Pharmacokinetic/Pharmacodynamic Modeling and Simulation of the Analgesic Effects of Pentazocine Using Perioperative Real-World Data.

Pentazocine (PTZ) is a widely used drug for postoperative pain. It should be administered at appropriate dosing intervals not only because of its morphine-like side effects but also because frequent inappropriate dosing can lead to dependence. Although perioperative patients reportedly have nonnegligible effects on placebo drugs and postoperative wound healing, no pharmacokinetic (PK)/pharmacodynamic (PD) model has been established and simulated using real-world data for the perioperative period. This study aimed to perform PTZ modeling and simulation and to establish an indicator of the timing of drug efficacy evaluation in clinical practice. Participants were in-hospital orthopedic surgery patients who received 15 mg of PTZ within 48 h postoperatively. Pain severity was assessed using the numerical rating scale (NRS). A two-compartment model was selected for the population PK model and an indirect response model for the PK/PD model. Using these models, a virtual population of 1000 patients with Painbase NRS of 5 and 6 and body weights of 40, 80, and 120 kg were treated with single and multiple PTZ administrations (4, 8, and 24 h apart) of 15 mg. Simulation results indicate that its analgesic efficacy should be evaluated within 1 h after administration of 15 mg of PTZ. Additional doses should be considered every 8-12 h in postoperative patients with Painbase NRS of 5 weighing 40-80 kg. Simulation using the PK/PD model developed in this study may provide useful information for determining the analgesic effects and timing of the dosing interval after PTZ administration in perioperative patients.

Fresh litter acts as a substantial phosphorus source of plant species appearing in primary succession on volcanic ash soil.

Plants have difficulty absorbing phosphorus from volcanic ash soils owing to the adsorption of phosphorus by aluminum and iron in the soils. Thus, on volcanic ash soils, the phosphorus source for natural vegetation is expected to be organic matter, however, there is a lack of experimental evidence regarding this occurrence. Here, we studied the effect of organic matter on plant growth of some species that occur in primary successions of volcanic ash soil ecosystems, based on growth experiments and chemical analyses. We found that a large amount of inorganic phosphorus (but only a limited amount of inorganic nitrogen) is leached from fresh leaf litter of the pioneer spices Fallopia japonica at the initial stage of litter decomposition. Phosphorus from the fresh litter specifically activated the growth of subsequently invading nitrogen-fixing alder when immature volcanic soil was used for cultivation. In contrast, old organic matter in mature soil was merely a minor source of phosphorus. These results suggest that fresh litter of F. japonica is essential for growth of nitrogen-fixing alder because the litter supplies phosphorus. We consider that rapid phosphorus cycles in fresh litter-plant systems underlie the productivity of natural vegetation even in mature ecosystems established on volcanic ash soils.

Monumental architecture at Aguada Fénix and the rise of Maya civilization.

Archaeologists have traditionally thought that the development of Maya civilization was gradual, assuming that small villages began to emerge during the Middle Preclassic period (1000-350 BC; dates are calibrated throughout) along with the use of ceramics and the adoption of sedentism1. Recent finds of early ceremonial complexes are beginning to challenge this model. Here we describe an airborne lidar survey and excavations of the previously unknown site of Aguada Fénix (Tabasco, Mexico) with an artificial plateau, which measures 1,400 m in length and 10 to 15 m in height and has 9 causeways radiating out from it. We dated this construction to between 1000 and 800 BC using a Bayesian analysis of radiocarbon dates. To our knowledge, this is the oldest monumental construction ever found in the Maya area and the largest in the entire pre-Hispanic history of the region. Although the site exhibits some similarities to the earlier Olmec centre of San Lorenzo, the community of Aguada Fénix probably did not have marked social inequality comparable to that of San Lorenzo. Aguada Fénix and other ceremonial complexes of the same period suggest the importance of communal work in the initial development of Maya civilization.

Coaxial semi-dipole antenna microwave feeding on electron cyclotron resonance multicharged ion source.

