Individualization of atrial tachycardia models for clinical applications: Performance of fiber-independent model

One of the challenges in the development of patient-specific models of cardiac arrhythmias for clinical applications has been accounting for myocardial fiber organization. The fiber varies significantly from heart to heart, but cannot be directly measured in live tissue. The goal of this paper is to evaluate in-silico the accuracy of left atrium activation maps produced by a fiber-independent (isotropic) model with tuned diffusion coefficients, compares to a model incorporating myocardial fibers with the same geometry. For this study we utilize publicly available DT-MRI data from 7 ex-vivo hearts. The comparison is carried out in 51 cases of focal and rotor arrhythmias located in different regions of the atria. On average, the local activation time accuracy is 96% for focal and 93% for rotor arrhythmias. Given its reasonably good performance and the availability of readily accessible data for model tuning in cardiac ablation procedures, the fiber-independent model could be a promising tool for clinical applications

Electroanatomic Mapping to determine Scar Regions in patients with Atrial Fibrillation

Left atrial voltage maps are routinely acquired during electroanatomic mapping in patients undergoing catheter ablation for atrial fibrillation. For patients, who have prior catheter ablation when they are in sinus rhythm, the voltage map can be used to identify low voltage areas using a threshold of 0.2 - 0.45 mV. However, such a voltage threshold for maps acquired during atrial fibrillation has not been well established. A prerequisite for defining a voltage threshold is to maximize the topologically matched low voltage areas between the electroanatomic mapping acquired during atrial fibrillation and sinus rhythm. This paper demonstrates a new technique to improve the sensitivity and specificity of the matched low voltage areas. This is achieved by computing omni-directional bipolar voltages and applying Gaussian Process Regression based interpolation to derive the atrial fibrillation map. The proposed method is evaluated on a test cohort of 7 male patients, and a total of 46,589 data points were included in analysis. The low voltage areas in the posterior left atrium and pulmonary vein junction are determined using the standard method and the proposed method. Overall, the proposed method showed patient-specific sensitivity and specificity in matching low voltage areas of 75.70% and 65.55% for a geometric mean of 70.69%. On average, there was an improvement of 3.00% in the geometric mean, 7.88% improvement in sensitivity, 0.30% improvement in specificity compared to the standard method. The results show that the proposed method is an improvement in matching low voltage areas. This may help develop the voltage threshold to better identify low voltage areas in the left atrium for patients in atrial fibrillation

Electroanatomic Mapping to Determine Scar Regions in Patients with Atrial Fibrillation

Left atrial voltage maps are routinely acquired during electroanatomic mapping in patients undergoing catheter ablation for atrial fibrillation (AF). For patients, who have prior catheter ablation when they are in sinus rhythm (SR), the voltage map can be used to identify low voltage areas (LVAs) using a threshold of 0.2 - 0.45 mV. However, such a voltage threshold for maps acquired during AF has not been well established. A prerequisite for defining a voltage threshold is to maximize the topologically matched LVAs between the electroanatomic mapping acquired during AF and SR. This paper demonstrates a new technique to improve the sensitivity and specificity of the matched LVA. This is achieved by computing omni-directional bipolar voltages and applying Gaussian Process Regression based interpolation to derive the AF map. The proposed method is evaluated on a test cohort of 7 male patients, and a total of 46,589 data points were included in analysis. The LVAs in the posterior left atrium and pulmonary vein junction are determined using the standard method and the proposed method. Overall, the proposed method showed patient-specific sensitivity and specificity in matching LVAs of 75.70% and 65.55% for a geometric mean of 70.69%. On average, there was an improvement of 3.00% in the geometric mean, 7.88% improvement in sensitivity, 0.30% improvement in specificity compared to the standard method. The results show that the proposed method is an improvement in matching LVA. This may help develop the voltage threshold to better identify LVA in the left atrium for patients in AF

Fiber Organization has Little Effect on Electrical Activation Patterns during Focal Arrhythmias in the Left Atrium

Over the past two decades there has been a steady trend towards the development of realistic models of cardiac conduction with increasing levels of detail. However, making models more realistic complicates their personalization and use in clinical practice due to limited availability of tissue and cellular scale data. One such limitation is obtaining information about myocardial fiber organization in the clinical setting. In this study, we investigated a chimeric model of the left atrium utilizing clinically derived patient-specific atrial geometry and a realistic, yet foreign for a given patient fiber organization. We discovered that even significant variability of fiber organization had a relatively small effect on the spatio-temporal activation pattern during regular pacing. For a given pacing site, the activation maps were very similar across all fiber organizations tested

Exurban and suburban forests have superior healthcare benefits beyond downtown forests

