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Machining contours on a large thin-walled part is a difficult task due to inevitable deformation of the actual part. The deformation of the contour can significantly influence the rigidity of the thin-walled part; thus, it is of importance to minimize the deformation of the contour compared with the design contour. This paper proposes a novel method to adaptively calculate the optimal contour on the deformed surface based on optimized parallel projection. The geometry data of free-form surface is obtained by on-machine measurement (OMM), and then, the actual surface is reconstructed using the measurement data. The reconstructed surface is matched with the design surface, and then, the design contour was projected onto the reconstructed surface to obtain the locating contour. The iterative nearest point (ICP) algorithm is used to adjust the design contour to match the locating contour. Finally, the projection direction is optimized to minimize contour deformation, and the adjusted contour is projected onto the reconstructed surface along the optimal direction to obtain the new contour. The effectiveness of this method is verified by machining and measuring experiments. [ABSTRACT FROM AUTHOR]

B-spline curve approximation is widely used for fitting linear toolpaths to improve machining quality and efficiency in CNC machining. For a high-quality smoothing method, the control of both approximation error and curve curvature needs to be taken into account. To reduce the maximum curve curvature while meeting the precision requirements, a B-spline approximation scheme with tool tip position adjustment is proposed in this paper. Toolpaths are first divided into several subdivisions according to the discrete curvature of each tool tip point. For subdivisions that need adjustment, tool tip positions are adjusted to minimize the maximum discrete curvature. An existing approximation method named energy-term-incorporated progressive and iterative approximation for least square fitting (ELSPIA) is selected and improved to fit the adjusted toolpaths and lower the chord errors. For improving the numerical stability of the ELSPIA method, the way of searching appropriate foot point parameters is discussed in this paper. Deviation expansion factors of tooltip points are also defined to make the ELSPIA method suitable for fitting the adjusted toolpaths. Both simulations and experimental studies are conducted to prove that the proposed method can significantly decrease the maximum curvature of fitted B-spline curves and improve the machining efficiency without exceeding the tolerance. For example, experimental results show that for the tested butterfly and rabbit toolpaths, the proposed method can improve the machining efficiency by 2.61% and 2.37%, compared with the ELSPIA method without tool tip position adjustment. [ABSTRACT FROM AUTHOR]

Purpose: To develop a mathematical model combined between physiologically based pharmacokinetic and BTK occupancy (PBPK-BO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of acalabrutinib (ACA) and active metabolite ACP-5862 in healthy humans as well as PD in patients. Next, to use the PBPK-BO to determine the optimal dosing regimens in patients alone, with different CYP3A4 variants, when co-administration with four CYP3A4 modulators and in patients with hepatic impairment, respectively. Methods: The PBPK-BO model was built using physicochemical and biochemical properties of ACA and ACP-5862 and then verified by observed PK and PD data from healthy humans and patients. Finally, the model was applied to determine optimal dosing regimens in various clinical situations. Results: The simulations demonstrated that 100 mg ACA twice daily (BID) was the optimal dosing regimen in patients alone. Additionally, dosage regimens might be reduced to 50 mg BID in patients with five CYP3A4 variants. Moreover, the dosing regimen should be modified to 100 mg (even to 50 mg) once daily (QD) when co-administration with erythromycin or clarithromycin, and be increased to 200 mg BID with rifampicin, and but be avoided co-administration with itraconazole. Furthermore, dosage regimen simulations showed that optimal dosing might be decreased to 50 mg BID in patients with mild and moderate hepatic impairment, and be avoided taking ACA in severely hepatically impaired patients. Conclusion: This PBPK-BO model can predict PK and PD in healthy humans and patients and also predict the optimal dosing regimens in various clinical situations. [ABSTRACT FROM AUTHOR]