Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem.
is a particularly difficult pathogen to treat effectively ...because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow-fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log
CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden
infections and requires further study.
The building of population pharmacokinetic models can be described as an iterative process in which given a model and a dataset, the pharmacometrician introduces some changes to the model ...specification, then perform an evaluation and based on the predictions obtained performs further optimization. This process (perform an action, witness a result, optimize your knowledge) is a perfect scenario for the implementation of Reinforcement Learning algorithms. In this paper we present the conceptual background and a implementation of one of those algorithms aiming to show pharmacometricians how to automate (to a certain point) the iterative model building process.We present the selected discretization for the action and the state space. SARSA (State-Action-Reward-State-Action) was selected as the RL algorithm to use, configured with a window of 1000 episodes with and a limit of 30 actions per episode. SARSA was configured to control an interface to the Non-Parametric Optimal Design algorithm, that was actually performing the parameter optimization.The Reinforcement Learning (RL) based agent managed to obtain the same likelihood and number of support points, with a distribution similar to the reported in the original paper. The total amount of time used by the train the agent was 5.5 h although we think this time can be further improved. It is possible to automatically find the structural model that maximizes the final likelihood for an specific pharmacokinetic dataset by using RL algorithm. The framework provided could allow the integration of even more actions i.e: add/remove covariates, non-linear compartments or the execution of secondary analysis. Many limitations were found while performing this study but we hope to address them all in future studies.
The International Telecommunications Union Radiocommunication Sector (ITU‐R) Study Group 3 identified the need for a number of radio channel models in anticipation of the World Radiocommunications ...Conference in 2019 when the frequency allocation for 5G will be discussed. In response to the call for propagation path loss models, members of the study group carried out measurements in the frequency bands between 0.8 GHz up to 73 GHz in urban low‐rise and urban high‐rise as well as suburban environments. The data were subsequently merged to generate site general path loss models. The paper presents an overview of the radio channel measurements, the measured environments, the data analysis, and the approach for the derivation of the path loss model adopted in Recommendation ITU‐R P.1411‐10 (2019‐08).
Plain Language Summary
Wireless communication networks require the estimation of the attenuation suffered by radio signals as they propagate between the transmitter and receiver in different environments. The International Telecommunications Union recommendation sector (ITU‐R) provides models that can be used by network planners to guide the installation of base stations. The paper presents an overview of the model adopted in the recommendation ITU‐R, P. 1411‐10.
Key Points
Path loss model in the built environment for future wireless networks
Impact of model coefficients on Monte Carlo simulation
Site general models in ITU‐R recommendations
Methods Data was gathered in a 4-way crossover study in 24 subjects with 4 different oral formulations of gabapentin previously concluded to be bioequivalent by non-compartmental analysis.1 The ...non-parametric pharmacokinetic modelling software Pmetrics was used, which is capable of identifying unprespecified subpopulations in pharmacokinetic data.2 Models were validated using visual...
High crystalline quality thick films of single crystal CdTe were grown directly on (211) Si substrates using MOVPE growth technique for gamma ray detector fabrication. A highest growth-rate of 65 ...mum/h was achieved at a substrate temperature of 600 deg C. Films were monocrystalline as confirmed from the X-ray diffraction pattern. Results from the 4.2 K photoluminescence measurement showed films were of good crystalline quality. The gamma detector was fabricated in a p-CdTe/n-CdTe/n + -Si heterojunction diode structure, which exhibited clear rectifying behavior with a low value of room-temperature reverse bias leakage current, typically 0.11 muA/cm 2 at 100 V bias. The detector leakage current was reduced by three orders of magnitude from the room-temperature value at -30 deg C. The detector clearly demonstrated its spectroscopy capability by resolving energy peaks from the 241 Am gamma isotope.
A three-dimensional presynaptic calcium diffusion model developed to account for characteristics of transmitter release was modified to provide for binding of calcium to a receptor and subsequent ...triggering of exocytosis. When low affinity (20 microM) and rapid kinetics were assumed for the calcium receptor triggering exocytosis, and stimulus parameters were selected to match those of experiments, the simulations predicted a virtual invariance of the time course of transmitter release to paired stimulation, stimulation with pulses of different amplitude, and stimulation in different calcium solutions. The large temperature sensitivity of experimental release time course was explained by a temperature sensitivity of the model's final rate limiting exocytotic process. Inclusion of calcium tail currents and a saturable buffer with finite binding kinetics resulted in high peak calcium transients near release sites, exceeding 100 microM. Models with a single class of calcium binding site to the secretory trigger molecule failed to produce sufficient synaptic facilitation under this condition. When at least one calcium ion binds to a different site having higher affinity and slow kinetics, facilitation again reaches levels similar to those seen experimentally. It is possible that the neurosecretory trigger molecule reacts with calcium at more than one class of binding site.
Prolonged exposure to hyperoxia causes lung inflammation, but the role of Toll-like receptor 4 (TLR4) in hyperoxia-induced signal transduction remains unclear.
We evaluated neutrophil accumulation, ...signal transduction and cytokine production during hyperoxia, comparing TLR4 mutant (C3H/HeJ) and wild type (C3H/HeN) mice.
The mice were exposed to 80% oxygen in a hyperoxic chamber for 0 (control), 48, or 96 h. After the exposure, bronchoalveolar lavage (BAL) was performed for differential cell counting and cytokine measurement. In lung homogenate, activation of NF-kappaB and STAT1 was also examined.
In C3H/HeJ mice, hyperoxia-induced neutrophil accumulation in BAL fluid was significantly decreased compared with C3H/HeN. Hyperoxia for 96 h caused NF-kappaB translocation in C3H/HeN mice, which was significantly attenuated in C3H/HeJ mice (p < 0.05). In contrast, STAT1 activation occurred as early as after 48 h of oxygen exposure, which did not differ between the two strains. The levels of TNF-alpha, IL-6, and KC in BAL fluid were increased after oxygen exposure, which was suppressed by the lack of TLR4 signaling.
These results suggest that TLR4-dependent NF-kB activation may be an important process of the upregulation of proinflammatory mediators and subsequent neutrophil accumulation into the lung during hyperoxia.
We studied the effect of iodine doping of CdTe films on Si substrates grown by MOVPE at different growth conditions. A high resistivity film was obtained by adjusting the growth temperature, Te/Cd ...precursor flow ratio and the dopant flow-rate. Our results show the film resistivity does not change linearly with the dopant flow-rate. The resistivity remains low and similar to that of undoped value for low dopant flow-rate, but increases abruptly when the dopant flow-rate is increased beyond certain value. Photoluminescence measurements of the films confirmed the dopant incorporation in the crystal. We explained the result of resistivity change due to the compensation of excess shallow acceptors by deep intrinsic donors.
The possibility of AgCl remainder was confirmed in the production process of nano-Fe3O4/Ag granular system. The AgCl impurities contributed to large negative MR-ratio of about -4 and -6% at 300K and ...1T for x*=0.05 and 0.20 samples, respectively, where x* is the nominal Ag volume fraction of VAg/(VFe3O4+VAg). It was suggested that the formation of insulating AgCl barriers were effective for the large MR ratio in nano-Fe3O4 system.
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