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The development of reduced models provide efficient methods that can be used to perform short term experimental data analysis or narrow down the parametric range of more sophisticated numerical approaches. Reduced models are derived by simplifying the physics description with the goal of retaining only the essential ingredients required to reproduce the phenomena under study. This is the role of the gyro-fluid code FAR3d, dedicated to analyze the linear and nonlinear stability of Alfvén Eigenmodes (AE), Energetic Particle Modes (EPM) and magnetic-hydrodynamic modes as pressure gradient driven mode (PGDM) and current driven modes (CDM) in nuclear fusion devices. Such analysis is valuable for improving the plasma heating efficiency and confinement; this can enhance the overall device performance. The present review is dedicated to a description of the most important contributions of the FAR3d code in the field of energetic particles (EP) and AE/EPM stability. FAR3d is used to model and characterize the AE/EPM activity measured in fusion devices as LHD, JET, DIII-D, EAST, TJ-II and Heliotron J. In addition, the computational efficiency of FAR3d facilitates performing massive parametric studies leading to the identification of optimization trends with respect to the AE/EPM stability. This can aid in identifying operational regimes where AE/EPM activity is avoided or minimized. This technique is applied to the analysis of optimized configurations with respect to the thermal plasma parameters, magnetic field configuration, external actuators and the effect of multiple EP populations. In addition, the AE/EPM saturation phase is analyzed, taking into account both steady-state phases and bursting activity observed in LHD and DIII-D devices. The nonlinear calculations provide: the induced EP transport, the generation of zonal structures as well as the energy transfer towards the thermal plasma and between different toroidal/helical families. Finally, FAR3d is used to forecast the AE/EPM stability in operational scenarios of future devices as ITER, CFETR, JT60SA and CFQS as well as possible approaches to optimization with respect to variations in the most important plasma parameters.

Recently, experiments on basic plasma physics issues for solving future problems in fusion energy have been performed on a Large Helical Device. There are several problems to be solved in future devices for fusion energy. Emerging issues in burning plasma are: alpha-channeling (ion heating by alpha particles), turbulence and transport in electron dominant heating helium ash exhaust, reduction of the divertor heat load. To solve these problems, understanding the basic plasma physics of (1) wave–particle interaction through (inverse) Landau damping, (2) characteristics of electron-scale (high- k ) turbulence, (3) ion mixing and the isotope effect, and (4) turbulence spreading and detachment, is necessary. This overview discusses the experimental studies on these issues and turbulent transport in multi-ion plasma and other issues in the appendix.

AbstractBackground Pre-emptive kidney transplantation (PEKT), i.e., transplantation performed before initiation of maintenance dialysis, is considered an ideal renal replacement therapy because there is no exposure to long-term dialysis therapy. Therefore, we summarized advantages/disadvantages of PEKT to assist in deciding whether kidney transplantation should be performed pre-emptively.Methods This study was registered with PROSPERO, CRD42021269163. Observational studies comparing clinical outcomes between PEKT and non-PEKT were included; those involving only pediatric recipients or simultaneous multi-organ transplantations were excluded. The PubMed/MEDLINE, Cochrane Library, and Ichushi-Web databases were searched on 1 August 2021. Studies were pooled using the generic inverse-variance method with random effects model, and risk of bias was assessed using ROBINS-I.Results Seventy-six studies were included in the systematic review (sample size, 23–121,853; enrollment year, 1968–2019). PEKT patients had lower all-cause mortality (adjusted HR: 0.78 [95% CI 0.66–0.92]), and lower death-censored graft failure (0.81 [0.67–0.98]). Unadjusted RRs for the following outcomes were comparable between the two patient groups: cardiovascular disease, 0.90 (0.58–1.40); biopsy-proven acute rejection, 0.75 (0.55–1.03); cytomegalovirus infection, 1.04 (0.85–1.29); and urinary tract infection, 0.89 (0.61–1.29). Mean differences in post-transplant QOL score were comparable in both groups. The certainty of evidence for mortality and graft failure was moderate and that for other outcomes was very low following the GRADE classification.Conclusions The present meta-analysis shows the potential benefits of PEKT, especially regarding patient and graft survival, and therefore PEKT is recommended for adults with end-stage kidney disease.

