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Background Systemic oxidative stress is known to be associated with the severity and prognosis in patients with cardiovascular diseases (CVD), including chronic heart failure. On the other hand, exercise tolerance is closely related to the prognosis in heart failure patients. However, no report has examined how oxidative stress is involved in each parameter evaluated by cardiopulmonary exercise testing (CPET) in patients with dilated cardiomyopathy (DCM). Purpose To examine the relationship between oxidative stress and CPET parameters such as peak VO2 and VE/VCO2 slope in patients with DCM Methods We recruited 214 patients with CVD who were performed CPET and measured brain natriuretic peptide (BNP) and haemoglobin (Hb). Finally, we enrolled 96 patients with DCM who have dilated dimensions of the left ventricular lumen by echocardiography and are diagnosed by endomyocardial biopsy. All patients underwent CPET using 0W warm-up and 10W ramp protocol on an upright electrical bicycle ergometer. We defined low peak VO2 as peak VO234. The oxidative stress level was evaluated by a d-ROMs test, in which the amount of organic hydroperoxide converted into radicals oxidizing N, N-diethyl-p-phenylenediamine hydroperoxide is measured. The high level of d-ROMs was defined as d-ROMs≥401 U.CARR. Results Mean age was 56±15 years old. Mean ejection fraction, peak VO2 and VE/VCO2 slope were 37±15%, 16.3±5.0 ml/min/kg, and 31.0±11.8, respectively. The percentage of the high level of d-ROMs was 25%. In univariable logistic regression analysis, Hb, log BNP, and the high level of oxidative stress were significantly associated with low peak VO2, whereas, in multivariable logistic regression analysis, age, Hb, and log BNP were significant factors for high VE/VCO2 slope. In multivariable logistic regression analysis, only the high level of d-ROMs was independently associated with low peak VO2 (OR 3.18, CI 1.12–9.04, p=0.030). While, in multivariable logistic regression analysis, Hb (OR 0.51, CI 0.32–0.81, p=0.004) and log BNP (OR 2.77, CI 1.33–5.76, p=0.006) were significantly related to high VE/VCO2 slope. Conclusions In patients with DCM, low peak VO2 was associated with the high level of d-ROMs, and high VE/VCO2 slope was associated with BNP. These results suggested that oxidative stress was only related to peak VO2. Funding Acknowledgement Type of funding sources: None.

Background Heart failure with preserved ejection fraction (EF) remains a poor prognosis as same as heart failure with reduced EF. Peak oxygen uptake (VO2) by cardiopulmonary exercise testing (CPET) is a useful parameter for predicting cardiovascular diseases prognosis. Furthermore, though there are some reports that CPET parameters are associated with indicators of diastolic dysfunction, each of these indicators has some limitations. Recently, recommendations for the evaluation of left ventricular diastolic function by echocardiography were reported from the ASE/EACVI. However, no reports have examined the association between exercise tolerance indices and diastolic dysfunction based on these recommended variables. Purpose To examine the relationship between peak VO2 and diastolic dysfunction using the recommendation from ASE/EACVI in cardiovascular diseases patients with preserved EF Methods We recruited 214 patients who were performed both CPX and echocardiography. EF ≥50% was 99 patients. All patients underwent 0W warm-up and 10W ramp on an upright electrical bicycle ergometer. Diastolic dysfunction was assessed using the recommendations for the evaluation of diastolic function by ASE/EACVI. We used abnormal cutoff values are annular e' velocity: septal e' 14, left atrial volume index >34 ml/m2, and peak tricuspid regurgitation (TR) velocity >2.8 m/s. Diastolic dysfunction is present if more than half of the available parameters meet these cutoff values. Results Mean age was 57±14 years old, the portion of women was 69%. The portion of diastolic dysfunction was 16%. In univariable logistic regression analysis, age, log BNP, septal e' 2.8 m/s, and the presence of diastolic dysfunction were significantly associated with peakVO2 Conclusions In preserved EF, low peak VO2 was significantly associated with diastolic dysfunction assessed by the recommendations from the ASE/EACVI. Funding Acknowledgement Type of funding sources: None.

The first enantioselective carbometalation reaction of azabicycloalkenes has been achieved by iron catalysis to in situ form optically active organozinc intermediates, which are amenable to further synthetic elaborations. The observed chiral induction, along with the DFT and XAS analyses, reveals the direct coordination of the chiral phosphine ligand to the iron centre during the carbon–carbon and carbon–metal bond forming step. This new class of iron-catalysed asymmetric reaction will contribute to the synthesis and production of bioactive molecules.

