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IntroductionSevere aortic stenosis, a highly-common valve disease in the elderly, has a poor prognosis if left untreated. To address the concern of effective procedures for severe aortic stenosis, a systematic TAVI program was established at the Dedinje Cardiovascular Institute (Belgrade, Serbia).MethodsOur cohort was composed of 56 patients (74±15 years old). The mean logistic EuroScore was 10.17%; the mean Society of Thoracic Surgeons score was 3.22%. One third of the patients were categorized as class III or IV of the New York Heart Association (NYHA). The valves selected for use were either self-expandable or balloon expandable (Evolut R, Medtronic; Acurate Neo, Boston Scientific and Myval, Meril). The choice of valve type was made by the Institute's Structural Heart Team, in accordance with the patient's native aortic valve, size and calcification of ilio-femoral vessels, as well as the need for alternative access. TAVI procedure was conducted according to current guidelines provided by the European Society of Cardiology.ResultsThe procedure success rate was 100%. Trans-femoral approach was achieved in 100% of patients; percutaneously in 87.5%, while a surgical cut was necessary in 12.5%. No patient showed moderate or severe aortic regurgitation after the procedure, although trace or mild regurgitation was recorded in 30.3%. Permanent pacemaker was implanted in one patient (1.78%), contrast induced acute kidney injury occured in one patient (1.78%), no stroke was recorded, and three pseudo-aneurysms which required surgical intervention occurred. Three patients required blood transfusions (5.33%). A 30-day all-cause mortality rate was 1.78%.ConclusionThe Dedinje Cardiovascular Institute spearheaded all efforts to establish a TAVI program in Serbia. Our initial TAVI results are promising, encouraging, and comparable with the results of previous large randomized trials. This initial experience opens the door for further development with a goal of our Institute to become a high-volume TAVI center.

Mineralocorticoid receptor antagonists have been shown to reduce mortality in patients after myocardial infarction with congestive heart failure. Whether routine use of spironolactone is beneficial after myocardial infarction is uncertain. In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients with myocardial infarction who had undergone percutaneous coronary intervention to receive either spironolactone or placebo and either colchicine or placebo. The results of the spironolactone trial are reported here. The two primary outcomes were a composite of death from cardiovascular causes or new or worsening heart failure, evaluated as the total number of events; and a composite of the first occurrence of myocardial infarction, stroke, new or worsening heart failure, or death from cardiovascular causes. Safety was also assessed. We enrolled 7062 patients at 104 centers in 14 countries; 3537 patients were assigned to receive spironolactone and 3525 to receive placebo. At the time of our analyses, the vital status was unknown for 45 patients (0.6%). For the first primary outcome, there were 183 events (1.7 per 100 patient-years) in the spironolactone group as compared with 220 events (2.1 per 100 patient-years) in the placebo group over a median follow-up period of 3 years (hazard ratio adjusted for competing risk of death from noncardiovascular causes, 0.91; 95% confidence interval [CI], 0.69 to 1.21; P = 0.51). With respect to the second primary outcome, an event occurred in 280 of 3537 patients (7.9%) in the spironolactone group and 294 of 3525 patients (8.3%) in the placebo group (hazard ratio adjusted for competing risk, 0.96; 95% CI, 0.81 to 1.13; P = 0.60). Serious adverse events were reported in 255 patients (7.2%) in the spironolactone group and 241 (6.8%) in the placebo group. Among patients with myocardial infarction, spironolactone did not reduce the incidence of death from cardiovascular causes or new or worsening heart failure or the incidence of a composite of death from cardiovascular causes, myocardial infarction, stroke, or new or worsening heart failure. (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).

