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Planar ultra-thin body and box (UTBB1–3) fully depleted silicon on insulator (FDSOI) devices have many advantages for future low-cost energy-efficient applications. However, process steps for scaling to ultra-thin FDSOI devices can be difficult to control, and extrinsic resistance can hinder any performance improvement. In this paper, we present a novel planar U-channel UTBB FDSOI device that can alleviate these problems.

In this paper, we discuss a technique for selective GeO x -scavenging which creates a GeO x -free interfacial layer (IL) on Si 1−x Ge x substrates. This process reduces interface trap density (N it ) and increases high-field hole mobility in Si 1−x Ge x pFETs. In addition, we identify the existence of electronic defect levels close to the Si 1−x Ge x band edges associated with the Ge surface concentration at the Si 1−x Ge x /IL interface. These electronic defects act as carrier scattering centers severely degrading the channel mobility and modulate the device threshold voltage. By successfully eliminating the GeO x component in the IL and electronic defects states at the Si 1−x Ge x /IL interface, high channel carrier mobility over a wide range of inversion carrier density in compressively-strained Si 1−x Ge x channel pFETs is demonstrated.

A 64-year-old man was admitted to our hospital for the hormonal evaluation of a right adrenal adenoma. He had been diagnosed with severe proteinuria and hypertension, and antihypertensive treatment was started at the age of 60. His renal function gradually declined, and hemodialysis was begun at the age of 64. Since his blood pressure was uncontrollable and resistant to antihypertensive treatment, an endocrinological examination was performed for an incidental right adrenal mass detected by computed tomography. The results of screening, including captopril challenge and an adrenocorticotropin stimulation test for primary aldosteronism, and adrenal venous sampling suggested excessive aldosterone secretion from the right adrenal gland. Adrenalectomy was performed; his blood pressure decreased and became well-controlled with a reduced antihypertensive regimen. Furthermore, he received renal transplantation which resulted in normalization of his serum potassium level, improvement of renal function and hormonal levels such as plasma renin activity and aldosterone concentration, and satisfactory blood pressure without any antihypertensive medications. This case is extremely important to demonstrate the effects of adrenalectomy for primary aldosteronism in a hemodialysis patient. It is possible that adrenalectomy may be a useful treatment for primary aldosteronism even in patients undergoing hemodialysis. Careful long-term follow-up of our case and investigations of the efficacy of adrenalectomy in similar cases are needed to address this issue.

We demonstrate scaled high-Ge-content (HGC) strained SiGe pMOS FinFETs with very high short channel (SC) performance using a Replacement High-K/Metal Gate (RMG) flow, for the first time. A novel RMG gate stack process was introduced to create Ge-free interface-layer (IL) with excellent reliability and sub-threshold swing (SS) as low as 62mV/dec, the best reported to date for Si-cap-free SiGe FinFETs. We also present some structural details of the gate stack, for the first time. Short channel characteristics of HGC SiGe FinFETs have also been studied for various fin widths. Compared to our earlier RMG work, improved I/I free process with ultra-thin spacers has led to considerable R on and R ext reduction. As a result, we have demonstrated very high SiGe performance with I on =0.45mA/μm at I off =100nA/μm at V dd =0.5V for L G =25nm, matching our record for gate-first SiGe FinFETs and outperforming the gate-first results at such LG.

To identify the characteristics of blood pressure (BP), heart rate (HR), and double product in a Japanese population sample.We pooled individual records from 1999 to 2005 for 111 007 participants in 25 community-based cohorts and seven worksite-based cohorts. The data were analyzed to provide information on BP, HR, and double product according to age-sex groups and use of antihypertensive medication.Average BP was 130/77 mmHg among men and women combined. Among untreated individuals, SBP increased with age, whereas DBP reached a ceiling around the age of 60 years. The average SBP of treated participants was around 140 mmHg, irrespective of age, whereas DBP decreased linearly with age, and 56.4% of treated participants had a BP of 140/90 mmHg or over. HR did not differ across age groups or treatment status. The double product, also called the rate-pressure product, calculated by multiplying the SBP and the HR, increased with age among untreated individuals, whereas it first decreased and then increased with age among treated individuals.Based on these collaborative data, insufficient BP control in Japan, where the average life expectancy is the longest in the world, was seen.

In this study, we propose a novel variable sample injection system based on full-loop injection, named the split-flow sample introduction system, for application in supercritical fluid chromatography (SFC). In this system, the mobile phase is split by the differential pressure between two back pressure regulators (BPRs) after full-loop injection suitable for SFC, and this differential pressure determines the introduction rate. Nine compounds with a wide range of characteristics were introduced with high reproducibility and universality, confirming that a robust variable sample injection system was achieved. We also investigated the control factors of our proposed system. Sample introduction was controlled by the ratio between the column-side pressure drops in splitless and split flow, ΔPcolumnsideinsplitless and ΔPcolumnsideinsplit, respectively, where ΔPcolumnsideinsplitless is related to the mobile phase flow rate and composition and the column resistance. When all other conditions are kept constant, increasing the make-up flow induces an additional pressure drop on the column side of the system, which leads to a reduced column-side flow rate, and hence decreased the amount of sample injected, even when the net pressure drop on the column side remains the same. Thus, sample introduction could be highly controlled at low sample introduction rate, regardless of the introduction conditions. This feature is advantageous because, as a control factor, the solvent in the make-up pump is independent of the column-side pressure drop.

