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Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

Effective treatment of diabetic kidney disease (DKD) remains a large unmet medical need. Within the disease’s complicated pathogenic mechanism, activation of the advanced glycation end-products (AGEs)–receptor for AGEs (RAGE) axis plays a pivotal role in the development and progression of DKD. To provide a new therapeutic strategy against DKD progression, we developed a vaccine against RAGE. Three rounds of immunization of mice with the RAGE vaccine successfully induced antigen-specific serum IgG antibody titers, and elevated antibody titers were sustained for at least 38 weeks. In addition, RAGE vaccination significantly attenuated the increase in urinary albumin excretion in streptozotocin-induced diabetic mice (type 1 diabetes model) and leptin-receptor–deficient db/db mice (type 2 diabetes model). In microscopic analyses, RAGE vaccination suppressed glomerular hypertrophy and mesangial expansion in both diabetic models and significantly reduced glomerular basement membrane thickness in streptozotocin-induced diabetic mice. Results of an in vitro study indicated that the serum IgG antibody elicited by RAGE vaccination suppressed the expression of AGE-induced vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 in endothelial cells. Thus, our newly developed RAGE vaccine attenuated the progression of DKD in mice and is a promising potential therapeutic strategy for patients with DKD.

Laboratory tests of adolescents are often interpreted by using reference intervals derived from adults, even though these populations differ in their physical and physiologic characteristics and disease susceptibility. Therefore, to examine the distribution of laboratory values specific for adolescents, we analyzed hematologic and biochemical measurements obtained from 12,023 healthy Japanese adolescents (ages 15 through 18 years; male, 9165; female, 2858) during 2009 through 2018. Distributions were shown as medians with 95% (2.5th and 97.5th percentiles) of values and were compared with those from previous studies that examined similar Asian populations. There were some differences between hematologic parameters, serum creatinine and uric acid concentration, and lipid levels of Japanese adults and adolescents. In comparison with other Asian populations, the distributions of serum uric acid and high-density–lipoprotein cholesterol in the present study were slightly higher than those in the other studies. Although further research is need, the distributions of hematologic and biochemical tests in adolescents may have the potential to facilitate the early identification and management of disease in this population.

Accumulation of DNA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DNA DSBs with altered DNA methylation in murine models of kidney disease. However, DSBs and DNA methylation in human kidneys was not adequately investigated. This study was a cross-sectional observational study to evaluate the glomerular DNA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance PCR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DNA methylation level in IgA nephropathy. Podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of PCR product of the nephrin gene, which indicate podocyte DNA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGFR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in IgA nephropathy.

Background and aims: Low birth weight is associated not only with poor birth outcome but also chronic health conditions such as hypertension in later life. B-type natriuretic peptide (BNP) is a prognostic factor of cardiovascular events in the general population. However, the association between birth weight and BNP remains unclear. Here, we examined the relationships among birth weight and risk factors for atherosclerosis, including BNP, in Japanese workers. Methods: A total of 1109 (517 male, 592 female; age 40–70 years) participants in an annual medical checkup were enrolled. Subjects were divided into three groups according to birth weight, and the associations between their birth weight and risk factors for atherosclerosis were examined by statistical analysis. Results: Jonckheere–Terpstra trend test according to birth weight category revealed that although birth weight was not correlated with BNP level, it was inversely associated with HbA1c in men and with diastolic blood pressure in women. Correlation coefficient tests for both categorical and continuous birth weight data confirmed the trend test findings. Multiple regression analysis indicated that birth weight was an explanatory factor for HbA1c in men and for diastolic blood pressure in women. Conclusions: Although no significant association was observed between birth weight and BNP, inverse associations between birth weight and HbA1c in men and diastolic blood pressure in women were found. These findings suggest that birth weight may partially predict future risk of cardiovascular events.

Clinical availability of anti-obesity drugs is limited, and their inadequate effectiveness and safety concerns sometimes discourage widespread use. A therapeutic vaccine has the potential to be an attractive tool for preventing and treating obesity, because of the possibility of prolonged therapeutic effect and low frequency of administration. Experimental investigations have shown that vaccines targeting endogenous molecules that promote obesity could be a viable alternative. Recent novelties in drug-delivery systems and biotechnology will support further progress in vaccine development. This chapter provides an overview of recent advances in the area.

