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To control the coronavirus disease 2019 (COVID-19) pandemic, there is a need to develop vaccines to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. One candidate is a nasal vaccine capable of inducing secretory IgA antibodies in the mucosa of the upper respiratory tract, the initial site of infection. However, regarding the development of COVID-19 vaccines, there is concern about the potential risk of inducing lung eosinophilic immunopathology as a vaccine-associated enhanced respiratory disease as a result of the T helper 2 (Th2)-dominant adaptive immune response. In this study, we investigated the protective effect against virus infection induced by intranasal vaccination of recombinant trimeric spike protein derived from SARS-CoV-2 adjuvanted with CpG oligonucleotides, ODN2006, in mouse model. The intranasal vaccine combined with ODN2006 successfully induced not only systemic spike-specific IgG antibodies, but also secretory IgA antibodies in the nasal mucosa. Secretory IgA antibodies showed high protective ability against SARS-CoV-2 variants (Alpha, Beta and Gamma variants) compared to IgG antibodies in the serum. The nasal vaccine of this formulation induced a high number of IFN-γ-secreting cells in the draining cervical lymph nodes and a lower spike-specific IgG1/IgG2a ratio compared to that of subcutaneous vaccination with alum as a typical Th2 adjuvant. These features are consistent with the induction of the Th1 adaptive immune response. In addition, mice intranasally vaccinated with ODN2006 showed less lung eosinophilic immunopathology after viral challenge than mice subcutaneously vaccinated with alum adjuvant. Our findings indicate that intranasal vaccine adjuvanted with ODN2006 could be a candidate that can prevent the infection of antigenically different variant viruses, reducing the risk of vaccine-associated enhanced respiratory disease.

本論文では，項目露出を考慮した整数計画法による等質テストの自動構成手法を提案する．等質テストとはテストに含まれる項目は異なるが，受験者得点の予測誤差が等質なテスト群である．等質テストでは同一能力の受験者ならば，どのテストを受験しても同一得点となる保証があり，出題可能な項目のデータベース（アイテムバンク）から自動構成される．項目の露出数（出題回数）が大きい項目は受験者間で共有されやすく，経年劣化につながりその項目の信頼性が失われやすいため，露出数の偏りの軽減が重要な課題の一つである．Ishii and Ueno (2015) は構成した等質テストを全て保存し，その中から最も露出率（＝露出数の最大値/テスト構成数）が小さい等質テストを出力して，露出率を軽減する手法を提案した．本論文では乱数を用いた整数計画法でテスト構成することで，露出数の偏りが改善されることを示し，整数計画法のみでは解決されなかった項目露出のバイアス問題を露出数上位の項目をアイテムバンクから除外しながらテスト構成することで解決する手法を提案する．評価実験では従来手法とテスト構成数及び露出率を比較し，提案手法の有効性を示す．

Understanding the differences in serum cross-neutralizing responses against SARS-CoV-2 variants, including Omicron sub-lineages BA.5, BA.2.75, and BQ.1.1, elicited by exposure to distinct antigens is essential for developing COVID-19 booster vaccines with enhanced cross-protection against antigenically distinct variants. However, fairly comparing the impact of breakthrough infection on serum neutralizing responses to several variants with distinct epidemic timing is challenging because responses after breakthrough infection are affected by the exposure interval between vaccination and infection. We assessed serum cross-neutralizing responses to SARS-CoV-2 variants, including Omicron sub-lineages, in individuals with breakthrough infections before or during the Omicron BA.1 epidemic. To understand the differences in serum cross-neutralizing responses after pre-Omicron or Omicron breakthrough infection, we used Bayesian hierarchical modeling to correct the cross-neutralizing responses for the exposure interval between vaccination and breakthrough infection. The exposure interval required to generate saturated cross-neutralizing potency against each variant differed by variant, with variants more antigenically distant from the ancestral strain requiring a longer interval. Additionally, Omicron breakthrough infection was estimated to have higher impact than booster vaccination and pre-Omicron breakthrough infection on inducing serum neutralizing responses to the ancestral strain and Omicron sub-lineages. However, the breadth of cross-neutralizing responses to Omicron sub-lineages, including BQ.1.1, after Omicron or pre-Omicron breakthrough infection with the ideal exposure interval were estimated to be comparable. Our results highlight the importance of optimizing the interval between vaccine doses for maximizing the breadth of cross-neutralizing activity elicited by booster vaccines with or without Omicron antigen.Significance StatementSARS-CoV-2 infections after vaccination with COVID-19 mRNA vaccines with the ancestral spike antigen induce high serum neutralizing responses against Omicron sub-lineages, which are antigenically distant from the ancestral antigen. In individuals with breakthrough infections, the exposure interval from vaccination to infection is critical for the induction of serum cross-neutralizing activity. We used statistical modeling to estimate the serum neutralizing response to Omicron sub-lineages corrected for the influence of different exposure intervals between vaccination and breakthrough infection in individuals with pre-Omicron and Omicron breakthrough infections. This enabled us to assess fairly the effects of exposure to distinct antigens on inducing serum cross-neutralizing responses with the ideal exposure interval, and revealed the clinical significance of optimizing the dose interval in COVID-19 booster vaccination.