FinFETs with strained-SiGe channel have recently drawn significant attention due to their built in uniaxial strain, higher mobility and better reliability over conventional Si FETs. Research on pure Ge has been the major focus of many institutes over the past few years. However, with high-Ge-content (HGC) SiGe one can benefit from competitive or better performance over pure Ge and overcome the thermal budget constraints required for Ge. In this paper, we briefly review our latest advancements in high-Ge-content strained-SiGe FinFETs featuring gate first and Replacement HK/MG (RMG) flows with record mobility and short-channel performance to extend the roadmap for advanced FinFET and FDSOI generations.

The patient was diagnosed with anuloaortic ectasia with localized dissection in the right Valsalva sinus. He underwent aortic root replacement with mechanical valve. But, he was re-admitted for mediastinitis. Although his serum (CRP) level was normalized for one month, his body temperature suddenly rose to 40°C. An emergency operation was performed including re-sternotomy, drainage, and irrigation. However, a proximal anastomotic site ruptured and he went into shock. Following cardiopulmonary bypass, we performed a second aortic root replacement. Therefore, the patient was operated for sternum debridement and to wrap the prosthetic vessel into an omental pedicle. Nine days after the last intervention, bleeding from the chest wound suddenly appeared and he went into shock. He was transported to the operating room to initiate cardiopulmonary bypass. During circulatory arrest, laceration was detected at the same annular position. Deep into the left ventricle, we made interrupted sutures in the left cardiac muscle. Next, we implanted a Freestyle aortic root bioprosthesis using the full root technique. After removing all former implants, another prosthetic vessel was anastomosed between the Freestyle conduit and the distal aorta, and wrapped with omental pedicle. After three weeks, his serum CRP level was normal. He remained free of infection for at least three years.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a familial neurodegenerative disease clinically characterized by progressive cognitive and motor dysfunction. Mutations in the colony-stimulating factor 1 receptor (CSF1R) gene have recently been identified in HDLS patients. The presence of diffuse axonal spheroids, myelin loss, and pigmented microglia in the white matter are pathologic hallmarks of HDLS; however, early pathologic findings have not been described in HDLS patients. We report a Japanese family with HDLS. A novel heterozygous c.653 C>Y mutation in the CSF1R gene was identified in the female proband who died at the age of 63 years; postmortem findings were compatible with HDLS. We also autopsied her sister who was considered to be neurologically asymptomatic and died of tuberculosis at the age of 44 years. Postmortem studies revealed patchy axonal degeneration and myelin loss, predominantly in the subcortical white matter. Pigmented microglia were distributed diffusely throughout the cerebral white matter and expressed CSF1R poorly. In conclusion, our observations suggest that the pathology of HDLS may initially be characterized by multifocal lesions in subcortical white matter regions. Moreover, pigmented microglia poorly express CSF1R and are distributed diffusely throughout the white matter at the early disease stage, preceding axonal damage and myelin loss.

To investigate the long-term outcome in children with frequently relapsing nephrotic syndrome (FRNS) we conducted a follow-up of a previous randomized controlled trial (RCT) 10 years after the initiation of the treatment protocol.We previously conducted an RCT on the efficacy of cyclosporine for treating children with FRNS. After 2 years of treatment, a recommended a management protocol of steroids, and immunosuppressants was provided.Valid information was available for 46 of the 56 patients (82.1 %) enrolled in the original RCT. The median follow-up period was 10.3 years from the start of protocol treatment with cyclosporine. At last follow-up (mean age 18.7 years), only ten patients (21.7 %) showed disease-free remission (no relapse for at least 2 years). In contrast, 23 (50.0 %) continued to relapse frequently or were on immunosuppressants, eight patients (17.4 %) had infrequent relapses without immunosuppressants. Adverse effects attributable to treatment included short stature (6 patients), osteoporosis (six patients), obesity (4 patients), cataracts (3 patients) and hypertension (3 patients). No lethal event or renal dysfunction occurred during follow-up.This 10-year follow-up study shows that most children with FRNS experience relapses after 2 years of cyclosporine treatment, in adolescence and into adulthood. Outcomes in terms of life expectancy and renal function are favorable.

報告(Reports)

Osteoarthritis (OA) is a group of common, chronic, and painful inflammatory joint diseases. One important finding in OA patients is a remarkable decrease in the molecular weight of hyaluronic acid (HA) in the synovial fluid of affected joints. Therapeutic HA is available to patients in most parts of the world as a viscosupplementation product for the treatment of OA. Previous clinical reports show that high molecular weight HA (HMWHA) more effectively relieves pain than low molecular weight HA (LMWHA). However, the mechanism behind this finding remains unclear. In this study, we investigated whether a LMWHA (Low-0.9 MDa) and two types of HMWHA (High-1.9 MDa and 6 MDa) differentially affected chondroregulatory action. We tested this using ATDC5 cell, a murine chondrocytic cell line widely used in culture systems to study chondrogenic differentiation. We found that HMWHA, especially hylan G-F 20 (High-6 MDa), significantly induced aggrecan and proteoglycan accumulation, nodule formation, and mRNA expression of chondrogenic differentiation markers in a time- and dose-dependent manner. In addition, we showed that HMWHA prevented TNF-α induced inhibition of chondrogenic differentiation, with no effect on cell proliferation or viability. These results reveal that HMWHA significantly promotes chondrogenic differentiation of ATDC5 cells in vitro, and suggest that HMWHA plays a significant chondroregulatory role in vivo. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1619–1627, 2014.

