Aortic valve replacement reduces mortality in moderate aortic stenosis:a systematic review and meta-analysis

BACKGROUND With the introduction of transcatheter aortic valve replacement and an evolving understanding of the natural progression and history of aortic stenosis,the potential for earlier intervention in appropriate patients is promising;however,the benefit of aortic valve replacement in moderate aortic stenosis remains unclear.METHODS Pubmed,Embase,and the Cochrane Library databases were searched up until 30th of December 2021 using keywords including moderate aortic stenosis and aortic valve replacement.Studies reporting all-cause mortality and outcomes in early aortic valve replacement(AVR)compared to conservative management in patients with moderate aortic stenosis were included.Hazard ratios were generated using random-effects meta-analysis to determine effect estimates.RESULTS 3470 publications were screened with title and abstract review,which left 169 articles for full-text review.Of these studies,7 met inclusion criteria and were included,totalling 4,827 patients.All studies treated AVR as a time-dependent co-variable in cox-regression multivariate analysis of all-cause mortality.Intervention with surgical or transcatheter AVR was associated with a 45% decreased risk of all-cause mortality(HR=0.55[0.42-0.68],I2=51.5%,P<0.001).All studies were representative of the overall cohort with appropriate sample sizes,with no evidence of publication,detection,or information biases in any of the studies.CONCLUSION In this systematic review and meta-analysis,we report a 45% reduction in all-cause mortality in patients with moderate aortic stenosis who were treated with early aortic valve replacement compared to a strategy of conservative management.Randomised control trials are awaited to determine the utility of AVR in moderate aortic stenosis.

Bleeding outcomes after non-emergency percutaneous coronary intervention in the very elderly

Background Octogenarians constitute an increasing proportion of patients presenting for non-emergency percutaneous coronary intervention （PCI）. Methods This study evaluated the in-hospital procedural characteristics and outcomes, including the bleeding events of 293 octogenarians presenting between January 2010 and December 2012 for non-emergency PCI to a single large volume tertiary care Aus- tralian center. Comparisons were made with 293 consecutive patients aged less than or equal to 60 years, whose lesions were matched with the octogenarians. Results Non-ST elevation myocardial infarction was the most frequent indication for non-emergency PCI in octoge- narians. Compared to the younger cohort, they had a higher prevalence of co-morbidities and more complex coronary disease, comprising more type C and calcified lesions. Peri-procedural use of low molecular weight heparin （LMWH; 1.0% vs. 5.8%; P 〈 0.001） and glycopro- tein IIb/IIIa inhibitors （2.1% vs. 9.6%; P 〈 0.001） was lower, while femoral arterial access was used more commonly than in younger patients （80.9% vs. 67.6%; P 〈 0.001）. Overall, there was a non-significant trend towards higher incidence of all bleeding events in the elderly （9.2% vs. 5.8%; P = 0.12）. There was no significant difference in access site or non-access site bleeding and major or minor bleeding between the two cohorts. Sub-analysis did not reveal any significant influence on bleeding rates by the use of LMWH, glycoprotein IIb/IIIa inhibitors or femoral arterial access. In addition, there were no significant differences in the rates of in-hospital mortality, stroke or acute stent thrombosis between the two groups. Conclusions In this single center study, we did not observe significant increases in adverse in-hospital outcomes including the incidence of bleeding in octogenarians undergoing non-emergency PCI.

Lipogenic effects of androgen signaling in normal and malignant prostate

Prostate cancer is an androgen-dependent cancer with unique metabolic features compared to many other solid tumors,and typically does not exhibit the“Warburg effect”.During malignant transformation,an early metabolic switch diverts the dependence of normal prostate cells on aerobic glycolysis for the synthesis of and secretion of citrate towards a more energetically favorable metabolic phenotype,whereby citrate is actively oxidised for energy and biosynthetic processes(i.e.de novo lipogenesis).It is now clear that lipid metabolism is one of the key androgen-regulated processes in prostate cells and alterations in lipid metabolism are a hallmark of prostate cancer,whereby increased de novo lipogenesis accompanied by overexpression of lipid metabolic genes are characteristic of primary and advanced disease.Despite recent advances in our understanding of altered lipid metabolism in prostate tumorigenesis and cancer progression,the intermediary metabolism of the normal prostate and its relationship to androgen signaling remains poorly understood.In this review,we discuss the fundamental metabolic relationships that are distinctive in normal versus malignant prostate tissues,and the role of androgens in the regulation of lipid metabolism at different stages of prostate tumorigenesis.