Relaxation dynamics of complex many-body quantum systems trapped into metastable states is a very active field of research from both the theoretical and experimental point of view with implications in a wide array of topics from macroscopic quantum tunnelling and nucleosynthesis to non-equilibrium superconductivity and energy-efficient memory devices. In this work, we investigate quantum domain reconfiguration dynamics in the electronic superlattice of a quantum material using time-resolved scanning tunneling microscopy and unveil a crossover from temperature to noisy quantum fluctuation dominated dynamics. The process is modeled using a programmable superconducting quantum annealer in which qubit interconnections correspond directly to the microscopic interactions between electrons in the quantum material. Crucially, the dynamics of both the experiment and quantum simulation is driven by spectrally similar pink noise. We find that the simulations reproduce the emergent time evolution and temperature dependence of the experimentally observed electronic domain dynamics. Metastable states found in superconductors and charge density wave materials are of fundamental interest. Vodeb et al. study the domain wall dynamics in 1T-TaS 2 using scanning tunneling microscopy and a quantum annealer, finding that in both cases the dynamics is driven by spectrally similar noise.

Van der Waals materials exhibit a variety of states that can be switched with low power at low temperatures, offering a viable cryogenic ‘flash memory’ required for the classical control electronics for solid-state quantum information processing. In 1 T -TaS 2 , a non-volatile metallic ‘hidden’ state can be induced from an insulating equilibrium charge-density wave ground state using either optical or electrical pulses. Given that conventional memristors form localized, filamentary channels which support the current, a key question for design concerns the geometry of the conduction region in highly energy-efficient 1 T -TaS 2 devices. Here, we report in operando micro-beam X-ray diffraction, fluorescence, and concurrent transport measurements, allowing us to spatially image the non-thermal hidden state induced by electrical switching of 1 T -TaS 2 . The results reveal a long-range ordered switching region that extends well below the electrodes, implying that the self-organized, collective growth of the hidden phase is driven by charge rearrangement and concomitant lattice strain. Our combination of techniques showcases the potential of non-destructive, three-dimensional X-ray imaging to study bulk switching in microscopic detail, exemplified here by electrical control of the charge-density wave state of a van der Waals material. In operando three-dimensional X-ray imaging of a 1 T -TaS 2 cryomemory device reveals van der Waals layer restacking, resulting in a bulk metallic switching region, driven by charge rearrangement and concomitant lattice strain.

Metastability of many-body quantum states is rare and still poorly understood. An exceptional example is the low-temperature metallic state of the layered dichalcogenide 1T-TaS 2 in which electronic order is frozen after external excitation. Here we visualize the microscopic dynamics of injected charges in the metastable state using a multiple-tip scanning tunnelling microscope. We observe non-thermal formation of a metastable network of dislocations interconnected by domain walls, that leads to macroscopic robustness of the state to external thermal perturbations, such as small applied currents. With higher currents, we observe annihilation of dislocations following topological rules, accompanied with a change of macroscopic electrical resistance. Modelling carrier injection into a Wigner crystal reveals the origin of formation of fractionalized, topologically entangled networks, which defines the spatial fabric through which single particle excitations propagate. The possibility of manipulating topological entanglement of such networks suggests the way forward in the search for elusive metastable states in quantum many body systems. The metastable state with a complex domain structure in 1T-TaS 2 has been intensively studied. Using a multi-tip scanning tunnelling microscope, Mraz et al. reveal the microscopic dynamics of the current-pulse-induced metastable state and interpret it in terms of transport in a doped Wigner crystal lattice.

PurposeThe purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.MethodsComplications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.ResultsClinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.ConclusionsCurrent issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.

Van der Waals materials exhibit a variety of states that can be switched with low power at low temperatures, offering a viable cryogenic 'flash memory' required for the classical control electronics for solid-state quantum information processing. In 1T-TaS , a non-volatile metallic 'hidden' state can be induced from an insulating equilibrium charge-density wave ground state using either optical or electrical pulses. Given that conventional memristors form localized, filamentary channels which support the current, a key question for design concerns the geometry of the conduction region in highly energy-efficient 1T-TaS devices. Here, we report in operando micro-beam X-ray diffraction, fluorescence, and concurrent transport measurements, allowing us to spatially image the non-thermal hidden state induced by electrical switching of 1T-TaS . The results reveal a long-range ordered switching region that extends well below the electrodes, implying that the self-organized, collective growth of the hidden phase is driven by charge rearrangement and concomitant lattice strain. Our combination of techniques showcases the potential of non-destructive, three-dimensional X-ray imaging to study bulk switching in microscopic detail, exemplified here by electrical control of the charge-density wave state of a van der Waals material.