Inhibition of the renin-angiotensin system (RAS) has been shown to have beneficial effects in cardiovascular disease prognosis and therapy.Discovery of (pro)renin receptor [(P)RR] revealed that (P)RR upon binding to both renin or prorenin in their proenzyme inactive form made them enzymatically active, thus aiding the catalytic conversion of angiotensinogen (AGT) to angiotensin (Ang) I. This binding also transduces intracellular signal to the nucleus via various pathways. Our recent research elucidated the physiological roles of (P)RR in cell life, wherein it acts as an essential accessory protein of vacuolar H(+)-ATPase (V-ATPase) as well as an adaptor protein of Wnt signaling. The present review provides insights into a novel approach to cardiovascular diseases, which will open the gates to new therapeutic approaches for treating cardiovascular diseases.

Osteosarcoma is the most common primary malignant tumor of bone and accounts for around 50% of all primary skeletal malignancies. In addition to novel chemotherapies, there is a need for adjuvant therapies designed to inhibit osteosarcoma proliferation and tumor-induced osteolysis to attenuate tumor expansion and metastasis. As such, studies on the efficacy of bisphosphonates on human osteosarcoma are planned after feasibility studies determined that the bisphosphonate zoledronic acid (ZOL) can be safely combined with conventional chemotherapy. However, the molecular mechanisms responsible for, and means of inhibiting, osteosarcoma-induced osteolysis are largely unknown. We establish that osteosarcoma growth directly correlates with tumor-induced osteolysis and activation of osteoclasts in vivo. In vitro, tumor cells were determined to expresses surface, but not soluble, receptor activator of NF-κB ligand (RANKL) and stimulated osteoclastogenesis in a manner directly proportional to their malignant potential. In addition, an aggressive osteosarcoma cell line was shown to secrete monocyte chemoattractant protein-1 (MCP-1), resulting in robust monocyte migration. Because MCP-1 is a key cytokine for monocyte recruitment and surface-bound RANKL strongly supports local osteoclastogenesis, we suggest that high levels of these signaling molecules are associated with the aggressive potential of osteosarcoma. Consistent with these findings, abundant expression of RANKL/MCP-1 was observed in tumor in vivo, and MCP-1 plasma levels strongly correlated with tumor progression and osteolysis. ZOL administration directly attenuates osteosarcoma production of RANKL/MCP-1, reducing tumor-induced bone destruction. In vivo, these findings also correlated with significant reduction in osteosarcoma growth. ZOL attenuates tumor-induced osteolysis, not only through direct inhibition of osteoclasts, but also through direct actions on tumor expression of osteoclast activators. These data provide insight regarding the effect of ZOL on osteosarcoma essential for designing the planned upcoming prospective randomized trials to determine the efficacy of bisphosphonates on osteosarcoma in humans.

Deposition of a metal gate on high-K dielectric HfO2 is known to generate oxygen vacancy (OVs) defects. Positively charged OVs in the dielectric affect the gate electrostatics and modulate the effective gate workfunction (WF). Count and spatial allocation of OVs varies from device-to-device and induces significant local variability in WF and Vth. This paper presents the statistical models to simulate OV concentration and placement depending on the gate formation conditions. OV-induced variability is studied for SOI FinFET, and compared against the other sources of variability across the technologies. The implications of gate first and gate last processes to the OV concentration/distribution are studied. Simulations show that with channel length and gate dielectric thickness scaling, the OV-induced variability becomes a significant concern.

Dielectric thin film spacers play a very important role in defining the silicon channel boundary and junction geometries as well as proximity to silicon stressors and strongly affect key transistor electrical characteristics [1]. Another important application of sidewall spacers is in patterning of 3D FinFETs (Field Effect Transistor), where the Sidewall Image Transfer (SIT) technology [2] helps to overcome the limitations of conventional lithography and to improve control of critical dimensions. Sidewall spacers are also used to control critical dimension (CD) by depositing a spacer film inside a feature to achieve a CD shrink. Tolerance for variability of TFin(Fin width) has to be in the sub nm range to significantly reduce variability in FinFET performance. The need for precise scaling of conventional spacers as well as new patterning applications put very stringent requirements on spacer thin film depositions and on control of spacer film properties during subsequent integration processes. The need for greatly improved spacer process step coverage, tighter thickness control, pattern effects and more stringent film properties requirements strongly influenced the transition from Chemical Vapor Deposition (CVD) to Atomic Layer Deposition (ALD) spacers in the industry. This paper discusses the properties of ALD silicon nitride and silicon oxide spacer films from the perspectives of ALD and MLD (Molecular Layer Deposition) techniques, precursor chemistries and compositional stability after subsequent integration steps like implant anneals and spacer sculpting reactive ion etching processes. Advanced imaging techniques like EELS (Electron Energy Loss Spectroscopy) and XPS (X-ray Photoelectron Spectroscopy) techniques have been used to analyze sidewall spacer transformation. Special attention has been paid to the microloading effect - the dependence of thin film deposition rate on pattern density [3]. Microloading data for CVD, MLD and ALD techniques are compared based on a specially designed microloading measurement vehicle. This is especially useful with geometries needing a sub nm tolerance and when patterning endpoint detection schemes are highly dependent on film properties. The effect of ALD deposition parameters on film electrical characteristics like dielectric breakdown and leakage are also delineated. Silicon strain engineering issues related to the implementation of ALD spacers and techniques aimed at varying and controlling an intrinsic stress level in ALD films are also discussed. The findings helped to optimize the existing ALD/MLD processes for conventional epi and source/drain spacers as well for oxide sidewall ALD spacers for SIT fins patterning and CD shrink on 14nm FinFET technology. References: 1. J-H Yan, J-E Park, L-W Lee, K-S Chu , et.al., VLSI Tech Digest, p.55, (2003) 2. Y-K Choi, T-J King and C. Hu, IEEE Trans. Electron Devices, 49, 3, p.435, (2002) 3. M. Belyansky in ‘Handbook of Thin Film Deposition”, 3rd. Ed., K. Seshan Editor, Elsevier, p.46, (2012)

