Lower Rate Limit Research Articles

Evaluation of the liver targeting and anti‑liver cancer activity of artesunate‑loaded and glycyrrhetinic acid‑coated nanoparticles.

Globally, liver cancer ranks among the most lethal cancers, with chemotherapy being one of its primary treatments. However, poor selectivity, systemic toxicity, a narrow treatment window, low response rate and multidrug resistance limit its clinical application. Liver-targeted nanoparticles (NPs) exhibit excellent targeted delivery ability and promising effectivity in treating liver cancer. The present study aimed to investigate the liver-targeting and anti-liver cancer effect of artesunate (ART)-loaded and glycyrrhetinic acid (GA)-decorated polyethylene glycol (PEG)-poly (lactic-co-glycolic acid) (PLGA) (ART/GA-PEG-PLGA) NPs. GA-coated NPs significantly increased hepatoma-targeted cellular uptake, with micropinocytosis and caveolae-mediated endocytosis as its chief internalization pathways. Moreover, ART/GA-PEG-PLGA NPs exhibited pro-apoptotic effects on HepG2 cells, mainly via the induction of a high level of reactive oxygen species, decline in mitochondrial membrane potential and induction of cell cycle arrest. Additionally, ART/GA-PEG-PLGA NPs induced internal apoptosis pathways by upregulating the activity of cleaved caspase-3/7 and expression of cleaved poly (ADP-Ribose)-polymerase and Phos-p38 mitogen-activated protein kinase in HepG2 cells. Furthermore, ART/GA-PEG-PLGA NPs exhibited higher liver accumulation and longer mean retention time, resulting in increased bioavailability. Finally, ART/GA-PEG-PLGA NPs promoted the liver-targeting distribution of ART, increased the retention time and promoted its antitumour effects in vivo. Therefore, ART/GA-PEG-PLGA NPs afforded excellent hepatoma-targeted delivery and anti-liver cancer efficacy, and thus, they may be a promising strategy for treating liver cancer.

Differences in pacemaker programming between electrophysiology specialists and other physicians

BackgroundAppropriate programming of cardiovascular implantable electronic devices (CIED) is essential to ensure adequate function and avoid harmful effects. In underdeveloped countries, CIED monitoring and programming are often performed by physicians involved in their implantation. However, many of them often do not have sufficient training in CIED programming. ObjectiveWe aimed to assess the differences in pacemaker programming between electrophysiology (EP) specialists and other physicians. MethodsWe retrospectively reviewed changes in pacemaker programming performed by an EP specialist in patients who attended for pacemaker evaluation and reported previous follow-ups by a non-EP specialist. ResultsAmong 58 patients (26 males), 41 patients (71%) had programming errors and required setting modifications. The rate adaptative pacing function (R-mode) was incorrectly deactivated in 9 patients (15%) and improperly activated in 2 patients (3%). Unnecessary ventricular stimulation was detected in 23 patients (40%) with a pacing burden of 60% (32–95%). The lower rate limit was unnecessarily high in 12 patients (21%).Atrial or ventricular pacing output was inappropriate in 15 patients (26%) and was consequently modified (4 patients unnecessarily high, 9 patients below requirements). The auto-adapted pacing output was switched off in 17 of 18 patients (16 due to physician's preference, and 1 due to algorithm inaccuracy). The programmed sensitivity was inaccurate in 2 patients (3%). In 2 patients (3%) switching from DDDR to VVIR mode was required. ConclusionWe found a high prevalence of errors in pacemaker programming by non-EP specialists. An EP specialist should always be responsible for CIED follow-up.