Machine learning is a powerful tool used in many different areas, from image processing to space navigation and high-energy physics. In this paper we present a configuration of different artificial intelligent tools aimed at the extraction of features from data registered in the SciBar Cosmic Ray Telescope (SciCRT). The SciCRT is an array of plastic scintillator bars that work nearly independently as particle detectors. When a particle crosses inside the telescope, scintillation photons are emitted by the plastics. The intensity of photons is directly proportional to the energy deposited in each bar. Taking advantage of the construction of the telescope, the small transverse area of the scintillator bars, it is possible to do particle tracking and analysis. The main purpose of SciCRT is the detection of solar neutrons originated in the violent phenomena taking place at the surface of the Sun. Nonetheless, the SciCRT is capable of detecting different kinds of secondary particles produced by the interactions of primary cosmic rays with the atmospheric nuclei. For this reason, the task of signal classification is essential. Our final goal will be the classification of detected cosmic ray particles, as well as, the unfolding of the neutron energy spectrum and the estimation of the angular distribution. To achieve this our methodology relies of pattern recognition, artificial neural networks, k-means clustering and k-Nearest Neighbors. In addition, our paper presents a Monte Carlo simulation of the SciCRT for the training and evaluation of the machine learning algorithms.

We measured both the differential cross section ($\sigma_{p,p^\prime}$ $=d^2\sigma/d\Omega dE_{x}$) and the $\gamma$-ray emission probability ($R_\gamma(E_x)$ $=\sigma_{p,p^\prime\gamma}$/$\sigma_{p,p^\prime}$) from the giant resonances excited by $\rm^{12}C$(\textit{p,p}$^\prime$) reaction at 392 MeV and 0$^\circ$, using a magnetic spectrometer and an array of NaI(Tl) counters. The absolute value of $R_\gamma(E_x)$ was calibrated by using the well-known $\gamma$-ray emission probability from $\rm^{12}C^* ( 15.11$ MeV, $ 1^+$, $T=1$) and $\rm^{16}O^* ( 6.9$ MeV, $2^+$, $T=0$) states within 5\% uncertainty. We found that $R_\gamma(E_x)$ starts from zero at $E_x=16$ MeV, increases to a maximum of 53.3$\pm$0.4$\pm$3.9\% at $E_x=27$ MeV and then decreases. We also compared the measured values of $R_\gamma(E_x)$ with statistical model calculation based on the Hauser-Feshbach formalism in the energy region $E_x=$ 16-32 MeV and discussed the features of $\gamma$-ray emission probability quantitatively.

This paper presents a simulation/experimental technique used in the design of optimum performance read-out electronics for a new cosmic ray telescope composed of scintillator bars. This new detector, called SciBar Cosmic Ray Telescope (SciCRT), is installed on top of Sierra Negra volcano in Mexico, operating at an atmospheric depth of 575 g cm−2. The severe atmospheric conditions and high background rate of the place currently limit the performance of the detector, therefore the requirements of our design are low power consumption and high throughput rate. The simulation developed considers the interaction of high energy cosmic ray muons with the scintillator bar, generation and propagation of photons inside a wavelength shifting fiber (WLS) fiber and the detection by a multi-anode photomultiplier (MAPMT). To produce realistic signals coming from the interaction of particles, our method relies on the extraction of different parameters throughout experiment to include them in the simulation. In addition, the paper presents a muon cosmic ray experiment designed to validate the results of the simulation and test the performance of the new electronics.

We perform the first direct mass measurements of neutron-rich calcium isotopes beyond neutron number 34 at the RIKEN Radioactive Isotope Beam Factory by using the time-of-flight magnetic-rigidity technique. The atomic mass excesses of ^{55-57}Ca are determined for the first time to be -18650(160), -13510(250), and -7370(990) keV, respectively. We examine the emergence of neutron magicity at N=34 based on the new atomic masses. The new masses provide experimental evidence for the appearance of a sizable energy gap between the neutron 2p_{1/2} and 1f_{5/2} orbitals in ^{54}Ca, comparable to the gap between the neutron 2p_{3/2} and 2p_{1/2} orbitals in ^{52}Ca. For the ^{56}Ca nucleus, an open-shell property in neutrons is suggested.

The (^{12}N, ^{12}C) charge-exchange reaction at 175 MeV/u was developed as a novel probe for studying the isovector spin giant monopole resonance (IVSMR), whose properties are important for better understanding the bulk properties of nuclei and asymmetric nuclear matter. This probe, now available through the production of ^{12}N as a secondary rare-isotope beam, is exothermic, is strongly absorbed at the surface of the target nucleus, and provides selectivity for spin-transfer excitations. All three properties enhance the excitation of the IVSMR compared to other, primarily light-ion, probes, which have been used to study the IVSMR thus far. The ^{90}Zr(^{12}N,^{12}C) reaction was measured and the excitation energy spectra up to about 70 MeV for both the spin-transfer and non-spin-transfer channels were deduced separately by tagging the decay by γ emission from the ^{12}C ejectile. Besides the well-known Gamow-Teller and isobaric analog transitions, a clear signature of the IVSMR was identified. By comparing with the results from light-ion reactions on the same target nucleus and theoretical predictions, the suitability of this new probe for studying the IVSMR was confirmed.