The utility of coronary computed tomography angiography in elderly patients

Background Coronary computed tomography angiography(CCTA)is often avoided in elderly patients due to a presumption that a high proportion of patients will have heavily calcified plaque limiting an accurate assessment.We sought to assess the image quality,luminal stenosis and utility of CCTA in elderly patients with suspected coronary artery disease(CAD)and stable chest pain.Methods Retrospective analysis of elderly patients(>75 years)who underwent 320-detector row CCTA between 2012–2017 at MonashHeart.The CCTA was analysed for degree maximal coronary stenosis by CAD-RADS classification,image quality by a 5-point Likert score(1-poor,2-adequate,3-good,4-very good,5-excellent)and presence of artefact limiting interpretability.Results 1011 elderly patients(62%females,78.8±3.3 years)were studied.Cardiovascular risk factor prevalence included:hypertension(65%),hyperlipidaemia(48%),diabetes(19%)and smoking(21%).The CCTA was evaluable in 68%of patients which included 52%with non-obstructive CAD(<50%stenosis),48%with obstructive CAD(>50%)stenosis.Mean Likert score was 3.1±0.6 corresponding to good image quality.Of the 323(32%)of patients with a non-interpretable CCTA,80%were due to calcified plaque and 20%due to motion artefact.Male gender(P=0.009),age(P=0.02),excess motion(P<0.01)and diabetes mellitus(P=0.03)were associated with non-interpretable CCTA.Conclusion Although CCTA is a feasible non-invasive tool for assessment of elderly patients with stable chest pain,clinicians should still be cautious about referring elderly patients for CCTA.Patients who are male,diabetic and>78 years of age are significantly less likely to have interpretable scans.

In vitro and in vivo evaluation of the antiangiogenic activities of Trigonella foenum-graecum extracts

Objective: To assess the antiangiogcnic activity of fenugreek.Methods: Different fractions of fenugreek crude extracts were prepared and their antiangiogenic properties were assessed using the ex vivo rat aortic ring assay and in vivo chicken embryo chorioallantoic membrane(CAM) assay. They were investigated for their direct cytotoxic activity in the MCF7 cells using the MTT assay.Results: The ethanol extract showed 100% inhibition of blood vessel outgrowth from primary tissue explants in the rat aortic ring assay at a concentration of 100μg/mL while the other extracts did not show significant antiangiogenic activity. The ethanol extract was therefore investigated at varying concentrations and exhibited a significant dose dependent effect. The CAM assay coincided with the results of the aortic ring assay as ethanol extract showed a significant inhibition of formation of new blood vessels. The extracts only showed anti-proliferative activity at the highest concentration of 400μg/mL towards MCF7 breast cancer cell lines in the MTT assay.Conclusions: Findings of the both assays confirmed that the ethanol extract inhibited vascularization significantly. Further studies on the ethanol extract would be beneficial in isolating the active ingredient responsible for the inhibition.

The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance.In osteoblasts(OBs),insulin signaling plays a crucial role in the control of systemic glucose homeostasis.We utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary states.Compared to the controls,chow-fed Rptorob−/−mice had substantially less fat mass and exhibited adipocyte hyperplasia.Remarkably,upon feeding with high-fat diet,mice with pre-and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels,increased glucose tolerance and insulin sensitivity.This leanness and resistance to weight gain was not attributable to changes in food intake,physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate flexibility.RNA-seq revealed an increase in glycolysis and skeletal insulin signaling pathways,which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptorknockout osteoblasts.Collectively,these findings point to a critical role for the mTORC1 complex in the skeletal regulation of wholebody glucose metabolism and the skeletal development of insulin resistance.