High-k gate dielectrics such as HfO2 and metal gate electrodes such as TiN have been deployed across a wide range of CMOS logic products in both the low-power (e.g., mobile) and the high-performance (e.g., server) space. Available device geometries include planar field-effect transistors on bulk Si, on partially depleted silicon-on-insulator (PDSOI), and on fully depleted SOI (FDSOI), as well as FinFETs. During the decade-long effort leading up to successful high-k/metal gate (HKMG) implementation, much has been learnt about the fundamental materials science underlying such gate stacks. Yet, research continues in order to ensure continued circuit density and performance scaling. After reviewing the gate-first and gate-last (or replacement gate) approaches to HKMG implementation, I will discuss device challenges that can be resolved by materials engineering on the atomic scale. A prime example is the threshold voltage (Vt) challenge, which is caused by charged oxygen vacancies in hafnium-based gate dielectrics formed at elevated temperatures, thus increasing pFET Vt. These vacancies can be filled by lateral or top-down oxidation. As an alternative, additional Vt-setting techniques can be employed, such as metal oxide capping layers (e.g., Al2O3 or La2O3 for pFET and nFET, respectively) that form permanent electrical dipoles, or SiGe channels (cSiGe) which modulate the band offsets while additionally providing a welcome hole mobility boost. A second example is continued equivalent oxide thickness (EOT) scaling. We have developed the approach of metal-gate-induced remote oxygen scavenging, which results in a thinning of the SiO2 layer at the high-k/channel interface. In this way, EOT of 0.4-0.5 nm can be reached for both nFET and pFET. I will in particular discuss our recent results on aggressive cSiGe pFET scaling (Fig. 1), including the dependence of hole mobility (Fig. 2) and of negative bias temperature instability (NBTI) reliability on EOT and thus on interfacial SiO2thickness [1]. In the second part of my talk, I will show that HKMG not only provides the well-known gate-length scaling benefit through improved electrostatics, but it can also directly enable aggressive device pitch and density scaling through borderless (semi-self-aligned) source-drain (S/D) contacts [2]. Conventional gate-first high-k/metal gate (HKMG) CMOS technologies employ metal-inserted poly-Si stacks (MIPS) such as a-Si/TiN, where the amorphous Si serves as a precursor for low-sheet-resistance (Rs) self-aligned NiSi on the gates and as an oxygen barrier preventing high-k/Si interfacial SiO2 growth. A full metal gate (FMG, Fig. 3), instead containing a deposited low-Rs metal layer, can be encapsulated in a dielectric resistant to the S/D contact etch, resulting in borderless contacts. We have developed two FMG electrodes based on TiSix/TiN and W/TaMN/TiN (M = oxygen scavenging metal). With both FMG on Hf-based gate dielectrics, Si channel nFET and SiGe channel pFET parametrics and reliability similar to those of poly-Si/TiN control devices are achieved, with good EOT scalability [3,4]. Finally, I will provide an outlook on high-k gate dielectrics for high-mobility III-V channel materials. Specifically, I will compare three interface approaches to InGaAs channel nFET gate stack formation. The first is based on direct high-k deposition onto InGaAs, while the other two approaches rely on the insertion of an amorphous Si or an epitaxial InP capping layer to passivate the InGaAs. The impact of such caps on interface trap density and scalability will be discussed. [1] M.M. Frank et al., ECS Solid State Lett. 2, N8 (2013). [2] S.-C. Seo, et al., VLSI, p. 36 (2011). [3] M. M. Frank et al., as discussed at SISC 2011. [4] M. M. Frank et al., as discussed at SISC 2013. .

The (pro)renin receptor ((P)RR) is expressed in several tissues including kidney, heart and brain, and is thought to regulate the tissue renin–angiotensin system (RAS) through the non-proteolytic activation of prorenin. (P)RR is cleaved by furin to generate soluble (P)RR (s(P)RR), which is secreted into the extracellular space. s(P)RR is a candidate biomarker reflecting the status of the tissue RAS. Here, we investigated the relationship between background factors and serum s(P)RR levels. We measured s(P)RR levels in 122 patients with essential hypertension (EH) and assessed the relationships between background factors and s(P)RR levels. Serum s(P)RR levels were 19.0 ± 4.9 ng ml−1. Single regression analyses showed that age (r =0.251, P