The SciBar Cosmic ray telescope (SciCRT) is installed on the top of the Sierra Negra volcano with the main goal of observing solar neutrons to investigate the ion acceleration process during solar flares. Using scintillator bars as a medium to stop energetic particles, the SciCRT is capable of recording both energy deposited on the bars and direction of the incoming particles with high resolution. The original DAQ system was used in neutrino oscillation experiment (low event rate), therefore operation of the electronics on cosmic ray experiment is limited. To improve the SciCRT performance as a solar neutron telescope, development of custom made DAQ electronics is essential. Our first step onto this task was the design and construction of a new fast readout back-end board using SiTCP. The installation of this new system on Sierra Negra and its further improvement on the data acquisition for the detector will be analyzed on separate paper on this conference. The development of new front end electronics is the next stage of the upgrading process. To achieve this goal, we are developing new electronics applying the time over threshold (ToT) technique, using a FPGA to process the signal from one 64 channel multi anode photomutiplier tube (MAPMT). In this paper we will present the details of this new system and several tests performed to guarantee its proper operation to detect solar neutrons.

The SciBar Cosmic Ray Telescope (SciCRT) is aimed to help elucidate the acceleration mechanism of high-energy ions that may produce neutrons at the Sun. It is a fully active scintillator tracker which consists of 14,848 plastic scintillator bars, originally constructed for accelerator neutrino oscillation experiments. The SciCRT; it has a huge detector volume compared with conventional Solar Neutron Telescopes (SNTs), e.g. 15 times larger than Mexico SNT. Furthermore, the SciCRT can measure the energy deposition of each particle as neutron ADC data which have not been registered before. Neutron ADC data provide us with a precise measurement of energies deposited at the detector. The SciCRT was deployed at the summit of Mt. Sierra Negra (4,600 m) and began to acquire data in September 2013. Then we partially upgraded the DAQ system developed originally for an accelerator experiment, as the readout rate of the DAQ system was significantly limited for our experiment. This paper highlights sensitivity numerical studies of solar neutrons that the SciCRT is able to register. At first, we focus in the accuracy to determine the spectrum power-law index, assuming an instantaneous emission of solar neutrons. This is required to determine the power-law index within an error of ±1.0 in order to discuss the efficiency of the acceleration. Then in the case of the fixed power-law index, we discuss the capability of discriminating three different lengths of emission times: 0 min, 5 min, and 8 min. Finally we evaluate whether it is possible to discriminate a different combination of these two parameters simultaneously. Thus, we show that data from the SciCRT will unlock the degeneracy problem amid the emission time and the energy spectrum of solar neutrons.

18th EISCAT symposiumSession E3: Ionoshere/thermosphere/mesosphereMay 27 (Sat), NIPR Auditorium

The reactivation of varicella zoster virus (VZV), also known as herpes zoster (HZ) or shingles, is of substantial public health importance, as up to one-third of adults in the US will develop HZ within their lifetime (1–4). Nearly 100% of individuals in the US age 40 years or older have been exposed to this virus, and its reactivation is related to diminished VZV-specific cell-mediated immunity associated with increasing age and immunosuppressive conditions. Among patients who develop HZ, postherpetic neuralgia occurs in ∼15%, causing long-term disability. More rarely, disseminated forms of HZ occur, potentially leading to encephalitis and death. In the US, the annual incidence rates (IRs) of HZ vary between 0.4 and 1.1 per 100 patient-years in patients ages 50–80 years, with the highest rates seen in women (1). In patients with rheumatoid arthritis (RA), the risk of HZ is elevated 2–3-fold (5,6). Although certain disease-modifying therapies, such as anti–tumor necrosis factor α (anti-TNFα) therapies, have been linked to further increases in risk, studies evaluating this have produced conflicting results. To date, only prednisone has been consistently shown to increase the risk of shingles by an additional 1.5–2-fold (7). Furthermore, although disseminated HZ is much more common in immunosuppressed populations, it is unclear whether RA and/or its disease-modifying therapies increase the risk (7,8). Tofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib preferentially inhibits JAK-3 and/or JAK-1, modulating the immune response via down-regulation of several cytokines (e.g., interleukins 2, 4, 7, 9, 15, and 21) that are integral to lymphocyte development and function (9). Given its mechanism of action and the increased baseline risk of HZ among patients with RA, an increased risk of HZ is a theoretical concern. Accordingly, we undertook a retrospective evaluation of HZ cases as reported within the Tofacitinib RA Development Program, with the objectives of describing the outcomes of and identifying risk factors for HZ among tofacitinib-treated patients, as well as evaluating the relative incidence of HZ in tofacitinib-treated patients as compared with those receiving placebo.