Pathophysiology of obesity and its associated diseases

The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver diseases. Adipose tissue can also secrete adipokines and inflammatory cytokines to affect the local microenvironment,induce insulin resistance, hyperglycemia, and activate associated inflammatory signaling pathways. This further exacerbates the development and progression of obesity-associated diseases. Although some progress in the treatment of obesity has been achieved in preclinical and clinical studies, the progression and pathogenesis of obesity-induced diseases are complex and unclear. We still need to understand their links to better guide the treatment of obesity and associated diseases. In this review, we review the links between obesity and other diseases, with a view to improve the future management and treatment of obesity and its co-morbidities.

Effect of coronary artery dynamics on the wall shear stress vector field topological skeleton in fluid–structure interaction analyses

In this paper,we investigate the impact of coronary artery dynamics on the wall shear stress(WSS)vector field topology by comparing fluid–structure interaction(FSI)and computational fluid dynamics(CFD)techniques.As one of the most common causes of death globally,coronary artery disease(CAD)is a significant economic burden;however,novel approaches are still needed to improve our ability to predict its progression.FSI can include the unique dynamical factors present in the coronary vasculature.To investigate the impact of these dynamical factors,we study an idealized artery model with sequential stenosis.The transient simulations made use of the hyperelastic artery and lipid constitutive equations,non‐Newtonian blood viscosity,and the characteristic out‐of‐phase pressure and velocity distribution of the left anterior descending coronary artery.We compare changes to established metrics of time‐averaged WSS(TAWSS)and the oscillatory shear index(OSI)to changes in the emerging WSS divergence,calculated here in a modified version to handle the deforming mesh of FSI simulations.Results suggest that the motion of the artery can impact downstream patterns in both divergence and OSI.WSS magnitude is also decreased by up to 57%due to motion in some regions.WSS divergence patterns varied most significantly between simulations over the systolic period,the time of the largest displacements.This investigation highlights that coronary dynamics could impact markers of potential CAD progression and warrants further detailed investigations in more diverse geometries and patient cases.

Prevalence and associated factors of myocardial involvement in Duchenne muscular dystrophy patients in the first decade of life

To the Editor:Duchenne muscular dystrophy(DMD)is a rare X-linked inherited disorder caused by dystrophin deficiency,which results in sarcolemmal fragility and degeneration of skeletal and cardiac myocytes.[1]Cardiac involvement ismanifested asDMDcardiomyopathy,which is the leading cause of disease-related morbidity and mortality among DMD patients.

Ultrathin monolithic 3D printed optical coherence tomography endoscopy for preclinical and clinical use

Preclinical and clinical diagnostics increasingly rely on techniques to visualize internal organs at high resolution via endoscopes.Miniaturized endoscopic probes are necessary for imaging small luminal or delicate organs without causing trauma to tissue.However,current fabrication methods limit the imaging performance of highly miniaturized probes,restricting their widespread application.To overcome this limitation,we developed a novel ultrathin probe fabrication technique that utilizes 3D microprinting to reliably create side-facing freeform micro-optics(<130μm diameter)on single-mode fibers.Using this technique,we built a fully functional ultrathin aberration-corrected optical coherence tomography probe.This is the smallest freeform 3D imaging probe yet reported,with a diameter of 0.457 mm,including the catheter sheath.We demonstrated image quality and mechanical flexibility by imaging atherosclerotic human and mouse arteries.The ability to provide microstructural information with the smallest optical coherence tomography catheter opens a gateway for novel minimally invasive applications in disease.