Synaptic elements capable of reversible multilevel analog switching have the potential to become key components in future neuromorphic computing technologies and exceed the practical limits of current digital technology. Artificial neural networks based on analog synapses could potentially deliver performance one step closer to the human brain which far surpasses the efficiency of current computing capabilities by many orders of magnitude. For example, this could be achieved by mapping the synaptic weights of deep neural net on the multi-bit device and performing the multiply-accumulate operation in-memory during learning or inferencing cycles [1]. While different types of 2-terminal emerging non-volatile memory, such as phase change memory (PCM) or resistive RAM (ReRAM), permit some degree of reversible analog tuneability, they exhibit significant stochasticity, and asymmetry which are detrimental to learning accuracy. In addition to precise and predictable control of the resistance state, decoupling the write and read cycle is a major challenge for the practical application of such devices. Memistor-based three-terminal devices allow decoupling the read and write steps, potentially permitting drastic increase in device operational precision and reliability. Electrochemical copper plating devices of this type for the purpose of “adaptive switching circuits” were conceived as early as the1960s in the ADALINE neuron element [2] and more recently as “atomic transistors” [3], however these devices utilized liquid electrolytes which are a big challenge for practical fabrication of an integrated chip. Other systems, such as lithium-based intercalation materials have been used for solid-state three-terminal synaptic devices and scaled to sub-micron dimensions [4], [5]. However. Li+ based systems are chemically reactive and sensitive to atmospheric exposure while also possessing a residual open circuit potential which opposes continued potentiation and creates challenges for voltage-driven neural networks. Here, we report a solid-state, lithium-free, Cu+-based 3-terminal synaptic device capable of reversible multilevel switching. Cu+ is driven in or out of a channel to create a conductance change and Cu+ ion transport is achieved through a solid electrolyte by writing pulses of only 100mV with near-zero open circuit potential. We analyze device performance, physical, and chemical characteristics, and provide insight into operation mechanisms and limitations. Exceptionally high ionic conductivity of 0.36S/cm (significantly higher than any reported solid-state lithium-based system) was measured in the electrolyte by impedance spectroscopy which is critical for high speed device operation. The first device prototypes were over 100 microns in size with very low dynamic range and channel resistance of only several hundred ohms, which is too low for practical applications. We demonstrate a path for increasing the dynamic range and channel resistance of our devices, as well as first steps towards transfer to sub-micron scale fabrication. Figure 1 Impedance spectrum of solid copper electrolyte with inset micrograph of completed device in measurement setup (a). Schematics of device structure and operation (b). Channel resistivity change during cycling measured between writing pulses (two consecutive cycles of 5, +100mV, and 5,-100mV pulses each). Reference: [1] T. Gokmen, Y Vlasov, Frontiers in Neuroscience 2016, 10, 333 [2] B. Wirdow. Technical Report No1553-2, Office of Naval Research 1960 [3] Xie et al. Beilstein J. Nanotechnol. 2017, 8, 530–538 [4] Fuller et al. Li-Ion Synaptic Transistor for Low Power Analog Computing. Adv. Mater. 2017, 29 [5] J.Tang et al, presented at IEEE IEDM 2018, 13.1 Figure 1

There are currently no factors that have been shown to predict gestational diabetes mellitus (GDM) during early pregnancy. The soluble (pro)renin receptor [s(P)RR] may contribute to the development of GDM.The objective of the study was to determine whether plasma s(P)RR concentrations during early pregnancy are associated with the development of GDM later in pregnancy.This prospective cohort study was conducted at a referral birth center. Pregnant women who first visited our hospital during the first trimester (14 weeks of gestation) between 2010 and 2011 were enrolled. Inclusion criteria included singleton pregnancy and the absence of preexisting diabetes mellitus. A total of 716 women participated in this study.The association of plasma s(P)RR concentrations with the onset of GDM later in pregnancy was measured.Among 716 participants, 44 (6.1%) had GDM and 672 (93.9%) did not. There were 176 participants in the first plasma s(P)RR concentration quartile (Q1:25.8 ng/mL), 179 in the second (Q2: 25.8-30.2 ng/mL), 181 in the third (Q3: 30.2-34.2 ng/mL), and 180 in the fourth (Q4:34.2 ng/mL). GDM distribution was 7 (4.0%) in Q1, 5 (2.8%) in Q2, 13 (7.2%) in Q3, and 19 (10.6%) in Q4. A multivariate model adjusted for baseline characteristics, medical complications, and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90 (95% confidence interval 1.11-7.49).Increased s(P)RR concentrations during the first trimester may predict the development of GDM later in pregnancy.

A core challenge in administering immune-based treatments for cancer is the establishment of easily accessible immunological assays that can predict patients' clinical responses to immunotherapy. In this study, our aim was to predict the therapeutic effects of adoptive T-cell therapy in patients with advanced pancreatic cancer. To do this, we evaluated whole blood cytokine levels and peripheral regulatory T cells (Tregs) in 46 patients with unresectable or recurrent pancreatic cancer who received adoptive T-cell therapy at 2-week intervals. To test immune function, venous blood was obtained from patients before the start of therapy and 2 weeks after the 4th treatment. Whole blood interferon (IFN)-α levels (after stimulation with the Sendai virus) were evaluated, as well as the levels of 9 cytokines stimulated with phytohemagglutinin [interleukin (IL)−2, IL-4, IL-5, IL-10, IL-12(p70), IL-13, tumor necrosis factor-α, IFN-γ, and granulocyte-monocyte colony-stimulating factor]. Peripheral Tregs were analyzed by flow cytometry. Using the obtained data, we then observed the relationship between these immunological parameters and clinical outcome of patients. We found that the whole blood production of IFN-γ, IL-2, IL-4, IL-5 and IL-13 significantly increased after adoptive T-cell therapy, whereas the number of peripheral Tregs did not change. Multivariate Cox proportional hazards analyses indicated that the number of peripheral Tregs before receiving adoptive T-cell therapy and the change in IFN-γ levels after adoptive T-cell therapy were independent variables predicting overall survival. The findings of this study indicate that the assay of whole blood IFN-γ production offers promise for evaluating the clinical response of patients to cancer immunotherapy.

Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is highly expressed in herniated disc (HD) tissue and may act as a key molecule for the initiation of macrophage recruitment into the tissue and natural resorption of HD. However, it remains unclear how TSLP expression is regulated in the intervertebral discs. This study showed that expression of TSLP and phosphorylated NF-κB in HD tissue samples was inversely correlated with expression of phosphorylated Smad2/3 (an indicator of active TGF-β signaling) and vice versa in posterior lumbar spinal fusion samples. The pharmacological blockades of endogenous TGF-β activity induced TSLP expression in mouse intervertebral disc tissue culture, which was inhibited by NF-κB inhibitors. Additionally, phosphorylation of Smad2/3 was constitutively detected in mouse intervertebral disc tissue in the steady states. Collectively, these results suggest that endogenous TGF-β activity limits TSLP expression in intervertebral disc tissue in the steady states by suppressing NF-κB activation. The findings reveal a regulatory mechanism how TSLP expression is induced in the intervertebral disc tissue and suggest a novel role of TGF-β in maintaining the homeostasis of intervertebral disc tissue.

Background Intestinal metaplasia (IM) of the gastric mucosa has long attracted attention as a premalignant lesion involved in gastric carcinogenesis. However, endoscopic diagnosis of IM has remained unclear for a long time. In recent years, the methylene blue staining technique and narrow-band imaging (NBI) magnifying endoscopy have facilitated clinical diagnosis of IM, although these methods have some problems due to their complexity. Simple methods for diagnosis of IM using conventional endoscopy and the indigo carmine contrast (IC) method are necessary. Patients and Methods This study was a multicenter, prospective, randomized, comparative study involving 10 facilities. The appearance of IM was examined using conventional and IC methods with an electronic endoscope. Results Subjects included 163 patients, of whom 87 and 76 underwent conventional and IC methods, respectively. Sensitivity, specificity, and receiver operating characteristic/area under thecurve (ROC/AUC) of conventional and IC methods for the detection of IM in the gastric antrum showed that diagnostic performance of the conventional method was higher, but not significantly, than that of the IC method. Sensitivity, specificity and ROC/AUC of conventional and IC methods for the detection of IM in the gastric body showed that the IC method yielded better (but not significantly better) results than the conventional method. Conclusion The diagnostic performance of the conventional method did not significantly differ from that of the IC method. A villous appearance, whitish mucosa, and rough mucosal surface, as observed by both methods, and areae gastricae pattern, as observed by the IC method, were useful indicators for endoscopic diagnosis of IM.

The present study sought to establish a standard third-line eradication regimen for Helicobacter pylori in Japan.Subjects were 204 patients with H. pylori infection in whom the standard Japanese first- and second-line eradication therapies had proven unsuccessful. Patients were randomly assigned to one of the following third-line eradication therapy groups: (1) LA group: lansoprazole (LPZ) 30 mg 4 times a day (qid) + amoxicillin (AMPC) 500 mg qid for two weeks; (2) LAL group: LPZ 30 mg twice a day (bid) + AMPC 750 mg bid + levofloxacin (LVFX) 300 mg bid for one week; (3) LAS group: LPZ 30 mg bid + AMPC 750 mg bid + sitafloxacin (STFX) 100 mg bid for one week. Patients for whom these therapies failed underwent a crossover fourth-line eradication regimen. Drug sensitivity was also tested for AMPC, clarithromycin (CAM), MNZ, LVFX, and STFX.Drug resistance rates prior to third-line eradication therapy were 86.4 % for CAM, 71.3 % for MNZ, 57.0 % for LVFX, 8.2 % for AMPC, and 7.7 % for STFX. Intention-to-treat analysis of third-line eradication therapy eradication rates showed a significantly higher rate in the LAS group (70.0 %) compared with the LA group (54.3 %; p0.05) and the LAL group (43.1 %; p0.001). The significantly lower rate in the LAL group than the LAS group was caused by bacterial resistance to LVFX.The findings suggest that triple therapy with PPI, AMPC, and STFX for one week would be an effective standard third-line eradication regimen for H. pylori in Japan.

A new scheme of oxyfuel combustion combined with partial removal of CO2 from recycled gas and MILD combustion was proposed. Through experiments and theoretical analysis including the Monte Carlo method, the characteristics of in-furnace desulfurization in this new scheme was investigated. It was found that as the initial O2 concentration decreased, the gas recirculation ratio, SO2 concentration, and global efficiency of in-furnace desulfurization increased. On the other hand, the gas recirculation ratio, SO2 concentration, and global efficiency of in-furnace desulfurization increased as the CO2 removal ratio increased. The practical residence time of SO2 in oxyfuel-MILD coal combustion increased to about five to thirteen times as long as that of conventional pulverized coal combustion. The contributions of oxyfuel combustion, partial removal of CO2 from recycled gas, and MILD combustion, to the high desulfurization efficiency, were almost the same importance. At CO2 removal ratio = 11% and initial O2 conc...

During cardiac surgery through midline sternotomy, sternum closure metal wires are usually used for. However, metal wires may damage the sternum and cause artifacts on X-ray. Therefore, we use a novel sternum closure technique in which metal wire is replaced by ultra-high molecular weight polyethylene(UHMWP) sutures. We have used this technique for 89 patients in 2014 and reviewed our experience. UHMWPs are often used for bone fracture cerclage, particularly in the vertebral body. UHMWPs may avoid sternal "cheese-cut" dehiscence.

The effect of unilateral adrenalectomy on blood pressure (BP) outcome in primary aldosteronism (PA) is diverse. Therefore, we sought to investigate the preoperative factors contributing to postoperative BP outcome. Data for 96 PA patients who underwent unilateral adrenalectomy at our institution from January 2000 to February 2015 were retrospectively collected. Based on postoperative BP after a 12-month follow-up period, the patients were categorized into two groups: cured (C) (

Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5α-androstane-3β,17β-diol (3β-diol), which is inactive androgen metabolized from DHT. 3β-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3β-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Δ5-androstenediol but also converted directly to DHT which is the main pathway from 3β-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3β-diol, by the inhibition of the intratumoural 3β-hydroxysteroid dehydrogenase (3β-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3β-diol to DHT was catalysed by 3β-HSD and abiraterone could inhibit this activity of 3β-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3β-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3β-HSD activity could be a new approach to castration-resistant prostate cancer treatment.