Background Long-term outcomes of suppressing paroxysmal atrial fibrillation (PAF) with additive ganglionated plexus (GP) ablation (GPA) remains unknown. Objectives The aim of the study is to assess potential role of additional GPA for PAF suppression. Methods This study consisted of 225 patients; 68 (group A: 58 male, aged 60 ± 11 years) underwent pulmonary vein isolation (PVI) alone and 157 (group B: 137 male, aged 61 ± 11 years) GPA followed by PVI. GPA was performed based on the high-density mapping with high-frequency stimulation (HFS) delivered to left atrial (LA) major GP. The latter 85 group B patients (54%) underwent ablation to a posteromedial area within superior vena cava as a part of dorsal right atrial GP (SVC-Ao GP). Results In group B, HFS was applied to 126 ± 32 sites, with a median of 47 GP sites (40.0%) being ablated. In patients undergoing an SVC-Ao GPA, HFS and the SVC-Ao GPA were applied at a median of 15 and 4 sites (29.4%), respectively. The PVI with a GPA provided higher PAF suppression than a PVI alone during more than 4 years of follow-up (56.7% vs 38.2%, odds ratio: 0.42, 95% confidence interval: 0.23–0.76, P < .05), but the SVC-Ao GPA did not provide further suppressive effects. Multivariate analyses revealed that tachycardia-bradycardia syndrome and non-PV foci were independent predictors of PAF recurrence after PVI with a GPA (P < .01). Conclusion GPA to LA major GP by high-density mapping provides long-term benefits for PAF suppression over 4 years of follow-up, but the effect of an empiric SVC-Ao GPA could not be appreciated, suggesting little effect on suppressing non-PV foci.

Immunity to SARS-CoV-2 in COVID-19 cases has diversified due to complex combinations of exposure to vaccination and infection. Elucidating the drivers for upgrading neutralizing activity to SARS-CoV-2 in COVID-19 cases with pre-existing immunity will aid in understanding immunity to SARS-CoV-2 and improving COVID-19 booster vaccines with enhanced cross-protection against antigenically distinct variants. This study revealed that the magnitude and breadth of neutralization responses to SARS-CoV-2 infection in breakthrough infections are determined by upper respiratory viral load and vaccination-infection time interval, but not by the lineage of infecting viruses. Notably, the time interval, but not the viral load, may play a critical role in expanding the breadth of neutralization to SARS-CoV-2. This illustrates the importance of dosing interval optimization in addition to antigen design in the development of variant-proof booster vaccines.One-Sentence SummaryViral load and infection timing define the magnitude and breadth of SARS-CoV-2 neutralization after breakthrough infection.

SUMMARYBackgroundThe immune profile against SARS-CoV-2 has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by the Omicron in individuals with various immune histories.MethodsThe neutralization susceptibility of the variants including the Omicron and their ancestor was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections by the Alpha/Delta with multiple time intervals following vaccination.FindingsThe Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against the Omicron were induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies.ConclusionsImmune histories with breakthrough infections can overcome the resistance to infection by the Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against the Omicron and future variants.FundingThis study was supported by grants from the Japan Agency for Medical Research and Development (AMED).