Forests in urban areas provide great healthcare benefits to citizens, but it is less well known whether this benefit is related to different geographical spaces. We selected exurban forest, suburban forest, downtown forest, and urban control in Guangzhou, China to analyze the change characteristics of negative air ion concentration (NAIC), air oxygen content (AOC), and human comfort index (HCI). Based on Criteria Importance Through Intercriteria Correlation (CRITIC) method, the urban forest comprehensive healthcare index (UFCHI) was established. Finally, the evaluation criteria for UFCHI were identified by cluster analysis. The results demonstrated that (1) The NAIC in exurban forest (2,713 ± 1,573 ions/cm3) and suburban forest (2,147 ± 923 ions/cm3) was evidently better than downtown forest (1,130 ± 255 ions/cm3) and urban control (531 ± 162 ions/cm3). (2) The AOC was in the order of exurban forest (21.17 ± 0.38%) > suburban forest (21.13 ± 0.30%) > downtown forest (21.10 ± 0.16%) > urban control (20.98 ± 0.12%). (3) The HCI in urban control (5.56 ± 2.32) and downtown forest (5.15 ± 1.80) is higher than suburban forest (4.02 ± 1.53) and exurban forest (3.71 ± 1.48). (4) The UFCHI in exurban forest (1.000), suburban forest (0.790), and downtown forest (0.378) were beneficial to human health to some extent, while urban control (0.000) was at Level IV, having no healthcare benefit. Except in winter, the UFCHI in exurban forest and suburban forest were all at Level II and above; while downtown forest and urban control were all at Level III and below at all seasons. Overall, urban forests in the exurbs and suburbs have better healthcare benefits than those in the downtowns. Furthermore, it is recommended that urban residents visit exurban and suburban forests for forest therapy in spring, summer, and autumn

Comparative Pharmacokinetics and Preliminary Pharmacodynamics Evaluation of Piscidin 1 Against PRV and PEDV in Rats

Antimicrobial peptide (Piscidin-1) is an effective natural polypeptide, which has great influence and potential on porcine epidemic diarrhea virus (PEDV) and pseudorabies virus (PRV). As an alternative antibiotic substitute, Piscidin-1 was subjected for pharmacokinetics study with three administration routes (i.v, i.m, and p.o) after a single dose of 2 mg/kg in rats and preliminary pharmacodynamics including antiviral activity in cell against PEDV and PRV. Based on 50 percent tissue culture infective dose (TCID50), there were about 2 and 10% virus survived ratios for Piscidin-1 against PRV and PEDV, respectively. The plaque test showed 1 and 2 μg/ml Piscidin-1 could eliminate 95% PRV and 85% PEDV, respectively. The main pharmacokinetics parameters of Cmax, AUC0−∞, Ke, t1/2, Tmax, MRT, and Clb in plasma were not applicable value, 25.9 μg*h/ml, 0.041 h−1, 16.97 h, not available value, 22.77 h, 0.067 L/h*kg after i.v administration, 2.37 μg/ml, 18.95 μg*h/ml, 0.029 h−1, 23.50 h, 0.33 h, 30.12 h, 0.095 L/h*kg after i.m administration and 0.73 μg/ml, 9.63 μg*h/ml, 0.036 h−1, 19.46 h, 0.50 h, 26.76 h, 0.171 L/h*kg after p.o administration. The bioavailability values after i.m and p.o administrations were calculated as 73.17 and 37.18%, respectively. The i.m administration was selected for pharmacokinetics study in ileum content against PEDV. The main pharmacokinetic parameters of Cmax, AUC0−∞, Ke, t1/2, Tmax, MRT, and Clb in ileum content were 1.67 μg/ml, 78.40 μg*h/ml, 0.034 h−1, 20.16 h, 8.12 h, 36.45 h, 0.026 L/h*kg. The Cmax values in plasma (2.37 μg/ml) and ileum content (1.67 μg/ml) were higher than the effective inhibitory concentration determined in the plaque test, and this indicates that Piscidin-1 might have effective inhibition effect against PRV and PEDV after administration of 2 mg/kg i.m. The results of this study represent the first investigations toward the pharmacokinetic characteristics of piscidin-1 in plasma upon three different administration routes, among which i.m. resulted in the highest bioavailability (73.17%). Furthermore, the pharmacokinetics study of ileum content indicated Piscidin-1 might have good effect against PEDV and could be regarded as an alternative antibiotic in clinical veterinary in the future study

Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida

Pasteurella multocida (PM) can invade the upper respiratory tract of the body and cause death and high morbidity. Tildipirosin, a new 16-membered-ring macrolide antimicrobial, has been recommended for the treatment of respiratory diseases. The objective of this research was to improve the dose regimes of tildipirosin to PM for reducing the macrolides resistance development with the pharmacokinetic/pharmacodynamic (PK/PD) modeling approach and to establish an alternate cutoff for tildipirosin against PM. A single dose (4 mg/kg body weight) of tildipirosin was administered via intramuscular (i.m.) and intravenous (i.v.) injection to the pigs. The minimum inhibitory concentration (MIC) values of clinical isolates (112) were measured in the range of 0.0625–32 μg/ml, and the MIC50 and MIC90 values were 0.5 and 2 μg/ml, respectively. The MIC of the selected PM04 was 2 and 0.5 μg/ml in the tryptic soy broth (TSB) and serum, respectively. The main pharmacokinetic (PK) parameters including the area under the curve at 24 h (AUC24 h), AUC, terminal half-life (T1/2), the time to peak concentration (Tmax), peak concentration (Cmax), relative total systemic clearance (CLb), and the last mean residence time (MRTlast) were calculated to be 7.10, 7.94 μg∗h/ml, 24.02, NA h, NA μg/ml, 0.46 L/h∗kg, 8.06 h and 3.94, 6.79 μg∗h/ml, 44.04, 0.25 h, 0.98 μg/ml, 0.43 L/h∗kg, 22.85 h after i.v. and i.m. induction, respectively. Moreover, the bioavailability of i.m. route was 85.5%, and the unbinding of tildipirosin to serum protein was 78%. The parameters AUC24 h/MIC in serum for bacteriostatic, bactericidal, and elimination activities were calculated as 18.91, 29.13, and 34.03 h based on the inhibitory sigmoid Emax modeling. According to the Monte Carlo simulation, the optimum doses for bacteriostatic, bactericidal, and elimination activities were 6.10, 9.41, and 10.96 mg/kg for 50% target and 7.86, 12.17, and 14.57 mg/kg for 90% target, respectively. The epidemiological cutoff value (ECV) was calculated to be 4 μg/ml which could cover 95% wild-type clinical isolates distribution. The PK-PD cutoff (COPD) was analyzed to be 0.25 μg/ml in vitro for tildipirosin against PM based on the Monte Carlo simulation. Compared with these two cutoff values, the finial susceptible breakpoint was defined as 4 μg/ml. The data presented now provides the optimal regimens (12.17 mg/kg) and susceptible breakpoint (4 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice

PK-PD Analysis of Marbofloxacin against Streptococcus suis in Pigs

Marbofloxacin is a fluoroquinolone antibiotic and highly effective treatment for respiratory diseases. Here we aimed to evaluate the ex vivo activity of marbofloxacin against Streptococcus suis in pig serum, as well as the optimal dosages scheme for avoiding the fluoroquinolone resistance development. A single dose of 8 mg/kg body weight (bw) was administrated orally to healthy pigs and serum samples were collected during the next 72 h. Serum marbofloxacin content was determined by high-performance liquid chromatography. We estimated the Cmax (6.28 μg/ml), AUC0-24 h (60.30 μg.h/ml), AUC0-∞ (88.94 μg.h/ml), T1/2ke, (12.48 h), Tmax (0.75 h) and Clb (0.104 L/h) of marbofloxacin in pigs, as well as the bioavailability of marbofloxacin (94.21%) after a single 8 mg/kg oral administration. We also determined the pharmacodynamic of marbofloxacin against 134 Streptococcus suis strains isolated from Chinese cities in TSB and serum. These isolated strains had a MIC90 of 1 μg/ml. HB2, a virulent, serotype 2 isolate of SS, was selected for having antibacterial activity in TSB and serum to marbofloxacin. We determined the minimum inhibitory concentration (MIC, 1 μg/ml in TSB, 2 μg/ml in serum), minimum bactericidal concentration (MBC, 4 μg/ml in TSB, 4 μg/ml in serum), and mutant prevention concentration (2.56 μg/ml in TSB) for marbofloxacin against Streptococcus suis (HB2). In serum, by inhibitory sigmoid Emax modeling, the AUC0-24h/MIC values for marbofloxacin against HB2 were 25.23 (bacteriostatic), 35.64 (bactericidal), and 39.71 (elimination) h. Based on Monte Carlo simulations, the predicted optimal oral doses of marbofloxacin curing Streptococcus suis were 5.88 (bacteriostatic), 8.34 (bactericidal), and 9.36 (elimination) mg/kg.bw for a 50% target attainment ratio, and 8.16 (bacteriostatic), 11.31 (bactericidal), and 12.35 (elimination) mg/kg.bw for a 90% target attainment ratio. The data presented here provides optimized dosage information for clinical use; however, these predicted dosages should also be validated in clinical practice