Effects of self‐assembled nucleating agent on the crystallization behavior, thermal properties, and mechanical properties of polylactic acid

AbstractPolylactic acid (PLA) is a biodegradable polyester, but its low crystallization rate and excessive embrittlement limit its application. Decanedioic acid 1,10‐bis (2‐benzoylhydrazide) (TMC‐300) as an effective nucleating agent of PLA will induce PLA epitaxial crystallization and improve the crystallization rate of PLA. This article studied the promoting behavior of TMC‐300 with different contents in composite systems on PLA crystallization. The results showed that with the increase of TMC‐300 content, the crystallinity can be significantly increased, up to 22 times, and t1/2 significantly decreases. Meanwhile, with the addition of TMC‐300, the typical spherical crystal morphology of PLA gradually became attached to TMC‐300 fibrous crystal morphology. In terms of mechanical properties, the tensile strength reached its maximum at 0.5 wt% of TMC‐300 content, increasing from 60.60 MPa (PLA) to 74.59 MPa (0.5‐TMC‐300), an increase of 23.09%. At this time, due to the reduction in spherical crystal size, the elongation at break also increased significantly. However, the thermal stability of PLA composites deteriorated with the increase of nucleating agent content due to the low thermal decomposition temperature of TMC‐300 itself, and the Tmax decreased from 372°C (PLA) to 353°C (5‐TMC‐300), a decrease of 19°C.

Rod-climbing rheometry revisited.

The rod-climbing or "Weissenberg" effect in which the free surface of a complex fluid climbs a thin rotating rod is a popular and convincing experiment demonstrating the existence of elasticity in polymeric fluids. The interface shape and steady-state climbing height depend on the rotation rate, fluid elasticity (through the presence of normal stresses), surface tension, and inertia. By solving the equations of motion in the low rotation rate limit for a second-order fluid, a mathematical relationship between the interface deflection and the fluid material functions, specifically the first and second normal stress differences, emerges. This relationship has been used in the past to measure the climbing constant, a combination of the first (Ψ1,0) and second (Ψ2,0) normal stress difference coefficients from experimental observations of rod-climbing in the low shear rate limit. However, a quantitative reconciliation of such observations with the capabilities of modern-day torsional rheometers is lacking. To this end, we combine rod-climbing experiments with both small amplitude oscillatory shear (SAOS) flow measurements and steady shear measurements of the first normal stress difference from commercial rheometers to quantify the values of both Ψ1,0 and Ψ2,0 for a series of polymer solutions. Furthermore, by retaining the oft-neglected inertial terms, we show that the "climbing constant"  = 0.5Ψ1,0 + 2Ψ2,0 can be measured even when the fluids, in fact, experience rod descending. A climbing condition derived by considering the competition between elasticity and inertial effects accurately predicts whether a fluid will undergo rod-climbing or rod-descending. Our results suggest a more general description, "rotating rod rheometry" instead of "rod-climbing rheometry", to be more apt and less restrictive. The analysis and observations presented in this study establish rotating rod rheometry combined with SAOS measurements as a prime candidate for measuring normal stress differences in complex fluids at low shear rates that are often below commercial rheometers' sensitivity limits.

Lower rate limit in cardiac resynchronization therapy defibrillators

Abstract Background There is few data about programmed lower rate limit (LRL) in real world heart failure (HF) patients with cardiac resynchronization therapy–defibrillators (CRT-Ds) and its influence in clinical outcomes. Heart rate score (HRS) is the percentage of all atrial-paced and sensed events in the single tallest 10 beats/min device histogram bin and may indicate impaired heart rate variability. Purpose We hypothesized that higher LRL programming is associated with worse clinical outcomes as arrhythmic events and HF decompensations in chronic HF patients with CRT-Ds. Methods LRL was evaluated and HRS was calculated from remote monitoring in 126 HF patients with CRT-D. Primary outcome was defined as HF hospitalizations and related admissions to the emergency department and secondary outcome as number of device therapies, sustained ventricular tachycardia (VT) and ventricular fibrillation (VF). Results Mean age was 69,03±10,39 years, 81 (64,3%) were males and mean follow-up was 53,72±46,13 months. Mean left ventricular ejection fraction was 30,31±8,33% and 29 (23,0%) were in NYHA III–IV. HF aetiology was idiopathic in 39 (43,3%), ischemic in 32 (25,4%) and alcoholic cardiomyopathy in 8 (6,3%). Thirty-seven (29,4%) patients had atrial fibrillation and 33 (26,2%) coronary disease. LRL ranged from to 40 to 80 bpm and mean LRL was 52,64±9,64 and mean HRS 49,60±23,17%. Programmed LRL was higher in women (p=0,014), patients with atrial fibrillation (AF) (p=0,012) and coronary disease (p=0,015). Higher LRL correlated with HF hospitalizations and related admissions to the emergency department (ED) (r=0,541, p=0,001), VT or VF episodes (r=0,337, p=0,005) and CRT-D number of therapies (r=0,342, p=0,004) and higher HRS (r=0,547, p<0,05). Conclusion Higher LRL programming was associated with higher HRS, HF decompensations with hospitalization or admission to the emergency department, VT or VF episodes and CRT-D therapies in a real world population. More studies are required but lower LRL may be preferred in HF patients. Funding Acknowledgement Type of funding sources: None.