The Japan Proton Accelerator Research Complex (J-PARC) cesiated RF-driven H− ion source (IS) has been stably operated for about six years. From Sep. 2018, the J-PARC 400 MeV LINAC has been steadily operated with the design H− ion beam intensity (IH−) of 50 mA, when a 60 mA beam is injected from the IS. At each end of about 3 months J-PARC operation, the IS supplies a 52.5 keV 72 mA beam for the LINAC 60 mA acceleration. The IS superior emittances predicted in a test-stand were proven by the high RFQ acceleration efficiency of 94.3 % (IH− = 67.9 mA). The high intensity beam with transverse emittances suitable for the RFQ is produced with several unique measures, such as slight water molecule addition into hydrogen plasma; low temperature (about 70 °C) operation of 45°-tapered 16-mm thick plasma electrode with the precise cesium density control; impurity elimination in the hydrogen plasma along with the filter-field optimization; continuous-wave igniter plasma driven with a 50-W 30-MHz RF, and so on. The 110 mA operation results of the IS in the test-stand are presented in this paper. A 65 keV 110 mA H− ion beam, about 103 mA of which was inside the transverse emittances used for a common RFQ design, was stably operated with a duty factor of 4.5 % (1 ms x 45 Hz). The interesting relationship of the IH− without any emittance blowups upon the required beam energy (WH-) was derived as IH−(WH−) = 71.2 x (WH- / 52.5)^2.03. The IS is the benchmark one for the next generation high energy H− LINACs aiming for 100 mA class intensity.

Low temperature nitriding (LTN) was performed for titanium alloy (Ti-6Al-4V) to improve its fatigue properties. A nitrogen compound layer was formed on the surface nitrided at temperatures higher than 873 K, whereas nitrogen diffusion was observed on the surface nitrided at 823 K. Fatigue tests were performed by four-point bending in air under a stress ratio of 0.1. The fatigue limit for Ti-6Al-4V tended to increase with a decrease in the nitriding temperature. LTN at 823 K increased the fatigue limit of Ti-6Al-4V due to the formation of the surface with no nitrogen compound layer and suppression of grain-coarsening.

In the present work, the four-point bending loading fatigue properties of a heterogeneously distributed grain size microstructure consolidated from Ti-6Al-4V alloy powder are studied. The microstructure involved here, a so-called “harmonic structure”, possesses quasi-spherical large grain regions (“cores”) embedded in a continuous fine grain region (“shell”). Unlike the previous reports dealing with this issue, the effect of the specimen size on the fatigue characteristics is also probed, since two distinct specimen configurations are considered. Furthermore, the obtained experimental data are compared with the corresponding fatigue results derived from homogeneous coarse grain counterparts. Contrary to homogeneous structure material, discrepancies on both the fatigue strength and the fatigue crack initiation aspects are found for the harmonic structure material. Consequently, the present work aims to clarify the underlining phenomena involved in the specimen size effect detected for Ti-6Al-4V designed in the harmonic structure. A less active interface surface between the core and the shell combined with a wider critical volume in the large size specimen should be the main reasons of the fatigue strength discrepancy.

For prohibiting a global warming, fuel-cell systems without carbon dioxide emissions are a one of the promising technique. In case of a fuel-cell vehicle (FCV), high-pressure H2 gas is indispensable for a long running range. Although there are lot of paper for studying a hydrogen embrittlement (HE), there are few paper referred to the effect of high-pressure H2 on the HE phenomenon. In this study, an effect of high-pressure H2 gas on tensile & fatigue properties of stainless steel SUS316L were investigated by means of the internal high-pressure H2 gas technique. Main findings of this study are as follows; 1) Although there are almost no hydrogen embrittlement effect on the 0.2 % proof stress and tensile strength, elongation and reduction of area decrease in H2 gas environment, 2) For case of low Nieq material, fatigue life and fatigue limit decrease in H2 gas environment, 3) For case of low Nieq material, not a few α’ martensitic phase generated on the fatigue fractured specimen.

In July 2019, a design beam of 8.3 × 10

For the J-PARC operations, only three plasma chambers (PCHs) of #7, #8 and #9PCHs among ten PCHs have been used since the transverse emittances of the beam produced with them are more superior than those with others for unknown reasons. However, the #7PCH beam emittances were enlarged by 16 % with a brand-new plasma electrode temperature control plate (PETCP) to solve the air leak at the VCR vacuum fitting. The impurities from the new parts exposed to the plasma seemed to cause the degradation. The beam with almost the best emittances was reproduced by #4PCH with a new PETCP after a new impurities reduction conditionings for 48 hours, in which the impurities produced by the plasma were reduced as small as possible by scanning both of 2-MHz-RF power and axial magnetic field in #4PCH.