Abstract Background Previously, we isolated a riboflavin-overproducing Ashbya gossypii mutant (MT strain) and discovered some mutations in genes encoding flavoproteins. Here, we analyzed the riboflavin production in the MT strain, in view of flavoproteins, which are localized in the mitochondria. Results In the MT strain, mitochondrial membrane potential was decreased compared with that in the wild type (WT) strain, resulting in increased reactive oxygen species. Additionally, diphenyleneiodonium (DPI), a universal flavoprotein inhibitor, inhibited riboflavin production in the WT and MT strains at 50 µM, indicating that some flavoproteins may be involved in riboflavin production. The specific activities of NADH and succinate dehydrogenases were significantly reduced in the MT strain, but those of glutathione reductase and acetohydroxyacid synthase were increased by 4.9- and 25-fold, respectively. By contrast, the expression of AgGLR1 gene encoding glutathione reductase was increased by 32-fold in the MT strain. However, that of AgILV2 gene encoding the catalytic subunit of acetohydroxyacid synthase was increased by only 2.1-fold. These results suggest that in the MT strain, acetohydroxyacid synthase, which catalyzes the first reaction of branched-chain amino acid biosynthesis, is vital for riboflavin production. The addition of valine, which is a feedback inhibitor of acetohydroxyacid synthase, to a minimal medium inhibited the growth of the MT strain and its riboflavin production. In addition, the addition of branched-chain amino acids enhanced the growth and riboflavin production in the MT strain. Conclusion The significance of branched-chain amino acids for riboflavin production in A. gossypii is reported and this study opens a novel approach for the effective production of riboflavin in A. gossypii.

A method for finding the optimum distribution of the slit density in a shoe upper, such that the contact pressure with the foot approaches an ideal distribution is presented in this paper. In a shoe upper made of warp knitting, slits are made by discontinuously knitting the weft under a uniform arrangement of the warp fiber. In this study, the shoe upper is modeled as an orthotropic hyperelastic body in which the slit density is defined as the design variable for controlling the intermediate density for the maximum and minimum slit densities. Referring to a formulation of a topology optimization problem of the density variation type, an inverse problem for finding the optimum distribution of the slit density is formulated with the objective and constraint cost functions defined by the squared error norm between the actual and ideal contact pressures and the deviation of the rate of the material with the maximum slit density from a limit value, respectively. This problem is solved in the same way as a topology optimization problem. The validity of this method is confirmed by numerical examples using a simple finite element model, which resembles the domain around the big toe.

Abstract Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

Abstract There is a critical need for efficient treatment of chronic kidney disease (CKD). Renal fibrosis is a final common pathway to end-stage renal disease independent of the underlying etiology, and connective tissue growth factor (CTGF) is a well-recognized profibrotic factor in fibrosis of various organ systems. Here, we developed a novel peptide vaccine against CTGF to attenuate the development of renal fibrosis. Three inoculations with this CTGF vaccine at 2-week intervals elicited antibodies specifically binding to human full-length CTGF, and the antigen-specific serum IgG antibody titers were maintained for > 30 weeks. The efficacy of the CTGF vaccine on renal fibrosis was evaluated in adenine-induced CKD and unilateral ureteral obstruction (UUO) murine models. In adenine-induced CKD model, immunization with the CTGF vaccine attenuated renal interstitial fibrosis. Vaccinated mice showed low levels of serum creatinine and urea nitrogen and low urine albumin–creatinine ratio compared with vehicle-treated mice. In UUO model, the CTGF vaccination also suppressed the onset of renal fibrosis. In an in vitro study, CTGF vaccine-elicited IgG antibodies efficiently suppressed CTGF-induced- and transforming growth factor-β-induced α-smooth muscle actin expression in kidney fibroblasts. These results demonstrate that the CTGF vaccine is a promising strategy to attenuate the development of renal fibrosis.