Suppressors of fixation can increase average fitness beyond amplifiers of selection

Evolutionary dynamics on graphs has remarkable features: For example, it has been shown that amplifiers of selection exist that-compared to an unstructured population-increase the fixation probability of advantageous mutations, while they decrease the fixation probability of disadvantageous mutations. So far, the theoretical literature has focused on the case of a single mutant entering a graph-structured population, asking how the graph affects the probability that a mutant takes over a population and the time until this typically happens. For continuously evolving systems, the more relevant case is that mutants constantly arise in an evolving population. Typically, such mutations occur with a small probability during reproduction events. We thus focus on the low mutation rate limit. The probability distribution for the fitness in this process converges to a steady state at long times. Intuitively, amplifiers of selection are expected to increase the population's mean fitness in the steady state. Similarly, suppressors of selection are expected to decrease the population's mean fitness in the steady state. However, we show that another set of graphs, called suppressors of fixation, can attain the highest population mean fitness. The key reason behind this is their ability to efficiently reject deleterious mutants. This illustrates the importance of the deleterious mutant regime for the long-term evolutionary dynamics, something that seems to have been overlooked in the literature so far.

Interparticle and Brownian forces controlling particle aggregation and rheology of silicate melts containing platinum-group element particles

We study the rheology of silicate melts containing platinum-group element (PGE) particles. They exhibit a shear-thinning behaviour, an intense aggregation tendency, and an anomalously high apparent viscosity in the low shear rate limit, even at very low particle volume fraction. Using a compilation of published experimental data, we analyse these effects in three steps. Firstly, we observe that the viscosities of these suspensions are much higher than those of natural silicate crystal-bearing melts for low shear rate regimes. Secondly, we demonstrate that the viscosities at low shear rate limit cannot be estimated by classical rheological models but rather may be understood as the result of particle aggregation, trapping dead fluid, and thereby increasing the effective particle volume fraction. Finally, we scale the critical shear rates for shear-thinning using a Peclet number analysis—invoking a competition between random thermal particle motion and hydrodynamic shearing motion—and, using an empirical extension, we additionally account for the particle–particle interaction energetics. We propose a framework in which the rheology of this family of particle-bearing melts can be predicted, and demonstrate that at low Peclet numbers, PGE-bearing particle aggregation is driven by interparticle forces and Brownian motion.

Residual stress in athermal soft disordered solids: insights from microscopic and mesoscale models.

In soft amorphous materials, shear cessation after large shear deformation leads to configurations having residual shear stress. The origin of these states and the distribution of the local shear stresses within the material is not well understood, despite its importance for the change in material properties and consequent applications. In this work, we use molecular dynamics simulations of a model dense non-Brownian soft amorphous material to probe the non-trivial relaxation process towards a residual stress state. We find that, similar to thermal glasses, an increase in shear rate prior to the shear cessation leads to lower residual stress states. We rationalise our findings using a mesoscopic elasto-plastic description that explicitly includes a long range elastic response to local shear transformations. We find that after flow cessation the initial stress relaxation indeed depends on the pre-sheared stress state, but the final residual stress is majorly determined by newly activated plastic events occurring during the relaxation process, a scenario consistent with the phenomenology of avalanche dynamics in the low shear rate limit of steadily sheared amorphous solids. Our simplified coarse grained description not only allows capturing the phenomenology of residual stress states but also rationalising the altered material properties that are probed using small and large deformation protocols applied to the relaxed material.