How to produce multicharged ions efficiently on an electron cyclotron resonance ion source (ECRIS) has been investigated at Osaka University. Notably, in recent years, we have focused on heating by new resonance superimposing to electron cyclotron resonance (ECR) plasma. To evaluate its efficiency, we need to know the maximum efficiency of heating with ECR alone, and then, further optimization of ECR heating is required. In consideration of wave propagation, we installed the coaxial semi-dipole antenna on the mirror end along the geometrical axis of the vacuum chamber. We aim at exciting the strength of right-hand polarization (RHP) waves for efficient ECR because RHP waves give rise to ECR. We measure plasma parameters by Langmuir probes and charge state distributions (CSDs) of the extracted ion beams and investigate their qualitative tendencies to incident microwave powers and pressures. We compare the qualitative trend of ion beams and their CSD on microwave power in the case of both the microwave feeding system by the coaxial semi-dipole antenna and that by the rod antenna. Differences between the microwave feeding system before improving and then after upgrading are made clear.

Improving transport and optimizing deceleration of ion beams from electron cyclotron resonance multicharged ion sources.

Electron cyclotron resonance ion sources (ECRISs) are widely applied for ion beam applications, e.g., plasma processing, cancer therapy, and ion engine of an artificial satellite. In our ECRIS, we aim at producing and extracting various ion beams from this device, in particular, Xeq+ ion beams at low energy. In the aerospace engineering field, there are problems of accumulated damages on various component materials caused by low energy of Xe ions from the engine. There are not enough experimental sputtering data for satellite materials at the Xeq+ in the low energy region. Then, we are trying to investigate the sputtering yield experimentally by irradiating the low energy Xe ion beams. To perform this experiment, it is necessary to acquire a certain amount of beam current with low energy. Then, we generate the low energy ion beams by the following steps: First, the ion beams are extracted from the ECRIS at high voltage. Next, these are transported to an ion beam irradiation system (IBIS). Finally, the ion beams are decelerated by the deceleration voltage in the IBIS. We adjusted the beamline. We measure the characteristics of the transport efficiency and decelerated ion beam currents. In this paper, we describe the experimental setup using an existing ECRIS for decelerated heavy ion beams and the results of decelerated ion beam currents.

Upper hybrid resonance heating experiments by X-mode microwaves on electron cyclotron resonance ion source.

We have considered the accessibility condition of electromagnetic and electrostatic waves propagating in an electron cyclotron resonance (ECR) ion source (ECRIS) plasma and then investigated experimentally their correspondence relationships with production of multicharged ions. It has been clarified that there exists an efficient configuration of ECR zones for producing multicharged ion beams and has been suggested that a new resonance, i.e., upper hybrid resonance (UHR), must have occurred. We have been trying to perform advanced experiments with 4-6 GHz X-mode microwaves to the 2.45 GHz ECRIS plasma, and we have succeeded in enhancing the production of multicharged ions by launching X-mode microwaves of these bands. Furthermore, at the same time, we have observed sharp increases in electron energy distribution functions in the ECRIS plasma by means of probe methods. It has been concluded that the UHRs must have occurred when applying multiplex microwaves with their frequencies away from those frequencies for ECR in the ECRIS. In this paper, we will describe in brief the theoretical background and the results of these new experiments.

Improving multipole magnets and background vacuum conditions on electron cyclotron resonance ion sources.

Electron cyclotron resonance ion sources (ECRISs) are used in various fields such as accelerator physics, engineering, cancer therapy, and ion engines in the satellite. We are aiming to improve the production of multicharged ions efficiently at the point of view from the length of multipole magnets and vacuum conditions in the ECRIS. The diameter of the connection pipe between the main chamber and diffusion pump was made larger to improve vacuum conductance. Moreover, the length of multipole magnets with the direction along the geometrical axis in the ECRIS was extended. The effects of these improvements are investigated experimentally to measure the pressure in the vacuum chamber, beam intensity, charge state distributions of extracted ion beams, and plasma parameters. The purity of extracted ion beams and magnetic confinement have been enhanced. These results are expected to have positive effects on the production of various species and synthesized ion beams, e.g., production of iron endohedral fullerene in the future experiments in the ECRIS.