Hyperkalemia is a well-recognized electrolyte abnormality in patients with chronic kidney disease (CKD). Potassium binders are often used to prevent and treat hyperkalemia. However, few studies have evaluated the difference in serum potassium (K+) level-lowering effect during the post-acute phase between the novel potassium binder, sodium zirconium cyclosilicate (ZSC), and conventional agents. This retrospective study included patients who received potassium binders (either ZSC or calcium polystyrene sulfonate [CPS]) in our hospital between May 2020 and July 2022. The patients were divided into the ZSC and CPS groups. After propensity score matching, we compared changes from baseline to the first follow-up point, at least 4 weeks after initiating potassium binders, in electrolytes including K+ level between the two groups. Of the 132 patients, ZSC and CPS were administered in 48 and 84 patients, respectively. After matching, 38 patients were allocated to each group. The ZSC group showed greater reduction in K+ levels than did the CPS group (P < 0.05). Moreover, a significant increase in serum sodium minus chloride levels, a surrogate marker for metabolic acidosis, was observed in the ZSC group (P < 0.05). Our results demonstrated that ZSC could potentially improve hyperkalemia and metabolic acidosis in patients with CKD.

A class of optimization problems which are formulated using solutions to boundary value problems of partial differential equations (PDEs) as equality constraints is called PDE-constrained optimization problems. Specifically, when the variable in the optimization problem is given by a function defined in the PDE, the problems are classified as PDE-constrained non-parametric optimization problems. The topology and shape optimization problems of density and domain variation type, respectively, are included in this category. This paper is written to convey the idea of the author who worked on this topic for over 30 year, unlike the usual review papers. After showing real images of the problems, the author’s theoretical image is introduced. Based on the theoretical image, basic questions about the structure of the problems when viewed as a function optimization problem are proposed. The author’s answers to these basic questions are presented in the next section. Based on the understanding, some numerical results in which anxious phenomena are observed are presented and their causes are discussed. The expectation of applying the basic theory to real-world problems is presented using examples. Applying the theory of shape optimization problem of domain variation type, a problem finding the optimum shape of a sole in sports shoes that maximizes the stability under keeping the ideal cushioning is introduced. Applying the theory of topology optimization problem of density variation type, a problem identifying the muscle activity in a tongue during swallowing is explained. From these examples, it is concluded that PDE-constrained non-parametric optimization problems can be effectively applied to real-world.

Abstract Background Ashbya gossypii naturally overproduces riboflavin and has been utilized for industrial riboflavin production. To improve riboflavin production, various approaches have been developed. In this study, to investigate the change in metabolism of a riboflavin-overproducing mutant, namely, the W122032 strain (MT strain) that was isolated by disparity mutagenesis, genomic analysis was carried out. Results In the genomic analysis, 33 homozygous and 1377 heterozygous mutations in the coding sequences of the genome of MT strain were detected. Among these heterozygous mutations, the proportion of mutated reads in each gene was different, ranging from 21 to 75%. These results suggest that the MT strain may contain multiple nuclei containing different mutations. We tried to isolate haploid spores from the MT strain to prove its ploidy, but this strain did not sporulate under the conditions tested. Heterozygous mutations detected in genes which are important for sporulation likely contribute to the sporulation deficiency of the MT strain. Homozygous and heterozygous mutations were found in genes encoding enzymes involved in amino acid metabolism, the TCA cycle, purine and pyrimidine nucleotide metabolism and the DNA mismatch repair system. One homozygous mutation in AgILV2 gene encoding acetohydroxyacid synthase, which is also a flavoprotein in mitochondria, was found. Gene ontology (GO) enrichment analysis showed heterozygous mutations in all 22 DNA helicase genes and genes involved in oxidation-reduction process. Conclusion This study suggests that oxidative stress and the aging of cells were involved in the riboflavin over-production in A. gossypii riboflavin over-producing mutant and provides new insights into riboflavin production in A. gossypii and the usefulness of disparity mutagenesis for the creation of new types of mutants for metabolic engineering.

