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Block copolymers are recognized as a valuable platform for creating nanostructured materials. Morphologies formed by block copolymer self-assembly can be transferred into a wide range of inorganic materials, enabling applications including energy storage and metamaterials. However, imaging of the underlying, often complex, nanostructures in large volumes has remained a challenge, limiting progress in materials development. Taking advantage of recent advances in X-ray nanotomography, we noninvasively imaged exceptionally large volumes of nanostructured hybrid materials at high resolution, revealing a single-diamond morphology in a triblock terpolymer–gold composite network. This morphology, which is ubiquitous in nature, has so far remained elusive in block copolymer-derived materials, despite its potential to create materials with large photonic bandgaps. The discovery was made possible by the precise analysis of distortions in a large volume of the self-assembled diamond network, which are difficult to unambiguously assess using traditional characterization tools. We anticipate that high-resolution X-ray nanotomography, which allows imaging of much larger sample volumes than electron-based tomography, will become a powerful tool for the quantitative analysis of complex nanostructures and that structures such as the triblock terpolymer-directed single diamond will enable the generation of advanced multicomponent composites with hitherto unknown property profiles.

Topological defects—extended lattice deformations that are robust against local defects and annealing—have been exploited to engineer novel properties in both hard and soft materials. Yet, their formation kinetics and nanoscale three-dimensional structure are poorly understood, impeding their benefits for nanofabrication. We describe the fabrication of a pair of topological defects in the volume of a single-diamond network (space group Fd3¯m) templated into gold from a triblock terpolymer crystal. Using X-ray nanotomography, we resolve the three-dimensional structure of nearly 70,000 individual single-diamond unit cells with a spatial resolution of 11.2 nm, allowing analysis of the long-range order of the network. The defects observed morphologically resemble the comet and trefoil patterns of equal and opposite half-integer topological charges observed in liquid crystals. Yet our analysis of strain in the network suggests typical hard matter behaviour. Our analysis approach does not require a priori knowledge of the expected positions of the nodes in three-dimensional nanostructured systems, allowing the identification of distorted morphologies and defects in large samples.

This systematic review and meta-analysis aimed to compare the effectiveness of selective neck dissection (SND) and comprehensive neck dissection (CND) in patients with oral squamous cell carcinoma N1 (Level I).

Remote monitoring (RM) of cardiac implantable electrical devices (CIEDs) can detect various events early. However, the diagnostic ability of CIEDs has not been sufficient, especially for lead failure. The first notification of lead failure was almost noise events, which were detected as arrhythmia by the CIED. A human must analyze the intracardiac electrogram to accurately detect lead failure. However, the number of arrhythmic events is too large for human analysis. Artificial intelligence (AI) seems to be helpful in the early and accurate detection of lead failure before human analysis. To test whether a neural network can be trained to precisely identify noise events in the intracardiac electrogram of RM data. We analyzed 21 918 RM data consisting of 12 925 and 1884 Medtronic and Boston Scientific data, respectively. Among these, 153 and 52 Medtronic and Boston Scientific data, respectively, were diagnosed as noise events by human analysis. In Medtronic, 306 events, including 153 noise events and randomly selected 153 out of 12 692 nonnoise events, were analyzed in a five‐fold cross‐validation with a convolutional neural network. The Boston Scientific data were analyzed similarly. The precision rate, recall rate, F1 score, accuracy rate, and the area under the curve were 85.8 ± 4.0%, 91.6 ± 6.7%, 88.4 ± 2.0%, 88.0 ± 2.0%, and 0.958 ± 0.021 in Medtronic and 88.4 ± 12.8%, 81.0 ± 9.3%, 84.1 ± 8.3%, 84.2 ± 8.3% and 0.928 ± 0.041 in Boston Scientific. Five‐fold cross‐validation with a weighted loss function could increase the recall rate. AI can accurately detect noise events. AI analysis may be helpful for detecting lead failure events early and accurately. A convolutional neural network with a pre‐trained model was used to predict noise or nonnoise events. In the analysis of five‐fold cross‐validation with weighted loss function, the trained artificial intelligence (AI) algorithm could predict noise events in intracardiac electrograms with high diagnostic performance. AI could focus on noise.

This systematic review and meta-analysis aimed to examine whether neoadjuvant chemotherapy (NAC) is useful against resectable oral squamous cell carcinomas.

A few reports have demonstrated the additional survival benefit obtained from induction chemotherapy. However, some facilities have differing opinions regarding the suitability of induction chemotherapy. The aim of this systematic review was to investigate the effectiveness of induction chemotherapy in patients with unresectable oral cancers without distant metastases.

