A useful testing strategy is proposed for a confirmatory phase III clinical trial. It consists of a combined test of superiority and test of equivalence, and it is easy to apply. By introducing the strategy, we can perform a post hoc analysis in a confirmatory experiment. Thus a more flexible decision will be possible than the usual single testing method provides. It is shown that the procedure needs no adjustment for multiplicity from the point of view of the closed testing procedure. The relationship between this strategy and a confidence interval is also discussed.

The preferential solvent interaction with bovine serum albumin in aqueous solution of polyhydric alcohols (ethylene glycol, glycerol, xylitol, sorbitol, mannitol, and inositol) was investigated by a densimetric method with the application of multicomponent theory. This proteins was preferentially hydrated in all solvent systems examined: the extent depended on the number and the steric configuration of the hydroxyl groups of alcohols. The absolute interactions of these alcohols with the protein were estimated by assuming that the amount of hydration of protein at every solvent composition used is identical with that in pure water. The preferential hydration of the protein in 30% aqueous solutions of glycerol and sorbitol was found to decrease as the temperature was increased, indicating that the increase in chemical potential of protein on transferring it from water to both aqueous solvents is generated by a large positive enthalpy change, sufficient to compensate for the positive entropy change in the transfer process. On the basis of these results, and mechanism of stabilization of protein structure by these alcohols was discussed from the viewpoint of the solvation of protein.

When designing a noninferiority/equivalence trial, the sponsor intends to show efficacy by demonstrating that a new treatment is as good as or not worse than a known effective treatment by a small predefined margin. To confirm noninferiority/equivalence of the new treatment to an active control, "sensitivity-to-drug-effects" and "assay sensitivity, " as defined in the International Conference on Hamnization (ICH) E l 0 Guideline (1,2) must be supported. Otherwise, a finding of mere nonsigni3cant difference between treatments in the traditional setting of significance testing leaves the question unanswered: Would the trial have concluded noninferiority while the new treatment was, in fact, inferior?This paper first reviews the choice of control and the crucial issues of sensitivity-todrug-effects and assay sensitivity. Then, it discusses the choice of the noninferiority/ equivalence margin and the forms of the null and alternative hypotheses and confidence intervals. Finally, it addresses the inherent difficulties and some useful design alternatives to the noninferiority/equivalence trials.

In order to clarify the mechanism of polyol-induced stabilization of protein, the thermodynamic parameters (delta G degree, delta H degree, and delta S degree) of thermal denaturation of chymotrypsinogen have been measured in aqeous solutions of some polyols (ethylene glycol, erythritol, adonitol, sorbitol, mannitol, and inositol) by a differential spectrophotometric method. On increasing the alcohol concentration and the number of hydroxymethyl groups of the alcohols, delta G degree increased as a result of a large decrease in delta S degree compensating for a decrease in delta H degree. This result means that the stabilization of this protein by polyols is due to the entropy effect, and that the free energy change of transfer of the denatured protein from water to aqueous media containing these alcohols must be larger than that of the native protein. This strongly supports the previous proposal that the driving force of protein stabilization induced by polyols is a solvent medium effect or a solvent ordering effect. The decreases in delta H degree and delta S degree with polyols are expected to be more due to the effects of polyols on peptide-water interactions than to exposed nonpolar groups of denatured protein.

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Brittle-ductile transition (BDT) behaviour was investigated in low carbon steel deformed by an accumulative roll-bonding (ARB) process. The temperature dependence of its fracture toughness was measured by conducting four-point bending tests at various temperatures and strain rates. The fracture toughness increased while the BDT temperature decreased in the specimens deformed by the ARB process. Arrhenius plots between the BDT temperatures and the strain rates indicated that the activation energy for the BDT did not change due to the deformation with the ARB process. It was deduced that the decrease in the BDT temperature by grain refining was not due to the increase in the dislocation mobility controlled by short-range obstacles. Molecular dynamics simulations revealed that moving dislocations were impinged against grain boundaries, creating a shielding field, and were reemitted from there with increasing strain. Grain refining led to an increase in the fracture toughness at low temperatures and a decrease in the BDT temperature. In the present paper, the roles of grain boundaries have been discussed in order to explain the enhancement in the fracture toughness of fine-grained materials at low temperatures, and the decrease in the BDT temperature.

The microstructures of ¡-Mg, long-period stacking ordered (LPSO) phases, and kink bands in a MgYZn alloy were observed by transmission electron microscopy (TEM). The results showed that extruded Mg 97 Zn 1 Y 2 alloy included different kinds of phases: 2H-Mg, 2H-Mg with many stacking faults, 14H and 18R. Kink bands tended to occur in areas where there were many intermetallic compounds. The element distribution of Zn/Y/Mg in the LPSO phase including kink boundaries was also analyzed by scanning TEM energy dispersive X-ray spectroscopy. The results showed that the concentrations of atomic Zn/Y decreased, while the concentration of atomic Mg increased at kink boundaries. This can be understood in terms of the dislocation structure of kink boundaries where extended a-dislocations lying on sequential stacking faults in the LPSO phase cause the annihilation of Zn/Y-rich stacking faults between two partial dislocations.