CRIB (CNS Radioactive Ion Beam separator) is a low-energy RI beam separator at the Center for Nuclear Study (CNS) of the University of Tokyo. An overview of the recent developments and status of CRIB, including a detailed summary of beam parameters, is presented. Studies on proton and α resonant scatterings, direct measurements of ( α , p ) reactions, and other types of measurements ( β -decay lifetimes, etc.) have been performed using RI beams at CRIB, motivated by interests in astrophysical reactions and exotic nuclear structure. Among the studies at CRIB, the measurement of 7Be + α resonant scattering is discussed.

SummaryBackground The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210). Objectives To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis. Methods Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up. Results Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B-cell counts. Natural killer cell counts declined with tofacitinib. Conclusions Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

Evidence suggests that bio-activation of drugs to generate chemically reactive metabolites (RM) that act as haptens to form immunogenic protein conjugates may be an important cause of immune-mediated drug hypersensitivity reactions (IDHR). Although many drugs that form RMs raise concerns about producing IDHR, standard non-clinical testing methods are rarely able to identify compounds with the potential to produce IDHR in humans. The objective of this study was to develop a predictive assay for IDHR that involves: (1) the use of an in vitro drug-metabolizing system to generate the RM that is captured by GSH, (2) conjugating the RM-GSH conjugate to mouse serum albumin (MSA) by using a chemical cross-linker, (3) immunization of mice with RM-GSH-MSA adducts, and (4) ex vivo challenge with RM-GSH-MSA adduct and measurement of lymphocyte proliferation to determine if the RM is immunogenic. The predictivity of the assay was evaluated by using drugs that produce RM and have been strongly, weakly, or not associated with IDHRs in the clinic. While this method requires additional validation with more drugs, the results demonstrate the feasibility of identifying drugs strongly associated with IDHR and the utility of the assay for rank ordering drugs with respect to their potential to cause IDHR.

The ICH S8 immunotoxicity testing guideline for human pharmaceuticals was published in 2006 and was intended to provide guidance for assessing the immunotoxicity potential of low-molecular-weight drugs that are not intended to alter the immune system. For drugs intended to modulate the immune system, immunotoxicity testing strategies are generally developed on a case-by-case approach since the targets, intended patient population, and mechanisms of action of the test compound will determine the type of testing needed. Some of the general principles of ICH S8, however, may be applied to immunotoxicity testing strategies for immunomodulatory drugs. A weight-of-evidence approach using factors discussed in ICH S8 in concert with an assessment of the potential value of additional immunotoxicity testing should be considered. For most situations, immunotoxicity studies with immunomodulatory compounds evaluate off-target effects on the immune system and exaggerated pharmacology. The potential use of data from these studies and considerations such as translatability to humans are discussed.

Epstein-Barr virus (EBV)-associated lymphomas are a known risk for immunosuppressed individuals. Non-clinical methods to determine the potential of new immunomodulatory compounds to produce EBV-associated lymphomas (hazard identification) have not been developed. Since lymphocryptovirus (LCV) in non-human primates (NHP) has similar characteristics to EBV in humans, a Roundtable meeting was held in October 2010 to explore how the potential for EBV-related lymphomas in humans can be assessed by using surrogate biomarkers for lymphoma risk in NHP toxicity studies. Stakeholders from regulatory agencies, academia, and industry came together to determine the research gaps and potential benefits and considerations of such an approach given the current state-of-the-science. Key conclusions from the discussion included considerations raised about the potential usefulness of LCV-related biomarkers from NHP studies since there is significant controversy over the reliability of using EBV viral load or EBV-specific T-lymphocytes to predict for lymphoproliferative disorders in transplant patients. In addition, there are technical challenges that need to be further addressed in order to develop methods to measure LCV viral load and LCV-specific T-lymphocytes from cynomolgus monkeys.

Up to 10% of patients with severe immune-mediated drug hypersensitivity reactions have tendencies to develop multiple drug hypersensitivities (MDH). The reason why certain individuals develop MDH and the underlying pathomechanism are unclear. We investigated different T cell subpopulations in MDH patients and compared them with patients allergic to a single drug and with healthy controls (HC).