Lower rate limit for pacing by cardiac resynchronization defibrillators: Should lower rate programming be reconsidered?

No real-world large database associates lower rate limit (LRL) programming and survival of subjects with cardiac resynchronization therapy-defibrillators (CRT-Ds). The purpose of this study was to test the hypothesis that lower LRL programming is independently associated with survival, and that LRL and heart rate score (HrSc) are associated. All dual-chamber CRT-D devices in the Remote Patient Monitoring (RPM) ALTITUDE database (2006-2011) were queried. Baseline HrSc was defined as the percentage of all atrial sensed and paced beats in the tallest 10-beat histogram bin postimplant. LRL was assessed during repeated RPM uploads. Using a Cox model multivariable analysis, relationships between LRL, survival, HrSc, and other variables were evaluated. Survival was determined by query of death indices. Data analyzed included 61,881 subjects (mean follow-up 2.9 years). LRL ranged from 40 to 85 bpm. Baseline lower LRL was associated with younger age, less atrial fibrillation, female sex, and lower HrSc (P <.001 for all covariates). Lower LRL was associated with improved survival, with LRL 40 associated with the largest survival benefit. This was significant for all 3 HrSc subgroups (P<.001). An interaction between HrSc and LRL was observed, with the largest survival difference between HrSc groups observed at LRL-40 (P <.001). LRL programming and HrSc were associated, and lower values of both were associated with improved survival in a large database of CRT-D subjects. Relationships between survival, LRL programming, and HrSc merit further study.

A cascade targeting strategy based on modified bacterial vesicles for enhancing cancer immunotherapy

BackgroundAs an efficient tumor immunotherapy, PD-1 antibody has been gradually used in clinical tumor treatment, but the low response rate and excessive immune response limit its extensive application.ResultsHerein, a therapeutic regime for the reinvigoration and activation of the tumor immune microenvironment is introduced to improve the anti-tumor effect of the PD-1 antibody. To comprehensively improve the effect of the immunotherapy and reduce excessive immune response, a biomimetic cascade targeting nanosystem, siRNA@PLOV, which was fused by photothermal sensitive liposomes (PTSLs) and attenuated Salmonella outer membrane vesicles (OMVs), was administered in the tumor therapy for targeting of tumor tissues and T cells within tumor respectively. The fused PLOVs which not only retained the biological character of the OMVs, but also enhanced the drug loading ability. The results demonstrated that the immunogenicity of OMVs and photothermal effects can obviously increase the infiltration of T cells and the silencing of CD38 can effectively improve the T cell cytotoxicity, especially combining with PD-1 antibody.ConclusionsInteresting, this study revealed that anti-PD-1 administration on the 5th day after siRNA@PLOV treatment had the best performance in killing tumors compared with other groups. In addition, this new therapeutic regime also presents a novel strategy for inducing “vaccine effects”, conclusively highlighting its potential in preventing tumor recurrence and improving prognosis.Graphical

Atrial pacing above the lower rate limit: What is the cause?

Atrial pacing above the lower rate limit: What is the cause?

An approach towards individualized lower rate settings for pacemakers.

Author(s): Infeld, Margaret; Avram, Robert; Wahlberg, Kramer; Silverman, Daniel N; Habel, Nicole; Lustgarten, Daniel L; Pletcher, Mark J; Olgin, Jeffrey E; Marcus, Gregory M; Meyer, Markus

Investigation on Operating Conditions Influencing the Aluminum Electrolysis Using Chloroaluminate Ionic Liquids