This systematic review (SR) and meta-analysis aimed to evaluate the outcomes of radiotherapy (RT) alone and chemoradiotherapy (CRT) in patients with primary unresectable locally advanced oral cancer without distant metastases.

Programmed-1 ribosomal frameshifting (-1 PRF) is a translational mechanism adopted by some viruses, including SARS-CoV-2. To find a compound that can inhibit -1 PRF in SARS-CoV-2, we set up a high-throughput screening system using a HeLa cell extract-derived cell-free protein synthesis (CFPS) system. A total of 32,000 compounds were individually incubated with the CFPS system programmed with a -1 PRF-EGFP template. Several compounds were observed to decrease the -1 PRF-driven fluorescence, and one of them had some suppressive effect on -1 PRF of a SARS-CoV-2 genome sequence in transfected cells. Thus the CFPS system can be used as a tool for a high-throughput screening of chemicals.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n= 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RASwild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n= 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS,PTENand extracellular domain EGFRmutations, HER2and METamplifications, and ALK, RETand NTRK1fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62–0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83–1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834and NCT02394795.

The aim of this systematic review (SR) was to verify whether soft tissue graft reconstruction or prosthetic obturator reconstruction alone is more useful for defects after partial maxillectomy.

We introduce a new methodology of estimation of the true distribution. The procedure of getting estimated distribution is constructed from Bayesian statistical models in which the statistical model is fixed and prior distributions for the parameters are varied. Then we consider the Kullback–Leibler divergence of the true distribution from the estimated one and derive variational formulae of the Kullback–Leibler divergence over prior distributions. Next, we propose a Newton–Raphson method for simulating the prior distribution, which is the critical point, based on the Riemannian geometry of the probability simplex. The method can run once a sample from the true distribution is obtained without any other knowledge of the true distribution. For the geometry, we employ the Riemannian metric induced from the characteristic function, which appears in Vinberg’s theory of homogeneous convex cones. As a by-product of the geometry, we derive an interpretation that the Kullback–Leibler divergence is the logarithm of a gauge transformation. From this, we obtain a viewpoint that envisaging the true distribution is nothing but gauge fixing, and this depiction as gauge theory seems to match the context of statistics. Also, we show some numerical results on how well our methodology works.

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.

Our recent study has revealed that SLC49A4, known as disrupted in renal carcinoma 2, is an H+-coupled lysosomal exporter for pyridoxine (vitamin B6), a cationic compound. We examined in the present study the possibility that this transporter might also transport cationic amphiphilic drugs (CADs) that are known to undergo lysosomal trapping, using pyrilamine, an H1-antagonist, as a model CAD. The COS-7 cell line was used as a model cell system for transient introduction of human SLC49A4 and a recombinant SLC49A4 protein (SLC49A4-AA), in which the N-terminal dileucine motif involved in lysosomal localization was removed by replacing with dialanine for redirected localization to the plasma membrane. The introduction of SLC49A4 into COS-7 cells induced a significant decrease in the accumulation of pyrilamine in the intracellular compartments in the cells treated with digitonin for permeabilization of plasma membranes, suggesting its operation for lysosomal pyrilamine export. Accordingly, functional analysis using the SLC49A4-AA mutant, which operates for cellular uptake at the plasma membrane in transiently transfected COS-7 cells, demonstrated its H+-coupled operation for pyrilamine transport, which was saturable with a Michaelis constant of 132 μM at pH 5.5. In addition, many CADs that may potentially undergo lysosomal trapping, which include imipramine, propranolol, verapamil, and some others, were found to inhibit SLC49A4-AA–mediated pyrilamine transport, suggesting their affinity for SLC49A4. These results suggest the involvement SLC49A4 in the lysosomal trapping of pyrilamine as a lysosomal exporter. The CADs that inhibited SLC49A4-AA–mediated pyrilamine transport could also be SLC49A4 substrate candidates.SIGNIFICANCE STATEMENTSLC49A4 mediates the transport of pyrilamine in an H+-coupled manner at the lysosomal membrane. This could be a newly identified mechanism for lysosomal export involved in its lysosomal trapping.:

Introduction: Antimicrobial resistance (AMR) is one of the most serious public health challenges worldwide, including in Japan. However, there is limited evidence assessing the AMR burden in Japan. Thus, this systematic literature review (SLR) and meta-analysis (MA) were conducted to assess the clinical and economic burden of AMR in Japan. Methods: Comprehensive literature searches were performed on EMBASE, MEDLINE, the Cochrane Library, and ICHUSHI between 2012 and 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. MA estimated a pooled effect between the two comparative arms (AMR vs. non-AMR). The results were reported in measures of odds ratios (ORs) for in-hospital mortality and in standardized mean differences (SMDs) for length of stay (LOS) and direct medical costs. Results: Literature searches identified 1256 de-duplicated records, of which 56 observational studies (English, n= 35; Japanese, n= 21) were included. Of note, twenty-two studies (39.3%) compared the AMR group with non-AMR group. In the SLR, in-hospital mortality, LOS, and direct medical costs were higher in the AMR group compared to the non-AMR group. Eight studies were selected for the MA. In the AMR group, the pooled estimate showed a statistically higher in-hospital mortality [random effect (RE)—OR 2.25, 95% CI 1.34–3.79; I2= 89%; τ2= 0.2257, p< 0.01], LOS (RE—SMD 0.37, 95% CI  − 0.09–0.84; I2= 99%; τ2= 0.3600, p< 0.01), and direct medical cost (RE—SMD 0.53, 95% CI 0.43–0.62; I2= 0.0%; τ2= 0.0, p= 0.88) versus the non-AMR group. Conclusion: Our study presents an overview of the clinical and economic burden of AMR in Japan. Patients with AMR infections experience significantly higher in-hospital mortality, LOS, and direct medical costs compared with patients without AMR infections.

Sodium–glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.

The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population.

Block copolymers (BCPs) are particularly effective in creating soft nanostructured templates for transferring complex 3D network structures into inorganic materials that are difficult to fabricate by other methods. However, achieving control of the local ordering within these 3D networks over large areas remains a significant obstacle to advancing material properties. Here, we address this challenge by directing the self-assembly of a 3D alternating diamond morphology by solvent vapor annealing of a triblock terpolymer film on a chemically patterned substrate. The hexagonal substrate patterns were designed to match a (111) plane of the diamond lattice. Commensurability between the sparse substrate pattern and the BCP lattice produced a uniformly ordered diamond network within the polymer film, as confirmed by a combination of atomic force microscopy and cross-sectional imaging using focused ion beam scanning electron microscopy. The successful replication of the complex and well-ordered 3D network structure in gold promises to advance optical metamaterials and has potential applications in nanophotonics.

Precise recognition of peptides is a daunting task owing to the substantial number of available amino acids and their combination into various oligo/polymeric structures in addition to the high hydration of their flexible frameworks. Here, we report the selective recognition of a dipeptide through a closed cavity strategy, in contrast to previous synthetic receptors with open cavities. A polyaromatic receptor with a virtually isolated, hydrophobic cavity exclusively binds one molecule of phenylalanine dipeptide from a mixture with its amino acid and tripeptide in water via multiple CH−π and hydrogen-bonding interactions in the complementary cavity. The binding selectivity persists even in the presence of other dipeptides, such as leucine–leucine, leucine–phenylalanine, tyrosine–phenylalanine, tryptophan–tryptophan, and aspartame, revealed by NMR/MS-based competitive binding experiments. ITC studies reveal that the selective binding of the phenylalanine dipeptide is relatively strong (Ka= 1.1 × 105M–1) and an enthalpically and entropically favorable process (ΔH= −11.7 kJ mol–1and TΔS= 17.0 kJ mol–1). In addition, the present receptor can be used for the emission detection of the dipeptide through a combination with a fluorescent dye in water.

This study demonstrates that pendant chirality on building ligands functions as a valuable indicator for identifying metal-ligand dynamic assemblies in solution: Racemic ligands (L(R)and L(S)) with zinc ions (Zn2+) give (Zn2+)2(L(R))n(L(S))(4−n)(n= 0–4) assemblies with statistical L(R)and L(S)positioning, which can be analyzed by 1H NMR spectroscopy with a statistical model.Racemic ligands (L(R)and L(S)) with zinc ions (Zn2+) give (Zn2+)2(L(R))n(L(S))(4−n)(n= 0–4), which can be rationized by a statistical model.

Study Design Retrospective cohort study.Objectives Laminoplasty (LAMP) is one of the effective methods to successfully achieve surgical decompression in patients with degenerative cervical myelopathy (DCM). However, little evidence exists regarding the perioperative complications in LAMP for patients with ossification of the longitudinal ligament (OPLL) compared with cervical spondylotic myelopathy (CSM). We aimed to investigate the perioperative complication rates and medical costs of DCM, including OPLL and CSM patients who underwent LAMP using a large national inpatient database.Methods This study identified patients who underwent LAMP for OPLL and CSM from 2010 to 2016 using the Japanese Diagnosis Procedure Combination database. We compared the incidence of perioperative complications (systemic and local), reoperation rates, medical costs during hospitalization, and mortality were between the OPLL and CSM groups after propensity score matching.Results This study included 22,714 patients (OPLL: 7485 patients, CSM: 15,229 patients). Consequently, 7169 pairs were matched. More perioperative systemic complications were detected in the OPLL group (one complication: 9.1% vs 7.7%; P= .002), especially for pneumonia (.5% vs .2%; P= .001) and dysphagia (.5% vs .2%; P= .004). The local complication rate was also higher in the OPLL group (paralysis: 1.1% vs .6%, P= .006; spinal fluid leakage: .4% vs .1%, P= .002). The hospitalization costs were approximately $2300 higher ($19,024 vs $16,770; P< .001) in the OPLL group.Conclusions More perioperative complications and higher medical costs were noted in patients with OPLL than in patients with CSM who underwent LAMP.