Background. Long-term care for the elderly is largely shouldered by their family, representing a serious burden in a hyper-aging society. However, although family dynamics are known to play an important role in such care, the influence of caring for the elderly on burden among caregiving family members is poorly understood. Objective. To examine the influence of family dynamics on burden experienced by family caregivers. Methods. We conducted a cross-sectional study at six primary care clinics, involving 199 caregivers of adult care receivers who need long-term care. Participants were divided into three groups based on tertile of Index of Family Dynamics for Long-term Care (IF-Long score), where higher scores imply poorer relationships between care receivers and caregiving family: best

We demonstrate high-performance (HP) High-Ge-Content (HGC) SiGe pMOS FinFETs with scaled EOT and improved junction. For the first time, SiGe FinFET EOT scaling down to ∼7A has been achieved. In addition, improved junction and series resistance has been demonstrated for HGC SiGe, by a proper choice of spacer thickness and interface-layer as well as hot ion-implant (I/I), resulting in significant R on reduction down to 250 and 200Ω.µm, respectively. We report the highest “SiGe extrinsic g m ” reported to date with g m, LIN =0.5mS/µm and g m, SAT =2.7/2.5mS/µm at V DD =1.0/0.5V, the highest HGC SiGe I on =0.45mA/µm at fixed HP I off =100nA/µm at V DD =0.5V and the highest pMOS FinFET performance reported to date at sub-35nm L G .

High-Ge-content (HGC) SiGe FinFETs in a “replacement High-K and metal-gate” (RMG) process flow and with aggressive EOT scaling are demonstrated, for the first time. HGC SiGe pMOS FinFETs with high-mobility, record-low RMG long-channel SS=66mV/dec and great short-channel characteristics down to L G =21nm have been demonstrated. Gate stack and transport properties down to sub-4nm fin widths (W FIN ) have been also studied for the first time. We demonstrate excellent RMG mobility and reliability at aggressive EOT∼7A, and excellent μ eff =220cm2/Vs at N inv =1013 for fins with W FIN ∼4nm, outperforming state-of-the-art devices at such dimensions and providing very promising results for FinFET scaling for future high-performance FinFET generations.

Bias Temperature Instability (BTI) is a tremendous reliability concern for deeply scaled CMOS technologies, and is the limiting mechanism for further inversion layer thickness (Tinv) scaling for future nodes [1]. Replacement Metal Gate technologies are of particular concern, since the gate stack is not exposed to the high temperature source/drain anneals. We have identified four strategies for reducing BTI in Replacement metal gate technologies: Rapid Thermal Anneal (RTA) optimization, optimization of the HfO2 layer thickness, introducing a gate dielectric dopant for NBTI reduction, and effective Work Function tuning. Judiciously combining these four techniques enable further Tinv scaling for 10 nm and below.

The (pro)renin receptor [(P)RR] is cleaved by furin to generate soluble (P)RR [s(P)RR], which reflects the status of the tissue renin-angiotensin system. Hemodialysis patients have advanced atherosclerosis. The aim of this study was to investigate the relationships between serum s(P)RR levels and background factors, including indices of atherosclerosis, in hemodialysis patients. Serum s(P)RR levels were measured in hemodialysis patients and clearance of s(P)RR through the membrane of the dialyzer was examined. Furthermore, relationships between serum s(P)RR levels and background factors were assessed. Serum s(P)RR levels were significantly higher in hemodialysis patients (30.4 ± 6.1 ng/ml, n = 258) than those in subjects with normal renal function (21.4 ± 6.2 ng/ml, n = 39, P < 0.0001). Clearance of s(P)RR and creatinine were 56.9 ± 33.5 and 147.6 ± 9.50 ml/min, respectively. Serum s(P)RR levels were significantly higher in those with ankle-brachial index (ABI) of < 0.9, an indicator of severe atherosclerosis, than those with ABI of ≥ 0.9 (32.2 ± 5.9 and 30.1 ± 6.2 ng/ml, respectively, P < 0.05). An association between low ABI and high serum s(P)RR levels was observed even after correction for age, history of smoking, HbA1c, and LDL-C. Serum s(P)RR levels were significantly higher in hemodialysis patients when compared with subjects with normal renal function, although s(P)RR is dialyzed to some extent, but to a lesser extent than creatinine. High serum s(P)RR levels may be associated with atherosclerosis independent of other risk factors, suggesting that serum s(P)RR could be used as a marker for atherosclerotic conditions in hemodialysis patients.

Abdominal aortic aneurysm (AAA) is known to be rarely accompanied by disseminated intravascular coagulation (DIC). We report a case of AAA with DIC. An 81-year-old man with abdominal pain referred to our hospital. Computed tomography demonstrated an AAA (maximum diameter: 90 mm). The patient underwent a laparotomy, and an abdominal aorta replacement was performed. At the 3-month follow-up, the patient underwent Helicobacter pylori eradication treatment for 1 week. After treatment, the platelet count dramatically increased. The mechanism by which H. pylori eradication therapy improves hematological parameters has not been elucidated; however, this noninvasive treatment effectively resolved DIC associated with AAA.

