning algorithm.In this paper,according to geological evaluation data,hydraulic fracturing data,production data and EUR evaluation results of 282 wells in the WY shale gas field,a deep-learning-based algorithm for EUR evaluation of shale gas wells was designed and realized.First,the existing EUR evaluation methods of shale gas wells and the deep feedforward neural network algorithm was systematically analyzed.Second,the technical process of a deep-learning-based algorithm for EUR prediction of shale gas wells was designed.Finally,by means of real data obtained from the WY shale gas field,several different cases were applied to testify the validity and accuracy of the proposed approach.The results show that the EUR prediction with high accuracy.In addition,the results are affected by the variety and number of input parameters,the network structure and hyperparameters.The proposed approach can be extended to other shale fields using the similar technic process.

The serum anion gap is associated with disease severity and all-cause mortality in coronary artery disease

Objective To evaluate the associations between the serum anion gap （AG） with the severity and prognosis of coronary artery disease （CAD）. Methods We measured serum electrolytes in 18,115 CAD patients indicated by coronary angiography. The serum AG was calculated according to the equation： AG = Na^＋ [（mmol/L） ＋ K^＋ （mmol/L）] - [Cl^- （mmol/L） ＋ HCO3^- （mmol/L）]. Results A total of 4510 （24.9%） participants had their AG levels greater than 16 mmol/L. The serum AG was independently associated with measures of CAD severity, including more severe clinical types of CAD （P 〈 0.001） and worse cardiac function （P = 0.004）. Patients in the 4th quartile of serum AG （≥ 15.92 mmol/L） had a 5.171-fold increased risk of 30 days all-cause death （P 〈 0.001）. This association was robust, even after adjustment for age, sex, evaluated glomerular filtration rate [hazard ratio （HR）： 4.861, 95% confidence interval （CI）： 2.150–10.993, P 〈 0.001], clinical diagnosis, severity of coronary artery stenosis, cardiac function grades, and other confounders （HR： 3.318, 95% CI： 1.76–2.27, P = 0.009）. Conclusion In this large population-based study, our findings reveal a high percentage of increased serum AG in CAD. Higher AG is associated with more severe clinical types of CAD and worse cardiac function. Furthermore, the increased serum AG is an independent, significant, and strong predictor of all-cause mortality. These findings support a role for the serum AG in the risk-stratification of CAD.

Effects and mechanisms of glucose-insulin-potassium on post-procedural myocardial injury after percutaneous coronary intervention

Objective To evaluate the effects and mechanisms of glucose-insulin-potassium(GIK)on post-procedural myocardial injury(PMI)after percutaneous coronary intervention(PCI).Methods A total of 200 non-diabetic patients with documented coronary heart disease(CHD)were divided into the Group GIK and Group G,with 100 patients in each group.Patients in Group G were given intravenous infusion of glucose solution 2 hours before PCI.As compared,patients in Group GIK were given GIK.Results Both post-procedural creatine phosphokinase isoenzyme MB(CK-MB;62.1±47.8 vs.48.8±52.6 U/L,P=0.007)and cTnI(0.68±0.83 vs.0.19±0.24 ng/mL,P<0.001)in Group GIK were significantly higher than those in Group G.In Group G,9.0%and 4.0%of patients had post-procedural increases in CK-MB 1-3 times and>3 times,which were significantly lower than those in Group GIK(14.0%and 7.0%,respectively;all P values<0.01);13.0%and 7.0%of patients had post-procedural increases in cTnI 1-3 times and>3 times,which were also significantly lower than those in Group GIK(21.0%and 13.0%,respectively;all P<0.001).Pre-procedural(10.2±4.5 vs.5.1±6.3,P<0.001)and post-procedural rapid blood glucose(RBG)levels(8.9±3.9 vs.5.3±5.6,P<0.001)in Group G were higher than those in Group GIK.In adjusted logistic models,usage of GIK(compared with glucose solution)remained significantly and independently associated with higher risk of post-procedural increases in both CK-MB and cTnI levels>3 times.Furthermore,pre-procedural RBG levels<5.0mmol/L were significantly associated with higher risk of post-procedural increases in both CK-MB and cTnI levels.Conclusions In non-diabetic patients with CHD,the administration of GIK may increase the risk of PMI due to hypoglycemia induced by GIK.