We previously found that indole-3-acetic acid (IAA) produced from tryptophan by gut microbiota decreases the expression of tumor necrosis factor α (TNFα), which is implicated in the pathogenesis of colorectal cancer (CRC). The present study aimed to determine IAA involvement in the proliferation of CRC-derived Caco-2 cells. Cell proliferation was suppressed by IAA, whereas IAA-induced aryl hydrocarbon receptor activation had no impact. IAA activated extracellular signal-related (ERK) and c-Jun N-terminal (JNK) kinases, but not p38. Toll-like receptor 4 (TLR4) may be required to activate ERK and JNK, but only the TLR4-JNK pathway might elicit the anti-proliferative effects of IAA. Thus, IAA may be a ligand for TLR4 that contributes to inhibiting CRC cell proliferation by activating TLR4-mediated JNK. Because IAA did not induce cytotoxicity, inhibiting cell cycle progression might affect the anti-proliferative capacity of IAA. Therefore, colonic IAA accumulation might help to prevent CRC development and progression.Graphical AbstractIndole-3-acetic acid induced ERK and JNK activation by activating TLR4, and TLR4-JNK activation may induce anti-proliferative effects in Caco-2 cells.

Increased tumor necrosis factor α (TNFα) expression in intestinal epithelial cells (IECs) plays a major role in the development and progression of inflammatory bowel disease (IBD) and colorectal cancer (CRC). The present study aimed to clarify the relationship between TNFα and skatole, a tryptophan-derived gut microbiota metabolite. The aryl hydrocarbon receptor (AhR) antagonist CH223191 promoted, whereas the p38 inhibitor SB203580 suppressed the increase in TNFα mRNA and protein expression induced by skatole in intestinal epithelial Caco-2 cells. The c-Jun N-terminal kinase (JNK) inhibitor SP600125 repressed only the increased TNFα protein expression, whereas the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 did not affect increased TNFα expression at any level. A neutralizing antibody against TNFα partially inhibited skatole-induced cell death. Overall, these results suggested that TNFα expression is increased by the concerted actions of skatole-activated p38 and JNK, and that TNFα exerts autocrine/paracrine actions on IECs despite partial suppression by activated AhR. Therefore, skatole might play an important role in the development and progression of IBD and CRC via increased TNFα expression.Graphical AbstractAhR partially attenuates but p38 and JNK coordinately upregulate skatole-induced expression of TNFα, which exerts autocrine/paracrine actions on IECs.

Introduction: While incidence rates of vancomycin-resistant Enterococcus faeciumhave remained comparatively low in Japan, there have been increasing reports of more vancomycin-resistant Enterococcus(VRE) outbreaks, requiring costly measures to contain. Increased incidence of VRE in Japan may lead to more frequent and harder to contain outbreaks with current control measures, causing a significant burden to the healthcare system in Japan. This study aimed to demonstrate the clinical and economic burden of vancomycin-resistant E. faeciuminfections to the Japanese healthcare system and the impact of increasing rates of vancomycin resistance. Methods: A de novo deterministic analytic model was developed to assess the health economic outcomes of treating hospital-acquired VRE infections; patients are treated according to a two-line treatment strategy, dependent on their resistance status. The model considers hospitalisation costs and the additional cost of infection control. Scenarios investigated the current burden of VRE infections and the additional burden of increased incidence of VRE. Outcomes were assessed over a 1-year and 10-year time horizon from a healthcare payer’s perspective in a Japanese setting. Quality-adjusted life years (QALYs) were valued with a willingness-to-pay threshold of ¥5,000,000 ($38,023), and costs and benefits were discounted at a rate of 2%. Results: Current VRE incidence levels in enterococcal infections in Japan equates to ¥130,209,933,636 ($996,204,669) in associated costs and a loss of 185,361 life years (LYs) and 165,934 QALYs over 10 years. A three-fold increase (1.83%) is associated with an additional ¥4,745,059,504 ($36,084,651) in total costs on top of the current cost burden as well as an additional loss of 683 LYs over a lifetime, corresponding to 616 QALYs lost. Conclusion: Despite low incidence rates, VRE infections already represent a substantial economic burden to the Japanese healthcare system. The substantial increase in costs associated with a higher incidence of VRE infections could result in a significant economic challenge for Japan.

