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OBJECTIVE: We implemented a stepwise antimicrobial stewardship program (ASP). This study evaluated the effect of each intervention and the overall economic impact on carbapenem (CAR) use. METHOD: Carbapenem days of therapy (CAR-DOT) were calculated to assess the effect of each intervention, and antipseudomonal DOT were calculated to assess changes in use of broad-spectrum antibiotics. We carried out segmented regression analysis of studies with interrupted time series for 3 periods: Phase 1 (infectious disease [ID] consultation service only), Phase 2 (adding monitoring and e-mail feedback), and Phase 3 (adding postprescription review and feedback [PPRF] led by ID specialist doctors and pharmacists). We also estimated cost savings over the study period due to decreased CAR use. RESULTS: The median monthly CAR-DOT, per month per 100 patient-days, during Phase 1, Phase 2, and Phase 3 was 5.46, 3.69, and 2.78, respectively. The CAR-DOT decreased significantly immediately after the start of Phase 2, but a major decrease was not observed during this period. Although the immediate change was not apparent after Phase 3 started, CAR-DOT decreased significantly over this period. Furthermore, the monthly DOT of 3 alternative antipseudomonal agents also decreased significantly over the study period, but the incidence of antimicrobial resistance did not decrease. Cost savings over the study period, due to decreased CAR use, was estimated to be US $150 000. CONCLUSIONS: Adding PPRF on the conventional ASP may accelerate antimicrobial stewardship. Our CAR stewardship program has had positive results, and implementation is ongoing.

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To elucidate development of shear-induced damage in erythrocytes, it is necessary to visualize erythrocytes under high-shear flow. Therefore, we prototyped a special shear flow chamber with a counter-rotating mechanism consisting of a transparent acrylic cone and a glass plate. The flow chamber was mounted on an inverted microscope and illuminated by a 350-W metal halide lamp. This experimental system made it possible for a digital video camera to record through the microscopes' objective lens the rheological behavior in shear flow of erythrocytes diluted in highly viscous polyvinyl pyrrolidone. We successfully visualized the blood cells' ellipsoidal deformation response to an unphysiological, high shear stress of 288 Pa, their shift into abnormal rheological behavior, and final collapse. When abnormality first appeared, the membrane surface of some ellipsoidal erythrocytes started undulating and their shape became more asymmetric. Finally, the erythrocytes appeared to fragment, although the fragments continued tumbling together suggesting that they were all still connected. One such abnormal erythrocyte became segmented through collision with other cell. The undulation of the membrane surface when erythrocytes experienced trauma suggests possible detachment of the lipid bilayer from the membrane cytoskeleton. As the damage increased, the morphological abnormality of cells became greater with less tank-treading, and then, the erythrocytes started tumbling. This unstable behavior increases the volume of flow region occupied by the erythrocytes and increases the chance that neighboring cells will hit them and break them into segmented pieces. This study clearly showed that the beginning of erythrocytes' morphological abnormality was induced by shear stress.

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To understand the mechanism of muscle remodeling during Xenopus laevis metamorphosis, we examined the in vitro effect of insulin-like growth factor 1 (IGF-1) on growth and differentiation of three different-fate myogenic cell populations: tadpole tail, tadpole dorsal, and young adult leg muscle. IGF-1 promoted growth and differentiation of both tail and leg myogenic cells only under conditions where these cells could proliferate. Inhibition of cell proliferation by DNA synthesis inhibitor cytosine arabinoside completely canceled the IGF-1's cell differentiation promotion, suggesting the possibility that IGF-1's differentiation-promotion effect is an indirect effect via IGF-1's cell proliferation promotion. IGF-1 promoted differentiation dose dependently with maximum effect at 100-500 ng/ml. RT-PCR analysis revealed the upregulation (11-fold) of ifg1 mRNA expression in developing limbs, suggesting that IGF-1 plays a role in promoting muscle differentiation during limb development. The combined effect of triiodo-L-thyronine (T3) and IGF-1 was also examined. In adult leg cells, IGF-1 promoted growth and differentiation irrespective of the presence of T3. In larval tail cells, cell count was 76% lower in the presence of T3, and IGF-1 did not promote proliferation and differentiation in T3-containing medium. In larval dorsal cells, cell count was also lower in the presence of T3, but IGF-1 enhanced proliferation and differentiation in T3-containing medium. This result is likely due to the presence among dorsal cells of both adult and larval types (1:1). Thus, IGF-1 affects only adult-type myogenic cells in the presence of T3 and helps accelerate dorsal muscle remodeling during metamorphosis.

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Insertion of a solute into a vessel comprising biopolymers is a fundamental function in a biological system. The entropy originating from the translational displacement of solvent particles plays an essential role in the insertion. Here we study the dynamics of entropic insertion of a large spherical solute into a cylindrical vessel. The solute and the vessel are immersed in small spheres forming the solvent. We develop a theoretical method formulated using the Fokker-Planck equation. The spatial distribution of solute-vessel entropic potential, which is calculated by the three-dimensional integral equation theory combined with rigid-body models, serves as input data. The key quantity analyzed is the density of the probability of finding the solute at any position at any time. It is found that the solute is inserted along the central axis of the vessel cavity and trapped at a position where the entropic potential takes a local minimum value. The solute keeps being trapped without touching the vessel inner surface. In a significantly long time τ, the solute transfers to the position in contact with the vessel bottom possessing the global potential minimum along the central axis. As the solute size increases, τ becomes remarkably longer. We also discuss the relevance of our result to the functional expression of a chaperonin/cochaperonin in the assistance of protein folding.

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The pharmacokinetics of meropenem have not yet been examined in Japanese patients receiving Continuous venovenous hemodialysis (CVVHD). The aim of this clinical investigation was to determine the pharmacokinetic parameters of meropenem in critically ill patients receiving CVVHD in order to estimate dosing regimens for the patient population in Japan. The values of pharmacokinetic parameters were 17.5 ± 5.6 l for V1, 1.27 ± 0.38 h(-1) for K12, 0.71 ± 0.40 h(-1) for K21 and 0.17 ± 0.02 h(-1) for K10. Based on these mean parameters (V1, K12, K21 and K10), time above MIC (T > MIC) values were estimated at different MICs using various meropenem regimens. For bacteria with a meropenem MIC of ≤ 2 µg/ml, a dosing regimen of 0.25 g every 24 h achieved more than 40% T > MIC. For a MIC of 4 µg/ml, all the regimens tested, except for 0.25 g every 24 h, achieved more than 40% T > MIC. For a MIC of 16 µg/ml, dosing regimens of 0.5 g every 8 h, 1 g every 12 h, and 1 g every 8 h achieved 40% T > MIC, reaching the pharmacokinetic-pharmacodynamic target range. This is the first study to examine the pharmacokinetics of meropenem under a CVVHD setting in Japan. The pharmacokinetic-pharmacodynamic profile of dosing regimens tested in this study will assist in selecting the appropriate meropenem regimens for patients receiving CVVHD.

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