A high-throughput screening assay for eukaryotic elongation factor 2 kinase inhibitors

Eukaryotic elongation factor 2 kinase (eEF2K) inhibitors may aid in the development of new therapeutic agents to combat cancer. Purified human eEF2K was obtained from an Escherichia coli expression system and a luminescence-based high-throughput screening (HTS) assay was developed using MH-1 peptide as the substrate. The luminescent readouts correlated with the amount of adenosine triphosphate remaining in the kinase reaction. This method was applied to a large-scale screening campaign against a diverse compound library and subsequent confirmation studies. Nine initial hits showing inhibitory activities on eEF2K were identified from 56,000 synthetic compounds during the HTS campaign, of which, five were chosen to test their effects in cancer cell lines. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND

The long and winding road:homeostatic and disordered haematopoietic microenvironmental niches:a narrative review

Haematopoietic microenvironmental niches have been described as the‘gatekeepers’for the blood and immune systems.These niches change during ontogeny,with the bone marrow becoming the predominant site of haematopoiesis in post-natal life under steady state conditions.To determine the structure and function of different haematopoietic microenvironmental niches,it is essential to clearly define specific haematopoietic stem and progenitor cell subsets during ontogeny and to understand their temporal appearance and anatomical positioning.A variety of haematopoietic and non-haematopoietic cells contribute to haematopoietic stem and progenitor cell niches.The latter is reported to include endothelial cells and mesenchymal stromal cells(MSCs),skeletal stem cells and/or C-X-C motif chemokine ligand 12-abundant-reticular cell populations,which form crucial components of these microenvironments under homeostatic conditions.Dysregulation or deterioration of such cells contributes to significant clinical disorders and diseases worldwide and is associated with the ageing process.A critical appraisal of these issues and of the roles of MSC/C-X-C motif chemokine ligand 12-abundant-reticular cells and the more recently identified skeletal stem cell subsets in bone marrow haematopoietic niche function under homeostatic conditions and during ageing will form the basis of this research review.In the context of haematopoiesis,clinical translation will deal with lessons learned from the vast experience garnered from the development and use of MSC therapies to treat graft versus host disease in the context of allogeneic haematopoietic transplants,the recent application of these MSC therapies to treating emerging and severe coronavirus disease 2019(COVID-19)infections,and,given that skeletal stem cell ageing is one proposed driver for haematopoietic ageing,the potential contributions of these stem cells to haematopoiesis in healthy bone marrow and the benefits and challenges of using this knowledge for rejuvenating the age-compromised bone marrow haematopoietic niches and restoring haematopoiesis.

A simple and inexpensive enteric-coated capsule for delivery of acid-labile macromolecules to the small intestine

Understanding the ecology of the gastrointestinal tract and the impact of the contents on the host mucosa is emerging as an important area for defining both wellness and susceptibility to disease. Targeted delivery of drugs to treat specific small intestinal disorders such as small bowel bacterial overgrowth and targeting molecules to interrogate or to deliver vaccines to the remote regions of the small intestine has proven difficult. There is an unmet need for methodologies to release probes/drugs to remote regions of the gastrointestinal tract in furthering our understanding of gut health and pathogenesis. In order to address this concern, we need to know how the regional delivery of a surrogate labeled test compound is handled and in turn, if delivered locally as a liquid or powder, the dynamics of its subsequent handling and metabolism. In the studies we report on in this paper, we chose ^13 C sodium acetate（^13C-acetate）, which is a stable isotope probe that once absorbed in the small intestine can be readily measured non-invasively by collection and analysis of ^13CO2 in the breath. This would provide information of gastric emptying rates and an indication of the site of release and absorptive capacity. In a series of in vitro and in vivo pig experiments, we assessed the enteric-protective properties of a commercially available polymer EUDRAGIT L100-55 on gelatin capsules and also on DRcaps. Test results demonstrated that DRcaps coated with EUDRAGIT L100-55 possessed enhanced enteric-protective properties, particularly in vivo. These studies add to the body of knowledge regarding gastric emptying in pigs and also begin the process of gathering specifications for the design of a simple and cost-effective enteric-coated capsule for delivery of acid-labile macromolecules to the small intestine.