Lithic technology, chronology, and marine shells from Wadi Aghar, southern Jordan, and Initial Upper Paleolithic behaviors in the southern inland Levant.

The Initial Upper Paleolithic (IUP) temporally overlaps with the range expansion of Homo sapiens populations in various parts of Eurasia and is often considered a key archaeological phase for investigating behavioral changes from the Middle Paleolithic. This paper reports upon new data from IUP occupations at Wadi Aghar, a rock shelter site in the southern Levant. In combining the results of radiometric dates and lithic analyses, we clarify the chronological and cultural position of Wadi Aghar assemblages in the Levantine IUP. As for the records about mobility, on-site activities, and resource procurement behaviors, we present analyses of lithic use-wear, tool-type composition, soil micromorphology, and marine shells. The lithic analyses and the optically stimulated luminescence (and subsidiary radiocarbon) dating of the Wadi Aghar materials suggest their chronocultural position in the IUP (45-40 ka for Layers C-D1; 39-36 ka for Layer B; possibly 50 ka for Layer D2), providing the southernmost location for the IUP in Eurasia. In the Levant, Wadi Aghar represents one of the few IUP sites in the inland areas. The results also indicate that the timing and technological sequences from the IUP to the following bladelet industries differed between the inland and coastal zones, likely reflecting geographically variable adaptive behaviors and/or cultural transmissions. One of the behavioral characteristics of IUP foragers at Wadi Aghar is the procurement of remote resources, represented by the transportation of marine shells from the Red Sea: Canarium fusiforme and Canarium cf. mutabile. Whether it was a direct procurement with increased mobility or a result of intergroup exchanges, it was not part of behavioral repertoires during the late MP in the same area. This can be understood as the expansion of resource procurement range, functioning as additional buffers from risk in the semiarid environments in the inland Levant.

Interpretation of bulk nitrogen and carbon isotopes in archaeological foodcrusts on potsherds.

RATIONALE: Foodcrust, the charred deposit adhering to the surface of containers, is a possible source of information on the function of ancient vessels and the subsistence of prehistoric humans. While the carbon isotope ratios in those materials are useful in detecting the usage of C4 plants, the reliability of nitrogen isotopic signatures has not been fully investigated. METHODS: The validity of bulk nitrogen isotope ratios has previously been investigated in coastal or riverine environments, where multiple resources from terrestrial and aquatic ecosystems were available, but not in terrestrial settings which provide a simpler mixing of terrestrial animals and plants. Hence, we conducted an exhaustive study on charred deposits on potsherds at two inland archaeological sites belonging to prehistoric Jomon hunter-gathers in central Japan, focusing on δ15 N values and atomic N/C ratios determined using an isotope ratio mass spectrometer and an elemental analyzer, respectively. RESULTS: For both sites, the δ15 N values showed significant correlations with the N/C ratios among samples from the inner surface, suggesting that these have recorded animal contribution. Furthermore, previous studies of Neolithic pottery from North Europe and Far East Russia bearing strong marine signatures had shown reasonably higher δ15 N values and N/C ratios in comparison with our data from terrestrial settings. On the other hand, some charred materials probably originating from plant starch showed lower values with both parameters. Samples from the outer surface produced less meaningful isotopic and elemental ratios altered by a thermal effect and/or contamination from soot. CONCLUSIONS: When the samples of foodcrusts were selected carefully from the inner surface, bulk nitrogen isotopes and N/C ratios reflect the composition of what was cooked or processed in containers. This will provide useful information for understanding the human adaptation from the Late Pleistocene to the Holocene in conjunction with residual lipid analyses.

Origin and migration of trace elements in the surface sediments of Majuro Atoll, Marshall Islands.