Optical coherence tomography-guided excimer laser coronary angioplasty in overlapping stents with severe under-expansion and underlying calcification

Excimer laser coronary angioplasty(ELCA)modifies atherosclerotic plaques through its photochemical,photothermal and photodynamic characteristics,while making up for the limitations of intimal disassembly and restenosis of balloon angioplasty without causing significant damage.The American Food and Drug Administration approved of the first clinical application of ELCA in 1992.Since then,ELCA has been used as an adjunct therapy in the treatment of various subsets of coronary artery lesions.ELCA considered to be a relatively safe and effective technique for coronary lesions when routine angioplasty is technically insufficient.

Gut microbiota diversity and composition in predicting immunotherapy response and immunotherapy-related colitis in melanoma patients:A systematic review

BACKGROUND Gut microbiome(GM)composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy(ICB)and of ICBrelated colitis.AIM To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB.METHODS The review protocol was registered in PROSPERO:CRD42021228018.From a total of 300 studies,nine studies met inclusion criteria.Two studies were phase I clinical trials,while the remainder were prospective observational studies.All but one study has moderate risk of bias.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationanalysis.com).RESULTS Fecal samples enriched in Firmicutes phylum were associated with good response to ICB,whereas the Bacteroidales family was associated with poor response to ICB.Samples with greater GM diversity were associated with more favorable response to ICB[hazard ratio(HR)=3.57,95%confidence interval=1.02-12.52,P<0.05].Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis(P<0.01)whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis(P<0.05).Overall,there was limited concordance in the organisms in the GM identified to be associated with response to ICB,and studies evaluating GM diversity showed conflicting results.CONCLUSION This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients.

The sirtuin family in health and disease

Sirtuins(SIRTs)are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes,and are involved in numerous biological processes.Currently,seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified.Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions.Notably,this protein family plays a variety of important roles in cellular biology such as inflammation,metabolism,oxidative stress,and apoptosis,etc.,thus,it is considered a potential therapeutic target for different kinds of pathologies including cancer,cardiovascular disease,respiratory disease,and other conditions.Moreover,identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules,which can modify SIRT activity.Furthermore,several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples,and supplementation of SIRT modulators might have diverse impact on physiological function in different participants.In this review,we introduce the history and structure of the SIRT protein family,discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family,elaborate on the regulatory roles of SIRTs in human disease,summarize SIRT inhibitors and activators,and review related clinical studies.

Electrolytic silicon/graphite composite from SiO_(2)/graphite porous electrode in molten salts as a negative electrode material for lithium-ion batteries

Nano-silicon(nano-Si)and its composites have been regarded as the most promising negative electrode materials for producing the next-generation Li-ion batteries(LIBs),due to their ultrahigh theoretical capacity.However,the commercial applications of nano Si-based negative electrode materials are constrained by the low cycling stability and high costs.The molten salt electrolysis of SiO_(2)is proven to be suitable to produce nano-Si with the advantages of in-situ microstructure control possibilities,cheap affordability and scale-up process capability.Therefore,an economical approach for electrolysis,with a SiO_(2)/graphite porous electrode as cathode,is adopted to produce nano-Si/graphite composite negative electrode materials(SGNM)in this study.The electrolytic product of the optimized porous electrode is taken as the negative electrode materials for LIBs,and it offers a capacity of 733.2 mAh·g^(-1)and an initial coulombic efficiency of 86.8%in a coin-type cell.Moreover,the capacity of the SGNM retained 74.1%of the initial discharging capacity after 50 cycles at 0.2C,which is significantly higher than that of the simple mixture of silicon and graphite obtained from the formation of silicon carbide(SiC)between nano-Si and graphite particles.Notably,this new approach can be applied to a large-scale production.

Synthesis and densification of zirconium diboride prepared by carbothermal reduction

Using boron powder as additive, the preparation of zirconium diboride(ZrB 2) by carbothermal reduction was investigated. The results show that the carbothermal reduction cannot be completely done until the temperature is more than 1900 ℃. The ZrB2 particles prepared without boron(B) additive at 1900 ℃ for 3 h are rodlike and show a preferential grain growth along [001] direction. B additive changes the heat effect of the raw materials. With B additive, the morphology of ZrB2 particles turns to be regular shape. The average particle size is about 3.6 μm with 2.5 wt% B additives. With more B additive, the shape of particles turns to be round like and the average particle size is decreased to 2.3 μm when 5 wt% B is added. The existence of oxides in grain boundary is a key factor to keep ZrB2 ceramic from deep densification. Using ZrB2 powder prepared with 5 wt% B additives, by controlling carbon content in ZrB2 powder, ZrB2 ceramic with 93%relative density is hot-pressed.