Study Design: Retrospective single-center study.Objectives: K-line is a decision-making tool to determine the appropriate surgical procedures for patients with cervical ossification of the posterior longitudinal ligament (C-OPLL). Laminoplasty (LAMP) is one of the standard surgical procedures indicated on the basis of K-line measurements (+: OPLL does not cross the K-line). We investigated the impact of K-line tilt, a radiographic parameter of cervical sagittal balance measured using the K-line, on surgical outcomes after LAMP.Methods: The study included 62 consecutive patients with K-line (+) C-OPLL who underwent LAMP. The following preoperative and postoperative radiographic measurements were evaluated: (1) the K-line, (2) K-line tilt (an angle between the K-line and vertical line), (3) center of gravity of the head –C7 sagittal vertical axis, (4) C2–C7 lordotic angle, (5) C7 slope, and (6) C2–C7 range of motion. Clinical results were evaluated using the Japanese Orthopedic Association scoring system for cervical myelopathy (C-JOA score).Results: All the patients had non-kyphotic cervical alignment (CL ≥ 0°) preoperatively; however, kyphotic deformity (CL < 0°) was observed in 6 patients (9.7%) postoperatively. The recovery rate of the C-JOA scores was poor in the kyphotic deformity (+) group (7.8%) than in the kyphotic deformity (−) group (47.5%). The K-line tilt was identified to be a preoperative risk factor in the multivariate analysis, and the cutoff K-line tilt for predicting the postoperative kyphotic deformity was 20°.Conclusions: LAMP is not suitable for K-line (+) C-OPLL patients with K-line tilts >20°.

Type 2 ryanodine receptor (RyR2) is a Ca2+release channel on the endoplasmic (ER)/sarcoplasmic reticulum that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia and heart failure, where spontaneous Ca2+release via hyperactivated RyR2 depolarizes diastolic membrane potential to induce triggered activity. In such cases, drugs that suppress RyR2 activity are expected to prevent the arrhythmias, but there is no clinically available RyR2 inhibitors at present. In this study, we searched for RyR2 inhibitors from a well-characterized compound library using a recently developed ER Ca2+-based assay, where the inhibition of RyR2 activity was detected by the increase in ER Ca2+signals from R-CEPIA1er, a genetically encoded ER Ca2+indicator, in RyR2-expressing HEK293 cells. By screening 1535 compounds in the library, we identified three compounds (chloroxylenol, methyl orsellinate, and riluzole) that greatly increased the ER Ca2+signal. All of the three compounds suppressed spontaneous Ca2+oscillations in RyR2-expressing HEK293 cells and correspondingly reduced the Ca2+-dependent [3H]ryanodine binding activity. In cardiomyocytes from RyR2-mutant mice, the three compounds effectively suppressed abnormal Ca2+waves without substantial effects on the action-potential-induced Ca2+transients. These results confirm that ER Ca2+-based screening is useful for identifying modulators of ER Ca2+release channels and suggest that RyR2 inhibitors have potential to be developed as a new category of antiarrhythmic drugs.SIGNIFICANCE STATEMENTWe successfully identified three compounds having RyR2 inhibitory action from a well-characterized compound library using an endoplasmic reticulum Ca2+-based assay, and demonstrated that these compounds suppressed arrhythmogenic Ca2+wave generation without substantially affecting physiological action-potential induced Ca2+transients in cardiomyocytes. This study will facilitate the development of RyR2-specific inhibitors as a potential new class of drugs for life-threatening arrhythmias induced by hyperactivation of RyR2.