Buildings use a large amount of energy, depending on the climate. To design buildings with high energy and thermal performance in the future, it is necessary to use weather data that reflect future climatic information. Some future weather files for building simulations have been developed. However, these datasets are based on different predictions, and each future weather file has a different creation process. Such methodological differences may lead to differences in predicting the energy and thermal performance of buildings. Understanding the characteristics of each data type is necessary for its appropriate use. However, limited information is available for properly utilizing future weather data for building simulations. This study aims to provide information on the characteristics of future weather data for better utilization. After thoroughly reviewing the existing data and creation methods, we propose a framework for understanding future weather data based on their creative process. We collected five types of future weather datasets available in Japan and compared their characteristics. One of these datasets is the future weather dataset based on climate information provided by the National Institute for Environmental Studies (NIES). We confirmed the degree of variation in each weather element and predicted cooling/heating demand using future weather data available in Japan.

Summary: The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

In this study, a formulation of the inverse problem to identify the shape of a hyperelastic body in which the vibration mode is similar to the swimming mode of a fish is presented. This research aims to demonstrate the possibility of creating a fish robot that swims with a vibration mode in the water when excited with a vibration generator embedded in the body. Before this study, Chancharoen et al. attempted to formulate an inverse problem as a shape optimization problem for a linear elastic body without considering water. In this study, a cost function was defined by the squared error norm of the vibration mode and the ideal swimming mode. The result of a numerical example confirmed that the approach decreased the cost function, but the obtained vibration model was different from the ideal one. In contrast, in this study, a hyperelastic body is used to approach the actual movement of a fish. Using this replacement, the finite deformation theory is employed to formulate the periodic vibration of the hyperelastic body. The cost function is formulated using the squared error norm of the finite deformation in the cycle. Its shape derivative is evaluated using the solutions of the periodic vibration problem and its adjoint problem with respect to the cost function. To solve the shape optimization problem, an iterative scheme based on the H1 gradient method for domain variation problems is used. The effectiveness of this approach is illustrated through numerical examples using finite-element models.

This paper presents a method for reducing the computational time required to solve the shape optimization problem of a hyperelastic body. In a previous report, the authors presented a method for applying a model order reduction technique based on the Karhunen-Loève expansion (KLE) in a shape optimization problem of a linear elastic body. In the investigated case, we applied this method solely to solve a linear state determination problem. In this paper, we show that this idea is applicable not only to the adjoint problem and to the problems seeking domain variations through the H1 gradient method, but also to a nonlinear state determination problem. From a theoretical perspective, we assume that the solutions to these three problems for the domain obtained using a conventional shape optimization method at a prescribed number of iterations are random variables, and we apply the idea of KLE to such variables using the solutions obtained in the steps prior to the prescribed number of iterations through a conventional method as a sampling dataset. The orthonormal bases of KLE are defined as the eigenfunctions of the eigenvalue problems obtained as the optimality conditions of the variance maximization problems for the random variables. In the case of a nonlinear state determination problem, we use the incremental solutions instead of the solutions themselves. When using the finite element method to solve the three problems, these eigenfunctions become eigenvectors. Using the eigenvectors as the orthonormal bases in KLE, we define transformations from the coordinates of KLE to the physical coordinates and construct small problems for the variables of KLE. Our proposal is to solve the small problems instead of the original ones. The feasibility of the proposed method is illustrated by testing the numerical schemes using an end mean compliance minimization problem of a three-dimensional hyper elastic body.