The sediments of Majuro Atoll, Marshall Islands, consist of bioclastic materials, including foraminifera and coral debris. The sedimentary depth profiles of elements showed that various elements including zinc (Zn) and copper (Cu) were enriched in the upper layers of the islands of Majuro Atoll. Carbon-14 dating revealed that the sedimentation of the upper layer was completed before 1670 and 542 cal BP in Laura and Calalen, respectively. The enriched elements could be categorized by their origins: (a) terrestrial elements transported as dust (aluminum (Al) and rare earth elements (REEs)); (b) anthropogenic elements (Zn and Cu); and (c) elements supplied by seabirds (phosphorus (P)). From the results of the total amount of Al supplied to sediments for ca. 2000 years, Al in Majuro Atoll was suggested to be airborne origin. The enrichment factors of the elements normalized to Al concentration of continental crust showed that REEs were also transported as dust, while Zn and Cu were mainly of anthropogenic origin. The speciation analysis by X-ray absorption near-edge structure (XANES) showed the presence of Zn-Cu alloys originated from industrial products. It was also revealed that Zn was enriched in the surface due to anthropogenic emission after urbanization on Majuro Atoll and fixed by carbonate and phosphate at the upper layer, which inhibits migration of Zn into the deeper layer and its release to the groundwater and costal water. Hence, the fixation of heavy metals at the surface prevents their exposure to aquatic organisms and residents via fresh groundwater in the island.

Variability in Early Ahmarian lithic technology and its implications for the model of a Levantine origin of the Protoaurignacian.

This paper re-examines lithic technological variability of the Early Ahmarian, one of the early Upper Palaeolithic cultural entities in the Levant, which has often been regarded as a precursor of the Protoaurignacian (the early Upper Palaeolithic in Europe) in arguments for the occurrence of a cultural spread in association with the dispersal of Homo sapiens from the Levant to Europe. Using quantitative data on several lithic techno-typological attributes, we demonstrate that there is a significant degree of variability in the Early Ahmarian between the northern and southern Levant, as previously pointed out by several researchers. In addition, we suggest that the technology similar to the southern Early Ahmarian also existed in the northern Levant, i.e., the Ksar Akil Phase 4 group (the KA 4 group), by introducing new Upper Palaeolithic assemblages from Wadi Kharar 16R, inland Syria. We then review currently available stratigraphic records and radiocarbon dates (including a new date from Wadi Kharar 16R), with special attention to their methodological background. As a result, we propose alternative chronological scenarios, including one that postulates that the southern Early Ahmarian and the KA 4 group appeared later than the northern Early Ahmarian with little or no overlap. On the basis of the alternative scenarios of chronological/geographical patterns of the Early Ahmarian variability, we propose four possible relationships between the Protoaurignacian and the Early Ahmarian, including a new scenario that the appearance of the Protoaurignacian preceded those of similar technological entities in the Levant, i.e., the southern Early Ahmarian and the KA 4 group. If the last hypothesis is substantiated, it requires us to reconsider the model of a Levantine origin of the Protoaurignacian and its palaeoanthropological implications.

Pharmacokinetic/pharmacodynamic modeling and simulation of rosuvastatin using an extension of the indirect response model by incorporating a circadian rhythm.

Pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation enable the prediction of the effect of a medication in various situations in clinical practice. The aims of this study were to predict the relationships between the effect of rosuvastatin and various factors such as poor compliance, and morning and evening dosages, as well as the change in the pharmacokinetics of rosuvastatin. We characterized the PK/PD model of plasma mevalonic acid (MVA) profiles after rosuvastatin administration and simulated the plasma MVA concentration in various dosage regimens. The plasma rosuvastatin and MVA concentrations reported by Martin et al. were used as the source of PK/PD modeling data. For each simulation, a summary parameter, the area under the plasma MVA concentration-time curves for 24 h in the steady state (AUEC(24)), was used to characterize the time course of each endpoint. To estimate the influence of PK parameters on rosuvastatin effects, the AUEC(24) reduction ratio of baseline levels was simulated from the 0.33-3.0-fold value of each PK parameter estimate. The AUEC(24) reduction ratio was 7.7% lower after morning administration than after evening administration. The changes in the PK parameters more prominently affected the AUEC(24) reduction ratio after morning administration than after evening administration. The simulated plasma MVA concentrations almost reached their baseline levels in the case of patients who forgot to take rosuvastatin. These results suggest that the parameters can be used to determine the effective rosuvastatin dosage regimen.