Background: Antimicrobial resistance (AMR) is one of the most serious public health challenges worldwide, including in Japan. Globally, research and development of new antimicrobials has stalled due to unfavorable market conditions, which undervalue antimicrobials. Furthermore, Japan faces the additional challenge of delayed commercialization for a number of recently approved treatments. Objective: This study aims to examine the impact on AMR of introducing a new anti-infective treatment, ceftazidime/avibactam, into current treatment strategies. It reports the resulting clinical and economic outcomes from the perspective of healthcare payers in Japan. Methods: A previously published and validated dynamic disease transmission model was adapted to the Japanese setting. The model estimated health economic outcomes for treating three Gram-negative hospital-acquired infections, under different treatment strategies, from a healthcare payers’ perspective. Outcomes were assessed over a 10-year time horizon with a willingness-to-pay threshold of ¥5,000,000 (US$45,556) per quality-adjusted life-year (QALY) gained and an annual discount rate of 2% applied to costs and benefits. Results: Introducing ceftazidime/avibactam in the framework of a diversification strategy with piperacillin/tazobactam is associated with reducing 798,640 bed days, equating to ¥21.0 billion (US$190.9 million) savings in hospitalization costs, and a gain of 363,034 life-years, or 308,641 QALYs. This translates into a monetary benefit of ¥1.56 trillion (US$14.3 billion) to Japanese healthcare payers. Discussion: Introducing a new antimicrobial agent into clinical practice is associated with considerable clinical and economic benefits. This analysis demonstrates that the approach taken to incorporate a new antimicrobial agent into clinical practice impacts on the scale of these clinical and economic benefits; greater benefits are associated with earlier use of antimicrobials as part of an antimicrobial stewardship program. Conclusion: This analysis shows that changing the way in which a new antimicrobial is used within a treatment strategy has the potential for additional significant clinical and economic value.

In 519 eyes that underwent small-gauge vitrectomy for primary rhegmatogenous retinal detachment, drainage retinotomy was significantly associated with surgical failure in a propensity matching score. Postoperative epiretinal membrane was also associated with drainage retinotomy. Avoidance of drainage retinotomy may lead to better surgical success and less frequent epiretinal membrane formation.

Breads with different compositions of wheat flour (WF), soy protein isolate (SPI), and soybean soluble polysaccharide (SSPS) were prepared, and the relationships between their physical and nutritional properties, mastication, palatability were investigated and tests on elderly and young human subjects were conducted. Bread mixed with only SPI (SP1) showed a reduced specific volume and was hard, possibly making it difficult for elderly individuals to swallow. When 10 g of SPSS was added to the mixture (SP2), the bread improved in specific volume, became soft and moderately hard, and was as palatable as regular bread (control; without SPI and SPSS) for younger and older people. However, when 20 g of SSPS was added (SP3), the adhesiveness increased and palatability was impaired. In addition, SP2 bread required increased number of chews and chewing time compared to that required for control bread in older people but the difficulty of swallowing was similar for both in the sensory evaluation. SP2 bread can increase the intake of protein and dietary fiber and increase the number of chews without affecting palatability, and SPI and SSPS mixed bread was considered useful for maintaining the chewing ability and nutritional status of older people.

Biohybrid materials, which are defined as engineered functional materials combining living components with nonliving synthetic materials, are considered promising bioactive materials for applications in in vivo tissue engineering. However, the rational design of biohybrid materials applicable to in vivo tissue engineering faces major challenges associated with techniques for combining living cells with nonliving synthetic materials and cell sources. Here, we report injectable covalent stem cell-combing biohybrid materials prepared via a bio-orthogonal click cross-linking reaction of azide-modified adipose-derived stem cells (N3[+]ADSCs), one of the most promising cell sources utilized clinically, with alkyne-modified biocompatible alginate polymers. The mechanical properties of the covalent stem cell-combining biohybrid materials can be adapted to the mechanical properties of the surrounding environment in which they are transplanted by alternating the number of N3[+]ADSCs, the concentration of alkyne-modified alginate, and the number of alkyne groups. Importantly, ADSCs in the covalent biohybrid materials expressed a high level of CD-105, a marker for undifferentiated mesenchymal stem cells, in the body in the absence of differentiation signals, whereas very little CD-105 was expressed in the control physical cell-loading materials, demonstrating that this covalent stem cell-combining approach results in enhanced retention of the material’s “stemness” and controlled differentiation in the body. We assessed the potential utility of the covalent stem cell-combining biohybrid materials for in vivo tissue engineering using a murine severe skeletal muscle defect-healing model. Importantly, all of the tissues regenerated by the covalent biohybrid material treatment expressed MYH3, a myogenic marker protein, whereas no expression of MYH3 was detected in the tissues reconstructed by treatment with control physical stem cell-loading materials and Matrigel, indicating that this covalent stem cell-combining approach results in controlled differentiation in the body. Our data demonstrate the potential utility of covalent stem cell-combining biohybrid materials with host tissue-integrative and controlled differentiation capabilities available for in vivo tissue engineering.