Chapter 1 investigated explicit optimal design problems and illustrated different approaches for obtaining optimality conditions. Terminology and results utilized in optimization theory were also used. This chapter presents a systematic discussion of optimization theory.

The main topic of this book is optimal design. In order to understand the mathematical structures involved in our study, we will begin by examining two simple problems. Upon finishing this book, the reader should be able to understand that even shape optimization problems of continuum structures possess the same formulation as the problems dealt with in this chapter. Moreover, even if the target continuum is changed from linear elastic body or flow field dealt in this book, the reader will recognize that their corresponding shape optimization problems maintain the fundamental structures introduced in this book.

In Chap. 2, we discussed the conditions satisfied by a local minimum point (the required conditions of a local minimum point) and the conditions which guarantee it to be a minimum point (sufficient conditions for a minimum point) under a finite-dimensional vector space setting. No detailed explanation, however, was provided regarding the method (solution) for finding the local minimum point. In this chapter, we would like to address this ensuing matter. The computational formulation associated to such a problem is called an optimization problem or a mathematical programming problem, and active research is being conducted in the academic field referred to as operations research (OR). Here, we will consider algorithms while showing results that are theoretically obtained or ways to deal with the solution of optimization problems. Much of the content covered here is also valid for abstract optimal design problems in Chap. 7. In fact, in Chap. 7 we will see how the same algorithms can be adapted for function spaces.

In Chap. 5, covering several boundary value problems of elliptic partial differential equations, we saw that the existence of their unique solutions could be guaranteed using solutions of the weak form. These will be referred to as the exact solutions. Exact solutions can be found analytically if the shape of the domain is somewhat simple such as a rectangle or an ellipse. However, difficulties arise for domains whose shape may have arbitrarily moved as examined in this book. In order to solve a shape optimization problem, even if an exact solution is not possible, one can resort to a numerical analysis method to obtain an approximate solution.

The aim of the present study is to analyze the stability of the pressure gradient driven modes (PM) and Alfvén eigenmodes (AE) in the large helical device (LHD) plasma if the rotational transform profile is modified by the current drive of the tangential neutral beam injectors (NBI). This study forms a basic search for optimized operation scenarios with reduced mode activity. The analysis is performed using the code FAR3d which solves the reduced MHD equations describing the linear evolution of the poloidal flux and the toroidal component of the vorticity in a full 3D system, coupled with equations for density and parallel velocity moments of the energetic particle (EP) species, including the effect of the acoustic modes. The Landau damping and resonant destabilization effects are added via the closure relation. On-axis and off-axis NBI current drive modifies the rotational transform which becomes strongly distorted as the intensity of the neutral beam current drive (NBCD) increases, leading to wider continuum gaps and modifying the magnetic shear. The simulations with on-axis NBI injection show that a counter (ctr-) NBCD in inward shifted and default configurations leads to a lower growth rate of the PM, although strong n = 1 and 2 AEs can be destabilized. For the outward shifted configurations, a co-NBCD improves the AEs stability but the PM are further destabilized if the co-NBCD intensity is 30 kA T−1. If the NBI injection is off-axis, the plasma stability is not significantly improved due to the further destabilization of the AE and energetic particle modes (EPM) in the middle and outer plasma region. This work is supported in part by NIFS under contract NIFS07KLPH004.

We have seen in Chaps. 5 and 6 how boundary problems of partial differential equations are constructed and how they are solved. If we compare them to the optimum design problems looked at in Chap. 1, they correspond to state determination problems. From this chapter, we finally start thinking about optimum design problems targeting the shape or topology of a domain in which the boundary value problem is defined. In this chapter, we construct an abstract problem common to both problems, and explore the ways to solve them.

In Chap. 8 we looked at problems for obtaining the optimal topologies of continua with the densities of continua set to be the design variable. In this chapter, we shall look at the type of shape optimization problems in which the boundary of a continuum varies. The key theory of numerical solution shown in this chapter is published in the paper (Azegami, Trans. Jpn. Soc. Industrial Appl. Math. 23(2), 83–138 (2014)). In this book, we shall look at the theory used there by comparing it to the contents shown in Chaps. 1 to 7.