Background Recurrent ventricular tachycardia (VT) and fibrillation (VF), the so-called "electrical storm" (ES) occurs at various stages of acute myocardial infarction (AMI), but its incidence, background, and short-term prognosis remain unclear. Methods and Results: A retrospective observational study was performed using the registry database of the Tokyo CCU Network. The individual data of 6,003 patients with AMI during 2011-2012 was corrected. ES was defined as more than 3 episodes of sustained VT/VF during a 24-h period as first documented after hospitalization. ES occurred in 55 patients after admission (0.9%). The ES(+) group had more severe heart failure (Killip class >III), more extensive MI (peak-CK), greater inflammatory reaction (CRP), history of diabetes, and more frequent application of hemodialysis as compared with the ES(-) group (n=5,865). When the ES patients were divided into Early-ES (n=37: ES occurred ≤48 h after the onset of MI) and Late-ES (n=15 >48 h after onset of MI) groups, logistic regression analysis revealed that Early-ES was associated with severity of MI, whereas Late-ES was related to systemic disorders, including inflammation, renal dysfunction, or diabetes. Late-ES was an independent predictor of in-hospital death. Conclusions In-hospital ES was a rare clinical manifestation of AMI. The features and background of the ES varied as time elapsed after admission for MI.

High-entropy alloys (HEAs) have attracted a great deal of interest and high expectations not only from the scientific community, but also from the industrial point of view, mainly because of a remarkable combination of promising properties. However, the characterization of HEAs under fatigue loading is still very scarce, especially in the case of body centred cubic (BCC) HEAs. As an attempt to fill this gap, we report here the first study on the fatigue behavior of a refractory BCC HEA in four-point bending loading conditions. Equimolar HfNbTaTiZr HEA was subjected to load-control fatigue tests in air and at room temperature to assess its fatigue properties in the high-cycle regime. Experimental results show that the maximum stress level reached within one fatigue cycle exceeds the uniaxial yield stress of the material. This particularity is observed within the whole range of fatigue life investigated, i.e., from approximately 104 to 107 cycles, showing no macroscopic plastic deflection of the beam in the process. A fatigue endurance of approximately 430 MPa (at 107 cycles) is found, for a stress ratio of approximately 0.1. A fatigue crack initiation mechanism occurs at the specimen surface through an intergranular phenomenon and propagates in a transgranular crystallographic manner. The fatigued samples underlined the low local lattice rotation, implying a restrained cyclic strain hardening. Finally, the fatigue study of the HfNbTaTiZr HEA highlights a fatigue endurance over an ultimate tensile strength ratio of 0.43, which is significantly larger than the actual conventional structural metallic materials under similar conditions.

CP titanium with a bimodal microstructure consisting of a substrate surrounded by a network structure of nitrogen diffusion phase was fabricated by sintering nitrided powders, as a means of improving the mechanical and tribological properties. A nitrogen diffusion layer can be formed on CP titanium powder at temperatures above 873 K. The areal fraction of the nitrogen diffusion phase increased along with the sintering temperature. As results of ball-on-disk dry friction tests, CP titanium fabricated from powder nitrided at 873 K had a lower friction coefficient than compacts fabricated from as-received CP titanium powder. In contrast, adhesion of the counter material was observed over the worn surface of sintered compact fabricated from the powder nitrided at 973 K, which indicates a higher friction coefficient.

Commercially pure (CP) titanium with a bimodal harmonic structure, which is defined as coarse grained regions surrounded by a network of fine grains, was fabricated by consolidating mechanically milled powders to improve both strength and ductility. In order to determine the fatigue properties of bimodal harmonic structured CP titanium, four-point bending fatigue tests were conducted at a stress ratio of 0.1 under ambient conditions. The fracture surfaces were analyzed by scanning electron microscopy (SEM) and electron backscatter diffraction (EBSD) to identify the mechanisms of small fatigue crack initiation and propagation on the basis of fractography and crystallography. The fatigue crack initiation resistance was increased compared to sintered compacts fabricated from as-received initial powders, which was attributed to grain refinement during mechanical milling. Transgranular fracture occurred from coarse grains with a basal plane perpendicular to the loading direction. The fatigue crack path in harmonic structured CP titanium was not influenced by the microstructure.

Small fatigue crack propagation in bimodal harmonic structured titanium alloy (Ti-6Al-4V) with high strength and ductility was examined under four-point bending at a stress ratio of 0.1 in the ambient laboratory atmosphere. The crack profiles were observed using optical microscopy and scanning electron microscopy, and analyzed using an electron backscattered diffraction to examine the mechanism of small fatigue crack propagation. Fatigue crack paths were not influenced by the bimodal harmonic structure, and the crack growth rates, da/dN, in the harmonic structured Ti-6Al-4V were almost the same as those in a material with coarse acicular microstructure for comparable values of stress intensity range, ΔK. In contrast, the harmonic structured Ti-6Al-4V had a higher resistance of fatigue crack initiation due to the grain refinement induced by mechanical milling, which resulted in an increase of the fatigue life and fatigue limit. Furthermore, the statistical fatigue properties of Ti-6Al-4V alloy were analyzed using the stress dependence of Weibull parameters to quantitatively examine the effects of the bimodal harmonic structure on its fatigue life.