Anion-responsive sign inversion of circularly polarized luminescence (CPL) was successfully achieved by N3O6-type nona-coordinated europium(III) (Eu3+) complexes [(R)-1and (S)-1] composed of a less-hindered unsymmetrical N3-tridentate ligand (a chiral bis(oxazoline) ligand) and three O2-chelating (β-diketonate) ligands. Here, (R)-1exhibited a positive CPL signal (IL– IR> 0) at the 5D0→ 7F1transition of Eu3+, which can be changed to a negative sign (i.e., IL– IR> 0 → IL– IR< 0) by the coordination of trifluoroacetic anions (CF3COO–) to the Eu3+center. However, (R)-1preserved the original positive CPL signal (i.e., IL– IR> 0 → IL– IR> 0) in the presence of a wide range of competing anions (Cl–, Br–, I–, BF4–, ClO4–, ReO4–, PF6–, OTf–, and SbF6–). Thus, (R)-1acts as a smart target identifiable probe, where the CPL measurement (IL– IR) can distinguish the signals from the competing anions (i.e., IL– IR< 0 vs IL– IR> 0) and eliminate the background emission (i.e., IL– IR= 0) from the background emitter (achiral luminescent compounds). The presented approach is also promising in terms of bio-inspired optical methodology because it enables nature’s developed chiral sensitivity to use circularly polarized light for object identification (i.e., IL– IR= 0 vs | IL– IR| > 0).

A 73-year-old man diagnosed with moderate aortic insufficiency and dilatation of the aortic root and ascending aorta underwent a modified Bentall procedure and hemi-arch aortic replacement. During open distal anastomosis of the ascending aorta, the surgical needle was lost. Because of circulatory arrest, the operation was continued; before closing the chest, radiography and a transesophageal echo were located in the needle in the descending aorta. It was retrieved using a snare catheter via the graft branch under fluoroscopic guidance. Thus, locating the needle in the descending aorta and leaving the graft branch uncut led to its removal without a new incision.

An electrolysis cell was fabricated using a boron-doped diamond powder (BDDP)-packed bed as an anode. 30 mL of 50 µM methylene blue solution was decolorized to almost colorless within 60 min when a BDDP-packed electrolysis flow cell with a BDDP amount of 1.6 g was used for the electrolysis. The BDDP-packed electrolysis flow cell is considered useful for highly efficient and durable electrolysis flow systems because no significant deterioration was observed even after repeated electrolysis experiments.An electrolysis cell was fabricated using a boron-doped diamond powder (BDDP)-packed bed as an anode. The BDDP-packed electrolysis flow cell was found to be useful for highly efficient and durable electrolysis flow systems. No significant deterioration of the electrode was observed even after repeated electrolysis experiments.

Abstract In this paper, cement paste characteristics and porous concrete properties are studied. The results indicate that cement paste characteristics are dependent on the water to cement ratio (W/C), admixture [...]

When a water piping system operating under high temperatures and pressures is damaged and water is expelled into the atmosphere, a phenomenon known as depressurization boiling or flashing occurs. This flashing jet poses a risk to human safety and can damage safety equipment through impingement. Consequently, evaluating the region affected by the flashing jet impinging on the surrounding equipment and people is necessary. In this study, we conducted experiments to verify the affected region of the jet involving both saturated and subcooled water under low-pressure conditions at the jet inlet, up to 2 MPaA, and extended our investigation to high-pressure conditions up to 7 MPaA using computational fluid dynamics (CFD). The findings revealed that the mass flux predictions, according to the homogeneous equilibrium model (HEM) outlined in the American National Standards Institute (ANSI) standard, align with both experimental and CFD analysis results. However, the evaluations of both the asymptotic plane width and distance—parameters delineating the jet's affected region—were found to be underestimated in the ANSI standard compared with the experimental and CFD analysis results. To address this difference from real phenomena, we developed an improved model that incorporates mass flux and enthalpy as variables. This improved model more accurately predict the asymptotic plane width and distance than the ANSI standard. Utilizing this improved model enables precise prediction of the flashing jet's affected region, spanning conditions from saturated to subcooled water across various pipe diameters.

The position of women in Japanese labor markets with relation to gender discrimination is presented.

OBJECTIVE--Treatment of diabetic patients by pancreatic islet transplantation often requires the use of islets from two to four donors to produce insulin independence in a single recipient. Following isolation and transplantation, islets are susceptible to apoptosis, which limits their function and probably long-term islet graft survival. RESEARCH DESIGN AND METHODS--To address this issue, we examined the effect of the cell-permeable apoptosis inhibitor pentapeptide Val-Pro-Met-Leu-Lys, V5, on pancreatic islets in a mouse model. RESULTS--V5 treatment upregulated expression of anti-apoptotic proteins Bcl-2 and XIAP (X-linked inhibitor of apoptosis protein) by more than 3- and 11-fold and downregulated expression of apoptosis-inducing proteins Bax, Bad, and nuclear factor-κB-p65 by 10, 30, and nearly 50%, respectively. Treatment improved the recovered islet mass following collagenase digestion and isolation by 44% and in vitro glucose-responsive insulin secretion nearly fourfold. Following transplantation in streptozotocin-induced diabetic mice, 150 V5-treated islet equivalents functioned as well as 450 control untreated islet equivalents in normalizing blood glucose. CONCLUSIONS--These studies indicate that inhibition of apoptosis by V5 significantly improves islet function following isolation and improves islet graft function following transplantation. Use of this reagent in clinical islet transplantation could have a dramatic impact on the number of patients that might benefit from this therapy and could affect long-term graft survival., Pancreatic islet transplantation holds great promise as a treatment for type 1 diabetes. Insulin independence has been accomplished using a glucocorticoid-free immunosuppression regimen but often requires transplantation of islets from [...]