AlCl3-EMIC (1-ethyl-3-methylimidazolium chloride) melt has attracted attention as an efficient electrolyte for Al electrolysis. However, several problems such as the low deposition rate and rough surface limit its practical use. In this study, we have investigated the influence of the electrolytic condition on the surface roughness of electrolytic Al foil by using the AlCl3-EMIC (molar ratio 2 : 1) melt with/without 20 mmol dm−3 of an OP (1,10-phenanthroline anhydrate) additive as an electrolyte. The AFM image revealed that the surface roughness (Sa) value of the electrolytic Al foil obtained on the Ti plate substrate from the melt with the OP additive at 50 ℃ was 45.8 nm at the current density of 52.6mA cm−2. A smooth electrolytic Al foil was found to be obtained even at high current density by increasing the operating temperature and adding OP to the melt.

ELECTRICAL STORM FOLLOWING AV NODAL ABLATION FOR PERMANENT ATRIAL FIBRILLATION DESPITE USING STANDARD HIGH LOWER RATE LIMIT FOR PREVENTION OF TORSADES DE POINTES

Ablation of the atrioventricular (AV) node remains the only treatment for patients with permanent atrial fibrillation with pharmacologically-refractory fast ventricular. Ventricular arrhythmias have been described following this procedure but setting the pacemaker at a lower rate limit (LRL) of 80

Clinical Course of Dual-Chamber Implantable Cardioverter-Defibrillator Recipients followed by Cardiac Remote Monitoring: Insights from the LION Registry.

Patients receiving dual-chamber implantable cardioverter-defibrillator (DR-ICD) therapy are at risk of developing atrial arrhythmia because of the increased rate of ventricular pacing and the progression of heart failure. Remote monitoring (RM) may identify the patients at highest risk of adverse events such as atrial arrhythmias. A total of 283 patients with 91,632 remote transmissions during a 15-month follow-up (FU) period enrolled in the LION registry were analysed. The parameters retrieved included the pacing mode, lower rate limit, percentage of atrial (%AP) and ventricular pacing (%VP), and percentage of atrial arrhythmia burden (%AB). In 92.7% of patients, the devices were initially programmed in DDD(R) or DDI(R), with changes of the pacing mode in 19.3% only. The lower rate limit remained stable in 80.4% of patients. At the first transmission, 8.7% of patients suffered from RM-detected atrial arrhythmia, which reached 36% during FU. The %AP was not associated with increased AB (p = 0.67), but the %VP was different in patients developing RM-detected atrial arrhythmia (26.9% vs. 13.7%, p < 0.00001). The %VP increased in 105 patients (significance level of α = 0.05), and 11 patients crossed the border of 50% VP. The LION substudy supports the concept of using RM in a real-world DR-ICD population. Remote monitoring of DR-ICDs allows for the quantification of the course of the pacing parameters and AB. Based on these observations, device parameters can be adjusted and optimized.

Domain kinetics during polarization reversal in 36° Y-cut congruent lithium niobate

We present experimental study of domain kinetics in 36° Y-cut congruent lithium niobate during polarization reversal by increasing external electric field using liquid electrodes. The motion of the domain walls has been imaged on the Zs+ and Zs-polar surfaces of the crystal simultaneously. The linear dependence of the threshold field on the field rate has been revealed. The threshold field in low field rate limit has been estimated as 32.8 ± 0.3 kV/mm, which is lower than predicted value. The switching process for polarization reversal in the constant field has dramatically accelerated with increase of external electrical field above threshold. The new approach, which accelerates significantly the in situ study of 3D domain kinetics in CLN crystals, has been demonstrated.

Development of Algorithms for Integration and Reconfiguration of the Flight Control System and Interfaces

The integration potentiality is considered for the flight control system and interface algorithms to provide the flight accuracy and safety of highly augmented aircraft in the case of low maximum elevator rate limit and in the case of failures causing its sharp decrease.