In the field of innovative material processing, researches dealing with the mechanical properties of Bulk Metallic Glasses (BMGs) are incontestably one of the most topical issues in the latest years. Indeed, this type of materials presents some very interesting properties, such as a high yield stress, a noticeable elongation at fracture and a good corrosion resistance. Thus, it is though that, in a near future, metallic glasses would be able to fulfill structural material applications, which are currently restricted to conventional crystalline metallic materials. However, it is already known that BMGs usually show poor fatigue properties compared to its crystalline counterparts, reducing the actual use of BMGs to non-structural applications. Thus, such promising usages require a better understanding of the fatigue properties of BMGs, explaining the numerous works carried out to overcome this difficulty. Surprisingly, only a few literature reports are focused on the effect of the stress ratio R (= σ min / σ max ) on the high-cycle fatigue behavior of BMGs. In the present work, the effect of the stress ratio, up to R = 0.7, on both the fatigue properties and fatigue crack propagation behavior of Zr 55 Al 10 Ni 5 Cu 30 BMG have been studied. This first part is dealing with the fundamental fatigue resistance investigated at three distinct stress ratios of R = 0.1, 0.4 and 0.7. In addition, some discussions related to fracture observation will be discussed, revealing an irregularity of the fatigue crack propagation mechanism at R = 0.7. Finally, relative influences of both stress range and maximum stress level were analyzed using a phenomenological law.

Little is known about the permanent pacemaker implantation rate and predictors of permanent pacemaker implantation in patients admitted for complete atrioventricular block (cAVB). The present study was a retrospective analysis based on a multicenter cohort of 797 patients with cAVB (mean age: 79.6 ± 10.7 years; males: 48.4%) registered with the Tokyo Cardiovascular Care Unit Network multicenter registry between 2013 and 2016. Secondary cAVB due to acute coronary syndrome was excluded. The permanent pacemaker implantation rate was 82.9%. Multivariable logistic regression analysis revealed that systolic blood pressure (SBP) > 140 mmHg [odds ratio (OR) 2.10; 95% confidence interval (CI) 1.38–3.22; P

Titanium alloy (Ti-6Al-4V) with a bimodal harmonic structure, which is defined as a coarse-grained structure surrounded by a network structure of fine grains, was fabricated using powder metallurgy to improve both the strength and ductility. The microstructure of the sintered compacts was characterized using electron backscattered diffraction (EBSD). The areal fraction of the fine-grained structure in the harmonic structure tended to increase with the milling time. Tensile tests and four-point bending fatigue tests at a stress ratio of 0.1 were performed in air at room temperature. The tensile strength, 0.2% proof stress and fatigue limit of Ti-6Al-4V alloy with harmonic structure tended to increase as the areal fraction of the fine-grained structure increased. In contrast, elongation decreased due to the formation of a high areal fraction of the fine-grained structure (79.0%), which resulted in a reduction of the fatigue life with a low cycle regime. Thus, titanium alloy with high strength, ductility and fatigue resistance can be formed by optimization of the milling conditions. Furthermore, the mechanism for fatigue fracture of the Ti-6Al-4V alloy with a harmonic structure is discussed with respect to fractography and crystallography. A fatigue crack was initiated from the α-facet of the coarse-grained structure in the harmonic structure.

The hydrogen-related fracture propagation process in martensitic steel was investigated through crystallographic orientation and fracture surface topography analyses. The hydrogen-related fracture surface consisted of three typical surfaces, namely smooth surfaces, surfaces with serrated markings, and surfaces with dimples. Crystallographic orientation analysis suggested that the smooth surface was generated by intergranular fracture at prior austenite grain boundaries, and the surface with serrated markings originated from quasi-cleavage fracture propagated along $$\{011\}$$ planes. According to the reconstructed fracture propagation process by fracture surface topography analysis, the intergranular fracture at prior austenite grain boundaries initiated and propagated suddenly at the early stages of fracture. The quasi-cleavage fracture along $$\{011\}$$ planes then gradually propagated within the prior austenite grains. At the final stages of fracture, ductile fracture accompanied by dimples occurred around the edge of the specimen. The results clearly indicated that the fracture propagation path changed with the proceeding fracture from the prior austenite grain boundaries to along $$\{011\}$$ planes within the prior austenite grains.