Hypertension is the most common non-communicable disease among adults and is the most important modifiable risk factor for premature cardiovascular disease. The increasing worldwide burden of hypertension is a major global health issue. Early prevention with lifestyle modification or pharmaceutical treatment reduces the incidence of hypertension and the risk of subsequent cardiovascular disease. Therefore, identification of young persons at risk for hypertension has the obvious benefit of providing a chance for early intervention. Previous studies have demonstrated the positive association of elevated childhood blood pressure with hypertension in adulthood. Accumulated evidence also indicates the possibility that elevated pediatric blood pressure is associated with increased risk of future cardiovascular disease. In this article, we review the tracking of blood pressure from childhood to adulthood and emphasize the importance of pediatric blood pressure monitoring and control for predicting and preventing adult hypertension and cardiovascular disease.

This study presents methods to develop a three-dimensional numerical foot model and to identify the loading condition that is used to design a stable sole for running shoes. In a previous study, the authors proposed a method to optimize the shape of the sole to increase stability while maintaining the cushioning property. In the problem formulation, the loading condition was given as a boundary force distributed on the top surface of the sole. The aim of this study is to replace the loading condition with the force and moment at the origin of the ankle joint coordinate (AJC) system by modeling a foot with a finite element model. A finite element model of a foot is constructed using X-ray CT image data, and consists of bony structures, soft tissue, and plantar fascia. The plantar fascia is set at the bottom of the bony structures. The force and moment used in the finite element analysis are identified by inverse dynamic analysis using an experimental measurement in the practical operation of the ground reaction force (GRF) when the GRF in the direction of the foot length becomes minimum. In the finite element analysis, the finite deformation containing the contact condition between the bottom surface of the foot and the ground representing a sole made of resin is considered. For an index of the shoe stability, we define a heel eversion angle (HEA) by the rotational angle of the heel with respect to an axis in the foot length direction and evaluate it by finite element analysis. The validity of the finite element foot model as well as the force and moment obtained in this study are confirmed based on the agreement in the HEA results between the experiment and finite element analysis.

This paper presents a formulation to identify muscle activities from the variation in shapes of organs during swallowing. We assume that each organ consists of a three-dimensional hyperelastic body, and the contraction movement of the muscle is caused by a contractive inelastic stress in the organ. A function distributed in the organ domain to control the magnitude of the inelastic stress is chosen as a design variable in the same manner as the density in the topology optimization problem of density variation type. The identification problem is formulated as a problem of determining the design variable that minimizes an objective cost function defined by the squared L2 norm of the reaction force in the normal direction on the boundary when an enforced displacement to fit the varied boundary of the organ and the inelastic stress modeling the muscle activity are applied. The finite deformation problem of the hyperelastic body is analyzed using the finite element method. The direction of the muscle fiber is assumed to be the direction of the minimum principal stress obtained as the solution to the finite deformation problem. The solution to the identification problem is presented based on a scheme using the H1 gradient method for the topology optimization problem of density variation type. A numerical example using a previously developed model of the tongue is introduced to demonstrate the effectiveness of the proposed approach.

This paper proposes a solution to a multi-material robust topology optimization problem of density type considering material uncertainties based on H1 gradient method. A material interpolation with respect to the density is introduced using the rational approximation of material properties (RAMP) and generalized it for the case with an arbitrary number of materials. Material uncertainty is considered by introducing random variables in the material interpolation scheme. The probability density functions of the random variables are assumed to be given. The topology optimization is formulated using the density which is given by a sigmoid function of the design variable. A weighted sum of the mean and standard deviation of the mean compliance is used as the objective function to control the tradeoff between optimality and robustness. To evaluate statistical moments of the objective function effectively, the univariate dimension reduction (UDR) and the Gauss-type quadrature sampling are introduced. A scheme to solve the robust topology optimization problem is presented using an iterative algorithm based on the H1 gradient method for reshaping. Examples of a two-dimensional cantilever beam under various material uncertainty exhibit the efficiency and flexibility of the approach. The accuracy of UDR is validated by comparing the results to the Monte Carlo approach.