Study objectives: Exercise training has been shown to favorably affect the prognosis after acute myocardial infarction (AMI), but the mechanisms of such favorable effects remain speculative. The aim of this [...]

Insulin is a unique hormone that decreases the concentration of blood glucose rapidly in vivo. The insulin-stimulated disposal of blood glucose into skeletal muscle and adipose tissue occurs by the [...], Insulin stimulates the disposal of blood glucose into skeletal muscle and adipose tissues by the translocation of GLUT4 from intracellular pools to the plasma membrane, and consequently the concentration of blood glucose levels decreases rapidly in vivo. Phosphatidyl-inositol (PI) 3-kinase and Akt play a pivotal role in the stimulation of glucose transport by insulin, but detailed mechanisms are unknown. We and others reported that not only insulin but also platelet-derived growth factor (PDGF) and epidermal growth factor facilitate glucose uptake through GLUT4 translocation by activation of PI 3-kinase and Akt in cultured cells. However, opposite results were also reported. We generated transgenic mice that specifically express the PDGF receptor in skeletal muscle. In these mice, PDGF stimulated glucose transport into skeletal muscle in vitro and in vivo. Thus, PDGF apparently shares with insulin some of the signaling molecules needed for the stimulation of glucose transport. The degree of glucose uptake in vivo reached ~60% of that by insulin injection in skeletal muscle, but blood glucose levels were not decreased by PDGF in these mice. Therefore, PDGF-induced disposal of blood glucose into skeletal muscle is insufficient for rapid decrease of blood glucose levels.

The formation process of myrmekites in granitic rocks can help us to understand the mass transfer between minerals and hydrothermal fluids during the deuteric stage. The Toki granite, central Japan, has three types of myrmekites. Type A myrmekite is defined as a single layer. Type B myrmekite shows a composite texture consisting of two layers, namely, a myrmekite layer and an albite (Ab)-rich layer that is free of vermicular quartz. Type C has a composite texture with the following three layers: two myrmekite layers separated by one Ab-rich layer. Micropores are found in these myrmekites in the undeformed granite, which enable quantitative determinations of the volume decrease during myrmekite formation by measurement of the area of micropores. The areal relationship between the micropores and vermicular quartz in the myrmekites exhibited a high correlation (R2= 0.8352), thus indicating that the genesis of the micropores is evidently related to myrmekite formation. We derived the reaction equations for myrmekite formation based on the singular value decomposition method. The matrices for singular value decomposition involve the following volume factors: volume change during the reaction and volume ratios of the product minerals. The singular value decomposition indicates that the myrmekites are produced through the consumption of plagioclase and K-feldspar with an inflow of H4SiO4, Na+, and H+from the hydrothermal fluid, accompanied by an outflow of Al3+, Ca2+, and K+into the fluid, which constitute essential mass transfers during myrmekite formation. The diference of pH in the hydrothermal fluid and inflow amounts of H4SiO4and Na+can explain the reason why micropores occur in the myrmekites but not in the Ab-rich rim (layer); the smaller inflow of H4SiO4and Na+from the hydrothermal fluid with lower pH conditions yielded micropore production during myrmekitization, and the larger inflow of H4SiO4and Na+from the hydrothermal fluid with higher pH conditions yielded the formation of the Ab-rich rim (layer) with few micropores. The sequential variations in the chemical characteristics of the hydrothermal fluid during the sub-solidus conditions were characterized by a gradual decrease in H4SiO4(Si4+), Fe2+, Mn2+, Mg2+, and Na+and a gradual increase in Ca2+, K+, H+, and F–.

Study objective: To assess the effect of coronary flow to the infarct zone before primary coronary angioplasty on hospital complications in patients with acute myocardial infarction (MI). Design: Consecutive case [...]

The massive success in Japan of PlayStation 2 and i-mode technology seems to herald a time when they will dominate consumers' lives and may even replace personal computers. The i-mode mobile Internet service is user-friendly and offers strong content. In its first year it attracted 4.33 mil subscribers.