Background and purpose: Nitric oxide (NO) production and depression of neuromuscular transmission are closely related, but little is known about the role of L-citrulline, a co-product of NO biosynthesis, on neurotransmitter release. Experimental approach: Muscle tension recordings and outflow experiments were performed on rat phrenic nervehemidiaphragm preparations stimulated electrically.
In the 'Identification of eligible trials' of the Results section, we stated that a total of 1635 asthma patients were identified from six trials. Kerstjens et al. mention that the sum of the number of tiotropium patients and control patients exceeds the quoted total number of asthma patients. We acknowledge that this was ambiguous, and would like to clarify that of the trials that were finally included, three (Fardon et al, Peters et al, and Kerstjens et al. 2011) were originally designed as cross-over trials. So, although the actual number of patients totalled 1635 (as shown in Table 1), it was natural that the sum of number of patients from each group exceeded 1635, as patients from cross-over trials underwent both interventions. Finally as Drs Kerstjens and Moroni-Zentraf indicated, we need to highlight that the baseline FEV 1 (%) value from Bateman's trial refers to the placebo treatment arm. In addition, we would like to correct the baseline FEV 1 (%) for the tiotropium treatment arm as 74.1 6 16.12.
The aim of this work is the development of a novel framework for structural optimization using bio-inspired remodelling algorithm adapted to additive manufacturing. The fact that polylactic acid (PLA, E = 3145 MPa (Young’s modulus) according to the supplier for parts obtained by injection) shows a similar parameterized behavior with ductile metals, in the sense that both materials are characterized by a bi-linear elastic-plastic law, allows to simulate and prototype parts to be further constructed in ductile metals at a lower cost and then be produced with more expensive fabrication processes. Moreover, cellular materials allow for a significant weight reduction and therefore reduction of production costs. Structural optimization algorithms based on biological phenomena were used to determine the density distribution of the infill density of the specimens. Several simple structures were submitted to distinct complex load cases and analyzed using the mentioned optimization algorithms combined with the finite element method and a meshless method. The surface was divided according to similar density and then converted to stereolitography files and infilled with the gyroid structure at the desired density determined before, using open-source slicing software. Smoothing functions were used to smooth the density field obtained with the remodeling algorithms. The samples were printed with fused filament fabrication technology and submitted to mechanical flexural tests similar to the ones analyzed analytically, namely three- and four-point bending tests. Thus, the factors of analysis were the smoothing parameter and the remodeling method, and the responses evaluated were stiffness, specific stiffness, maximum force, and mass. The experimental results correlated (obtaining accuracy of 35% for the three-point bending load case and 5% for the four-point bending load case) to the numerical results in terms of flexural stiffness and it was found that the complexity of the load case is relevant for the efficiency of the functional gradient. The fused filament fabrication process is still not accurate enough to be able to experimentally compare the results based of finite element method and meshless method analyses.
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