Aims Phrenic nerve injury (PNI) is the most common complication during cryoballoon ablation. Currently, two cryoballoon systems are available, yet the difference is unclear. We sought to compare the acute procedural efficacy and safety of the two cryoballoons. Methods This prospective observational study consisted of 2,555 consecutive atrial fibrillation (AF) patients undergoing pulmonary vein isolation (PVI) using either conventional (Arctic Front Advance) (AFA-CB) or novel cryoballoons (POLARx) (POLARx-CB) at 19 centers between January 2022 and October 2023. Results Among 2,555 patients (68.8 ± 10.9 years, 1,740 men, paroxysmal AF[PAF] 1,670 patients), PVIs were performed by the AFA-CB and POLARx-CB in 1,358 and 1,197 patients, respectively. Touch-up ablation was required in 299(11.7%) patients. The touch-up rate was significantly lower for POLARx-CB than AFA-CB (9.5% vs. 13.6%, p = 0.002), especially for right inferior PVs (RIPVs). The touch-up rate was significantly lower for PAF than non-PAF (8.8% vs. 17.2%, P < 0.001) and was similar between the two cryoballoons in non-PAF patients. Right PNI occurred in 64(2.5%) patients and 22(0.9%) were symptomatic. It occurred during the right superior PV (RSPV) ablation in 39(1.5%) patients. The incidence was significantly higher for POLARx-CB than AFA-CB (3.8% vs. 1.3%, P < 0.001) as was the incidence of symptomatic PNI (1.7% vs. 0.1%, P < 0.001). The difference was significant during RSPV (2.5% vs. 0.7%, P < 0.001) but not RIPV ablation. The PNI recovered more quickly for the AFA-CB than POLARx-CB. Conclusions Our study demonstrated a significantly higher incidence of right PNI and lower touch-up rate for the POLARx-CB than AFA-CB in the real-world clinical practice. [ABSTRACT FROM AUTHOR]

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.

Context Renal sinus fat (RSF) accumulation is associated with cardiometabolic diseases, such as obesity, diabetes, hypertension, and chronic kidney disease. However, clinical implications of RSF in primary aldosteronism (PA) remain unclear. Objective We aimed to investigate relationships between RSF volume and key cardiometabolic and renin-angiotensin system (RAS) parameters in PA patients and clarify the differences in these relationships between unilateral and bilateral subtypes. Methods We analyzed data obtained from well-characterized PA patients that involved 45 unilateral (median age: 52 years; 42.2% men) and 92 bilateral patients (51 years; 42.4% men). Results RSF volume normalized by renal volume (RSF%) was greater in the unilateral group than in the bilateral group (P <.05). RSF% was greater in men than in women (P <.05). RSF% positively correlated with parameters related to cardiometabolic risk, including age, body mass index, visceral fat volume, creatinine, triglycerides/high-density lipoprotein cholesterol ratio, uric acid, fasting glucose, and C-reactive protein regardless of PA subtypes (all P <.05). Intriguingly, RSF% positively correlated with plasma aldosterone concentration (PAC), aldosterone-to-renin ratio, and intact parathyroid hormone (iPTH) (all P <.05) in bilateral patients but did not correlate with RAS parameters and even showed an opposite trend in unilateral patients. In subgroup analyses by sex, these distinctions became more evident in women. After adjustment for potential confounders, RSF% remained positively correlated with PAC and iPTH in bilateral patients. Conclusion Our results indicate that RSF accumulation is involved in cardiometabolic dysfunction associated with PA. However, there were distinct correlations between RSF volume and RAS parameters according to sex and PA subtypes. [ABSTRACT FROM AUTHOR]