Background The relationship between Helicobacter pylori infection and metabolic syndrome is not well understood. Adiponectin is an adipose-derived protein considered to play a significant role in the development of metabolic syndrome. The aim of this study was to clarify the influence of H. pylori infection on circulating adiponectin in humans. Methods In a prospective study, 456 patients underwent endoscopy and H. pylori testing. All of the 338 H. pylori -positive patients received eradication therapy. Treatment was successful in 241 patients. Circulating adiponectin and other metabolic parameters were measured at baseline in all patients and 12 weeks after eradication therapy in those initially positive for H. pylori. Results Circulating adiponectin levels were not different between H. pylori -positive and H. pylori -negative patients. In the group with successful eradication, levels of total adiponectin and each multimer form were significantly increased after therapy. Conversely, the levels of total adiponectin and high-molecular-weight adiponectin, but not middle-molecular-weight and low-molecular-weight adiponectin, were increased in the group with unsuccessful eradication after the therapy. Conclusions Eradication therapy of H. pylori increased circulating adiponectin levels in Japanese individuals and could be beneficial for preventing metabolic syndrome conditions.

Combination techniques such as gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) are commonly used for pesticide residue analysis, but there is no reported method for the simultaneous analysis of multiple pesticides in a sample using a single instrument. Supercritical fluid chromatography (SFC) offers high resolution at high flow rates and various separation modes and hence may aid the rapid simultaneous analysis of pesticide. We developed an SFC/MS/MS method and analyzed 17 pesticides with a wide range of polarities (logP(ow)=-4.6 to 7.05) and molecular weights (112.1-888.6) within 11min using a polar-embedded reversed-phase column. To the best of our knowledge, there is no previous report on the SFC analysis of a wide variety of compounds, including highly hydrophilic ones. By SFC, diquat dibromide (logP(ow)=-4.6), together with cypermethrin (logP(ow)=6.6) and tralomethrin (logP(ow)=5.05), could be detected in the presence of various other pesticides using a single mobile phase. SFC/MS allows for the rapid and simultaneous analysis of low concentrations (ng/L levels) of pesticides that typically need to be analyzed by GC/MS and LC/MS separately.

Summary Background andobjectivesAlthough thesafetyand efficacy of cyclosporinein children with frequentlyrelapsing nephrotic syndrome (FRNS) have been confirmed, no prospective follow-up data on relapse after cyclosporine have appeared. This study is a prospective follow-up trial after 2-year treatment with cyclosporine to investigate cyclosporine dependency after its discontinuation. Design, setting, participants, & measurements Participants who had undergone 2-year protocol treatment with microemulsified cyclosporine for FRNS between January 2000 and December 2005 were followed for an additional 2 years. The primary end point was relapse-free survival after the complete discontinuation of cyclosporine, and the secondary end point was regression-free survival (time to regression to FRNS). Results After exclusion of 7 patients who showed regression to FRNS during the 2-year treatment period, 49 children (median age, 6.5 years) were followed, and classified as children without (n=32; group A) and with (n=17; group B) relapse during the initial cyclosporine treatment. Overall, relapse-free survival probability at 24 months after cyclosporine discontinuation was 15.3% and regression to FRNS-free survival probability was 40.8%. By group, the probability of relapse-free survival was significantly higher in group A (17.9%) than in group B (8.3%) (P,0.001). Conclusions Children with FRNS who receive cyclosporine are at high risk of relapse after discontinuation, particularly those who experience relapse during cyclosporine treatment.

Sickle tail (Skt) was originally identified by gene trap mutagenesis in mice, and the trapped gene is highly expressed in the notochord, intervertebral discs (IVD), and mesonephros. Here, we report the generation of Skt(cre) mice expressing Cre recombinase in the IVD due to target insertion of the cre gene into the Skt locus by recombinase-mediated cassette exchange. Crossing a conditional lacZ Reporter (R26R), Cre expression from the Skt(cre) allele specifically activates β-galactosidase expression in the whole notochord from E9.5 onwards. In E15.5 Skt(cre);R26R embryos, reporter activity was detected in the nucleus pulposus and in a portion of the annulus fibrosus, resulting in expansion of Cre-expressing cells in the adult IVD. Reporter activity was also seen in the Skt(cre);R26R mesonephros at E15.5. These results suggest that Skt(cre) mice are useful for exploring the fate specification of notochordal cells and creating models for IVD-related skeletal diseases.

Aim: The main aim of this study was to determine whether questionnaire evaluations of clinical symptoms in gastroesophageal reflux disease were useful to assess proton pump inhibitor therapy. Methods: A total of 185 Japanese patients (men, 88; women, 97; age: 55.7 ± 16.1 years) with gastroesophageal reflux disease were enrolled. The patients were divided based on the frequency scale for symptoms of gastroesophageal reflux disease: severe symptoms with scores ≥8 and mild symptoms with scores ≤7. Quality of life was evaluated with the Medical Outcomes Study 8-Item Short-Form Health Survey. All patients were treated with a proton pump inhibitor, rabeprazole (10 mg/day), for 8 weeks. Results: Patients were classified into four groups: reflux esophagitis with severe symptoms (n = 92, 49.7%); reflux esophagitis with mild symptoms (n = 17, 9.2%); non-erosive reflux disease with severe symptoms (n = 66, 35.7%); and non-erosive reflux disease with mild symptoms (n = 10, 5.4%). The dysmotility score was high in non-erosive reflux disease with severe symptoms compared with reflux esophagitis with severe symptoms (9.1 ± 0.5 vs 6.8 ± 0.5, P