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An addendum to the International Conference on Harmonisation E9 (ICH E9) guidance document (Statistical Principles for Clinical Trials) is currently under development. The aim of the addendum is to promote harmonized standards on the choice of estimand (a well-defined measure of the treatment effect that is being estimated) in clinical trials and to describe a consensual framework for planning, conducting, and interpreting sensitivity analyses of clinical trial data.In order to help understand current practices relating to the choice of estimands and sensitivity analyses for clinical trials, the ICH E9 working group developing the addendum conducted a survey with a primary focus on clinical trials involving drugs, vaccines, and biologics. The survey was distributed electronically between May 19, 2015, and June 11, 2015, to various stakeholder groups within ICH, including industry, regulatory, and academic communities. A total of 1305 respondents participated.Of the 1305 respondents 547 (42%), 344 (26%) and 283 (22%) were from Europe, USA and Japan respectively. Over half of the respondents work in pharmaceutical companies, and approximately a quarter of respondents noted oncology as the primary therapeutic area they work in. Over half of the respondents (595, 55%) noted the treatment effect being estimated was 'in the entire target population of patients regardless of whether they will take treatment as instructed'. The most common methods for handling missing data in primary analyses were mixed-models repeated measures (555, 56% respondents) and last observation carried forward (549, 55% respondents). The majority of respondents (816, 83%) noted they conducted sensitivity analyses to estimate treatment effects in different ways compared to the primary analysis by using alternative assumptions (627, 78%) and/or using alternative statistical methods (616, 76%).The survey results have provided useful information to the ICH E9 working group on current practices on the choice of primary estimands for measuring treatment effects in confirmatory clinical trials, and approaches used to select sensitivity analyses.

It has long been known that several embryos are needed to establish and maintain pregnancy during early gestation in pigs. In this study, we assessed whether co-transfer of parthenogenotes with a single embryo was sufficient to maintain development of the embryo. Embryos were recovered at morula and early blastocyst stages from gilts that had been artificially inseminated. Parthenogenotes were produced from oocytes matured in vitro, activated by electrical stimulation, and then cultured for 110h. Those that had developed to morula- or blastocyst-like stages at 110h post-activation were transferred to recipient pigs either with or without morula or blastocyst stage embryos. Parthenogenotes that were transferred to recipients in the absence of embryos were viable up to 30 days post-activation and formed limb-buds; at 40 days, however, all were dead or degenerate. Among pigs that received both parthenogenotes and a single embryo, seven of nine (77.8%) delivered a normal piglet at full-term. This study therefore demonstrates that parthenogenotes can be used in place of embryos to establish pregnancy and promote development of a single co-transferred embryo. This method may be applied to rescue high value porcine embryos that are difficult to produce, such as transgenic cloned embryos, or for embryos frozen as a genetic resource.

Evergreen fir Abies mariesii growing at the tree line (near 2 500 m altitude) on Mt. Norikura (36°61'N, 137°33'E, 3 026 m altitude) in Central Japan is exposed to harsh winter stresses. To protect against these stresses, the deep-oxidation state of the xanthophyll cycle pigments increased, because the needles contained large amounts of zeaxanthin, which resulted in an increase of non-radiative thermal dissipation from the antenna system. Not only the antenna system but also the inactivated photosystem (PS) 2 reaction centre (RC) might contribute to the heat dissipation of absorbed excess photon energy. In addition, a decrease in the PS2 activity during winter was derived from the degradation of the PS2 RCs. Thus the needles acclimated to the strong sunlight during the harsh winter. Under such conditions, only the abaxial side of A. mariesii needles occasionally changed colour from green to reddish-brown in early spring. Since this needle damage was only observed in shoots that protruded from the snow surface, this phenomenon might be caused by the interaction between the strong sunlight reflected from the snow surface and the long period of sub-zero temperatures. We also examined how the photoprotective functions of A. mariesii growing at the tree line of a temperate zone mitigate the interactive stresses of high photon flux density and sub-zero temperature in harsh winter.

We have constructed and demonstrated levitating transporter models composed of the superconductor bulks (HTS bulks) and permanent magnets. The dynamic characteristics of lift force, lateral force and magnetic stiffness are very important for the design of superconducting devices such as a levitation system. The electromagnetic phenomenon should be clarified through the accurate analyses of the magnetic field and shielding current distributions within HTS bulks. In this study, we developed a new simulation program based on the three-dimensional hybrid finite element and boundary element (3D hybrid FE-BE) method, which combines with the fast multipole method (FMM). By using the FMM, it is possible to solve the large-scale problem with a reduction of the required memory size and improvement of the accuracy. This simulation program can consider the anisotropic and nonlinear E-J characteristics of HTS bulks. The results of experiment and numerical simulation are in good agreement

A model correctly predicting the observed atmospheric γ radiation from radon progeny adsorbed onto the surface of rain and snow enables monitoring of precipitation rates to better than 0.3 mm/h. This model predicts that the surface (volume) deposition of radon progeny yields γ-ray flux rates proportional to the 2/5 (3/5) power of rain rates, respectively. The γ-ray rates observed were proportional to the 0.45 power for rain, but for snow which does not form spherical droplets a linear relationship was observed with proportionality constant dependent upon snow type. Atmospheric γ radiation was measured at one site in Mitaka, Japan since 1999 and more recently at another site a distance 220 m from the first using 12.9 cm3 NaI detectors. Correlation coefficients ranging from 0.85 to 0.95 and improving with elevation were obtained when data were fit with predominantly surface adsorption model and an age correction factor for the 30 min half-life of dominant radon progeny. Measurement of atmospheric γ radiation from radon progeny naturally adsorbed by rain at 20 m above ground (moderate building height) may serve as a reliable, live monitor of precipitation rates limited only by counting statistics. The regional applicability of this technique has been confirmed and will most likely have global and remote applicability.