Pre-emptive kidney transplantation (PEKT), i.e., transplantation performed before initiation of maintenance dialysis, is considered an ideal renal replacement therapy because there is no exposure to long-term dialysis therapy. Therefore, we summarized advantages/disadvantages of PEKT to assist in deciding whether kidney transplantation should be performed pre-emptively. This study was registered with PROSPERO, CRD42021269163. Observational studies comparing clinical outcomes between PEKT and non-PEKT were included; those involving only pediatric recipients or simultaneous multi-organ transplantations were excluded. The PubMed/MEDLINE, Cochrane Library, and Ichushi-Web databases were searched on 1 August 2021. Studies were pooled using the generic inverse-variance method with random effects model, and risk of bias was assessed using ROBINS-I. Seventy-six studies were included in the systematic review (sample size, 23–121,853; enrollment year, 1968–2019). PEKT patients had lower all-cause mortality (adjusted HR: 0.78 [95% CI 0.66–0.92]), and lower death-censored graft failure (0.81 [0.67–0.98]). Unadjusted RRs for the following outcomes were comparable between the two patient groups: cardiovascular disease, 0.90 (0.58–1.40); biopsy-proven acute rejection, 0.75 (0.55–1.03); cytomegalovirus infection, 1.04 (0.85–1.29); and urinary tract infection, 0.89 (0.61–1.29). Mean differences in post-transplant QOL score were comparable in both groups. The certainty of evidence for mortality and graft failure was moderate and that for other outcomes was very low following the GRADE classification. The present meta-analysis shows the potential benefits of PEKT, especially regarding patient and graft survival, and therefore PEKT is recommended for adults with end-stage kidney disease. [ABSTRACT FROM AUTHOR]

Summary: Altered DNA methylation plays an important role in the onset and progression of kidney disease. However, little is known about how the changes arise in disease states. Here, we report that KAT5-mediated DNA damage repair is essential for the maintenance of kidney podocytes and is associated with DNA methylation status. Podocyte-specific KAT5-knockout mice develop severe albuminuria with increased DNA double-strand breaks (DSBs), increased DNA methylation of the nephrin promoter region, and decreased nephrin expression. Podocyte KAT5 expression is decreased, whereas DNA DSBs and DNA methylation are increased in diabetic nephropathy; moreover, KAT5 restoration by gene transfer attenuates albuminuria. Furthermore, KAT5 decreases DNA DSBs and DNA methylation at the same nephrin promoter region, which indicates that KAT5-mediated DNA repair may be related to DNA methylation status. These results suggest a concept in which an environment of DNA damage repair, which occurs with decreased KAT5, may affect DNA methylation status. : Hishikawa et al. reveal that KAT5-mediated DNA repair is essential for podocyte maintenance and is related to changes in DNA methylation status. Decreased podocyte KAT5 expression may contribute to the pathophysiology of diabetic nephropathy, suggesting a therapeutic target. Keywords: podocyte, DNA damage repair, DNA methylation, diabetic nephropathy

Hypertension is a global public health issue and the most important preventable cause of cardiovascular diseases. Despite the clinical availability of many antihypertensive drugs, many hypertensive patients have poor medication adherence and blood pressure control due, at least partially, to the asymptomatic and chronic characteristics of hypertension. Immunotherapeutic approaches have the potential to improve medication adherence in hypertension because they induce prolonged therapeutic effects and need a low frequency of administration. The first attempts to reduce blood pressure by using vaccines targeting the renin-angiotensin system were made more than half a century ago; however, at the time, a poor understanding of immunology and the mechanisms of hypertension and a lack of optimal vaccine technologies such as suitable antigen design, proper adjuvants, and effective antigen delivery systems meant that attempts to develop antihypertensive vaccines failed. Recent advances in immunology and vaccinology have provided potential therapeutic immunologic approaches to treat not only infectious diseases but also cancers and other noncommunicable diseases. One important biotechnology that has had a major impact on modern vaccinology is virus-like particle technology, which can efficiently deliver vaccine antigens without the need for artificial adjuvants. A human clinical trial that indicated the effectiveness and safety of a virus-like particle-based antiangiotensin II vaccine marked a turning point in the field of therapeutic antihypertensive vaccines. Here, we review the history of the development of immunotherapies for the treatment of hypertension and discuss the current perspectives in the field.