Plant-based vaccines (PbVs), developed with novel plant genetic engineering technologies, offer a new strategy for the production, storage, and delivery of vaccines. PbVs can overcome practical and economic concerns surrounding injectable vaccines, including the need for medical staff to perform the injections and the costs of production and refrigeration. The development of unrefrigerated, needle-free vaccines will support the prevention of infectious diseases in developing countries. Although no PbV has yet been licensed for human clinical use, some are now in clinical trials. Antigen-encoding genes introduced into potatoes, lettuce, spinach, corn, tobacco, soybeans, and rice can produce vaccines against mucosal and systemic infectious diseases, including enterotoxigenic Escherichia coli, Vibrio cholerae, norovirus, influenza virus, hepatitis B virus, and rabies virus. This chapter introduces the plant genetic engineering technologies used and clinical trials of PbVs.

In last chapters, we looked at the theory of solutions relating to optimization problems in finite-dimension. From this chapter onward, we shall consider optimization problems where the design variables are of function of time and space.

From this chapter, we finally examine shape optimization problems in continua. Firstly, let us think about a problem seeking the appropriate arrangement of holes in a domain where the boundary value problem of a partial differential equation is defined. Such a problem is known as the topology optimization problem. Here, the term topology refers to the study of geometrical properties and spatial relation of objects unaffected by the continuous change of their shape or size. In mathematics, two mathematical objects are said to belong to the same topology if they are images of two homotopic maps; that is, if one can be continuously deformed into the other. Therefore, letting n be a natural number, a set of n-connected domains are regarded as belonging to the same homotopy groups. Here, the term “topology optimization” in the topology optimization problem refers to the determination of the connectivity of the design domain that optimizes an object’s material distribution through insertion and arrangement of holes in its structure. However, as will be explained in detail later, the shape of the holes actually becomes the target. Therefore, the problems dealt with in this chapter also become included in shape optimization problems in a wider sense. In this book, it will be referred to as the topology optimization problem in the sense that topology is also in the scope of the design.

As seen in Chap. 1, optimal design problems are optimization problems whose state equations are considered as equality constraints. In Chap. 1, we have considered design variables and state variables as elements of a finite-dimensional vector space. However, in this book, our main interest focuses on the shape optimization problem of continuum. In this case, boundary value problems of partial differential equations, such as linear elastic bodies and Stokes flow field, are included in the equality constraints as state equations.

This paper presents the numerical results of a shape optimisation problem with regard to delaying the transition of a Navier–Stokes flow field from laminar to turbulent by using the theory developed by Nakazawa and Azegami. The theory was reviewed within the framework of functional analysis and updated with another expression of the shape derivative with respect to the objective function. A computer program was developed with the FreeFEM++. Numerical analyses were performed for two types of problems: a two-dimensional Poiseuille flow field with a sudden expansion and a two-dimensional uniform flow field around an isolated body. From the first example, two local minimum points of symmetric and asymmetric flow fields were determined, and the asymmetric flow field was found to be more stable. With regard to the second example, we reached the local minimum point of an elliptical shape, and infrequently determined a solution converging to an elliptical shape with the bluff in the leeward direction. By comparison, the superiority of the elliptical shape was obvious., ファイル公開：2019/08/01

This study demonstrates the use of Newton method to solve topology optimization problems of density type for linear elastic bodies to minimize the maximum von Mises stress. We use the Kreisselmeier–Steinhauser (KS) function with respect to von Mises stress as a cost function to avoid the non-differentiability of the maximum von Mises stress. For the design variable, we use a function defined in the domain of a linear elastic body with no restriction on the range and assume that a density is given by a sigmoid function of the function of design variable. The main aim of this study involves evaluating the second derivative of the KS function with respect to variation of the design variable and to propose an iterative scheme based on an H^1 Newton method as opposed to the H^1 gradient method that was presented in previous studies. The effectiveness of the scheme is demonstrated by numerical results for several linear elastic problems. The numerical results show that the speed of the proposed H^1 Newton method exceeds that of the H^1 gradient method., ファイル公開：2019/09/01