Normal stress effects on Knudsen flow

Normal stress effects are investigated on tube flow of a single-component non-Newtonian fluid under a constant pressure gradient in a constant temperature field. The generalized hydrodynamic equations are employed, which are consistent with the laws of thermodynamics. In the cylindrical tube flow configuration, the solutions of generalized hydrodynamic equations are exactly solvable and the flow velocity is obtained in a simple one-dimensional integral quadrature. Unlike the case of flow in the absence of normal stresses, the flow develops an anomaly in that the flow in the boundary layer becomes stagnant and the thickness of such a stagnant velocity boundary layer depends on the pressure gradient, the aspect ratio of the radius to the length of the tube, and the pressure (or density and temperature) at the entrance of the tube. The volume flow rate formula through the tube is derived for the flow. It generalizes the Knudsen flow rate formula to the case of a non-Newtonian stress tensor in the presence of normal stress differences. It also reduces to the Navier–Stokes theory formula in the low shear rate limit near equilibrium.

An Analysis of Unsteady Flooding Processes: Varying Force Balance and the Applicability of Steady-State Upscaling

A widely used approach for upscaling relative permeability is based on a steady-state assumption. For small time intervals and at small scales, the flooding process can be approximated as being in a steady state. However, at large scales with large time steps, water flooding of a reservoir is an unsteady process. In this article, we first investigate the balance of viscous, capillary and gravity forces on the fine scale during the water flooding of a reservoir at different flow velocities. We introduce a semi-analytical method to find the low-rate limit solution, while the high-rate limit solution is found by running a simulation without gravity and capillary pressure. These limit solutions allow us to understand when rate-dependent simulations approach a point where some forces become negligible. We perform a series of numerical simulations on the fine scale to construct solution transitions between the established outer limits. Simulations are run both on homogeneous models, on different layered models and on a more complex two-dimensional model. The rate-dependent simulations show smooth transitions between the low- and high-rate limits, and these transitions are in general non-trivial. In all our example cases, one of the limit solutions gives a lower bound for the rate dependent results, while they do not in general provide an upper bound. Based on the rate-dependence of the force balance, we evaluate when different steady-state upscaling procedures are applicable for an unsteady flooding process. We observe that the capillary-limit upscaling, which also takes gravity into account, reproduces the low-rate limit fine-scale simulations. Such capillary-limit upscaling is also able to reproduce the transition to capillary equilibrium normal to the flow direction. As already known, the viscous-limit upscaling is only applicable when we have close to constant fractional flow within each coarse grid block.

Survival After Rate-Responsive Programming in Patients With Cardiac Resynchronization Therapy-Defibrillator Implants Is Associated With a Novel Parameter: The Heart Rate Score.

Rate-responsive pacing (DDDR) versus nonrate-responsive pacing (DDD) has shown no survival benefit for patients undergoing cardiac resynchronization therapy defibrillator (CRT-D) implants. The heart rate score (HRSc), an indicator of heart rate variation, may predict survival. We hypothesized that high-risk HRSc CRT-D patients will have improved survival with DDDR versus DDD alone. All CRT-D patients in LATITUDE remote monitoring (2006-2011), programmed DDD, had HRSc calculated at first data upload after implant (median 1.4 months). Patients subsequently reprogrammed to DDDR 7.6 median months later were compared with a propensity-matched DDD group and followed for 21.4 median months by remote monitoring. Data were adjusted for age, sex, lower rate limit, percent atrial pacing, percent biventricular pacing, and implant year. The social security death index was used to identify deaths. Remote monitoring provided programming and histogram data. DDDR programming in CRT-D patients was associated with improved survival (adjusted hazard ratio =0.77; P<0.001). However, only those with baseline HRSc ≥70% (2308/6164) had improved HRSc with DDDR (from 88±9% to 78±15%; P<0.001) and improved survival (hazard ratio =0.74; P<0.001). Patients with a high baseline HRSc and significant improvement over time were more likely to survive (hazard ratio =0.63; P=0.006). For patients with HRSc <70%, DDDR reprogramming increased the HRSc from 46±11% to 50±15% (P<0.001); survival did not change. The HRSc did not change with DDD pacing over time. In CRT-D patients with HRSc ≥70%, DDDR reprogramming improved the HRSc and was associated with survival. Patients with lower HRSc had no change in survival with DDDR programming.