Contact herbicide diquat (DQ), redox cycling compound, mediates its systemic toxicity throughout the enlarged production of free radicals. Target organs are liver and kidney in humans. To-date, the mechanism of DQ-induced neurotoxicity has not been rationalized. The objectives of the study were to examine the ability of DQ to induce oxidative stress (OS) and/or nitrosative stress (NS) upon intrastriatal (i.s.) administration and to investigate the role of nitric oxide (NO(x)) using NG-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of nitric oxide synthase (NOS) in the pretreatment of DQ i.s. administration. The experiment was conducted on Wistar rats, randomly divided in experimental groups, receiving different treatments i.s. applied. Parameters of OS/NS such as: superoxide anion radical (O(2)(•-)), superoxide dismutase (SOD), malondialdehyde (MDA) and nitrates (NO(3)(-)) were measured in the cortex (bilaterally), at 30(th) min, 24 hours and 7 days after the treatments. Lethargy and high mortality rate were observed only in the DQ group (within 24 hours and 2-3 hours, respectively) after awakening from anesthesia. Markedly increased production of NO(x) and O(2)(•-) along with elevated lipid peroxidation altogether contributed to DQ neurotoxicity. The most importantly, the L-NAME i.s. pretreatment protected treated animals from dying and diminished OS/NS response against DQ-induced neurotoxicity. The i.s. pretreatment with L-NAME resulted in neuroprotection against DQ neurotoxity, based on animal survival and reduced LPO in the cortex.

Van der Waals (vdW) materials exhibit a variety of states that can be switched with low power at low temperatures, offering a viable cryogenic \"flash memory\" required for the classical control electronics for solid-state quantum information processing. In 1T-TaS2, a non-volatile metallic 'hidden' state can be induced from an insulating equilibrium charge-density wave ground state using either optical or electrical pulses. Given that conventional memristors form localized, filamentary channels which support the current, a key question for design concerns the geometry of the conduction region in highly energy-efficient 1T-TaS2 devices. Here, we report in operando micro-beam X-ray diffraction, fluorescence, and concurrent transport measurements, allowing us to spatially image the non-thermal hidden state induced by electrical switching of 1T-TaS2. Our results reveal a long-range ordered, non-filamentary switched state that extends well below the electrodes, implying that the self-organized, collective growth of the hidden phase is driven by a combination of charge flow and lattice strain. Our unique combination of techniques showcases the potential of non-destructive, three-dimensional X-ray imaging to study bulk switching properties in microscopic detail, namely electrical control of the vdW layer stacking.

Relaxation dynamics of complex many-body quantum systems brought out of equilibrium and subsequently trapped into metastable states is a very active field of research from both the theoretical and experimental point of view with implications in a wide array of topics from macroscopic quantum tunnelling and nucleosynthesis to non-equilibrium superconductivity and new energy-efficient memory devices. Understanding the dynamics of such systems is crucial for exploring fundamental aspects of many-body non-equilibrium quantum physics. In this work we investigate quantum domain reconfiguration dynamics in the electronic superlattice of a quantum material where classical dynamics is topologically constrained. The crossover from temperature to quantum fluctuation dominated dynamics in the context of environmental noise is investigated by directly observing charge reconfiguration with time-resolved scanning tunneling microscopy. The process is modelled using a programmable superconducting quantum simulator in which qubit interconnections correspond directly to the microscopic interactions between electrons in the quantum material. Crucially, the dynamics of both the experiment on the quantum material and the simulation is driven by spectrally similar pink noise. We find that the simulations reproduce the emergent time evolution and temperature dependence of the experimentally observed electronic domain dynamics remarkably well. The combined experiment and simulations lead to a better understanding of noise-driven quantum dynamics in open quantum systems. From a practical viewpoint, the results are important for understanding the origin of the retention time in non-volatile memory devices such as those based on 1T-TaS2.