Data taken at 6–20 m above ground from March through June of 2002 was used to confirm that the background subtracted atmospheric γ radiation (GRR) was directly related to precipitation rates. An anomalous increase in GRR (AGR) shortly after lightning strokes several times that expected from only the observed precipitation was concurrently observed at two sites separated by a distance of 220 m. The increase in activity in the detector environment subsequently decayed with a half-life of about 50 min. A model, which assumes the presence of an ensemble of radioisotopes produced by proton and photon-induced nuclear reactions in the atmosphere, fits the observed 50 min (33 min) decay half-life without (with) rain with correlation coefficients of 0.98. The possibilities that energetic protons and to a lesser extent brehmsstrahlung resulting from ions accelerated in electric fields during positive lightning produce this delayed activity and that AGR may be used as a remote monitor of lightning as well as the rel...

When operating space robots, safety and reliability are the most important issues-even at the expense of dexterity and swiftness. This makes it very stressful for operators to teleoperate space robots, especially since they cannot be repaired during operation, unlike ground robots. Furthermore, operators have to quickly analyze a large amount of information about the target objects and immediately make decisions on how to proceed. The majority of this information is presented visually, including digital values, status displays, 3D computer simulation, and camera images. Therefore, we developed an audio feedback system that can convey some of this information in order to improve the operator's decision-making and avoid accidents. We used an eye-mark-recorder to assess the performance of this system. Audio systems for information presentation have previously only been proposed for ground-based operation systems. This is the first case in which sound has been utilized for space robot operation, even though sound does not actually exist in space.

Background X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK) gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood. Methods Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, Results Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT), resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain. Conclusions This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients.

The development of large and precise space antennas is one of the most important topics in constructing space infrastructures. We evaluated an approach to assembling large and accurate space antennas which uses space robots. The assembly mechanism was launched together with the ETS-VII, the first telerobotic satellite from Japan, and its performance, including fully automatic assembling, was verified. The assembling-type antenna and the results of antenna assembly experiments are discussed.

Two chronic dialysis patients with massive ascites caused by cirrhosis were treated by infusion of their ascites directly into the blood circuit. This stabilized their hemodynamics during dialysis, facilitating the control of weight gain and ascites, and thus markedly improving their general condition. Long-term use of this therapy was able to prevent the accumulation of ascitic fluid. Interestingly, fever occurred when this therapy was performed with hemodialysis, but not with hemofiltration or hemodiafiltration, suggesting that a pyrogen in the ascites was removed by filtration.

We have investigated current transport characteristics in a mixed state of Bi-2223/Ag multifilamentary tape by varying the angle between the external magnetic field and the tape surface. It was shown that the so-called glass-liquid transition magnetic field, which is an important parameter for applications of persistent current mode, as well as the critical currents, was dominated by the c-axis component (perpendicular to the tape surface) of the external magnetic field in a wide range of the field direction.

Adaptation to partial failure is one of the most important requirements for space robotics, since space robots cannot be repaired after they have been launched. We propose a decentralized autonomous control algorithm for hyper-redundant manipulators that uses parallel processing with low-performance processors to achieve this adaptation. In this paper, a number of manipulator joints are locked at a certain angle in a computer simulation and the adaptability of the control algorithm to these failures is assessed. The control algorithm successfully continues its positioning task at a rate of more than 90%, even after half of its joints have failed. The control algorithm is also compared with behavior-based control architecture.

A pMOS pixel to be used in a striplike two-dimensional readout single-sided detector has been developed and tested. It is originally proposed for upgrades of the vertex detector of the BELLE experiment at the KEK B-factory: in order to overcome low signal-to-noise ratio of the double-sided silicon strip detector to be used presently. This device gathers the pMOS transistor amplification with the typical silicon pin diode used in particle detection. In a 100/spl times/100 /spl mu/m/sup 2/ n-type collecting electrode a double drain pMOS transistor is implanted, providing (1) a two-dimensional readout and (2) direct signal amplification. With the subdivision in pixels, which lowers the detector capacitance, a high signal-to-noise ratio is expected. The two-dimensional readout and the low noise advantages of this structure can be used for detection of any electromagnetic radiation as well as high energy charged particles. Nuclear physics, space and astrophysics instrumentation, are also potential field of application for the pMOS pixel. We briefly review here the principle of the structure and describe the test of the prototypes in detail.

In the pituitary gland, annexin-1 (lipocortin-1) located in folliculo-stellate (FS) cells has been advocated as one of the candidates for paracrine agents produced by FS cells that modulate the release of pituitary hormones. However, the expression and distribution pattern of annexin-1 in FS cells under different circulating corticosteroid conditions has not been examined. Thus, by means of pre-embedding immunoelectron microscopy, we investigated the expression of annexin-1 in FS cells under different corticosteroid conditions. Annexin-1-immunoreactivity was observed in the cytoplasm; especially intense immunoreactivity was detected in the follicle surface of FS cells under control conditions. After adrenalectomy, annexin-1-immunoreactivity almost disappeared, but the immunoreactivity recovered with corticosterone replacement. The expression of glucocorticoid receptor immunoreactivity in the nucleus of FS cells also showed a similar pattern to annexin-1 associated with the changes in the corticosteroid conditions. However, S-100 immunoreactivity, a marker for FS cells, was not changed whatever the corticosteroid conditions. These results confirm that glucocorticoids regulate the annexin-1 expression and demonstrate the translocation of annexin-1 from intracellular to pericellular sites in the FS cells of the rat anterior pituitary gland.

The two objectives of this study were to design potent phosphorothioate antisense oligonucleotides (AS-S-oligos) directed against the human interleukin-10 (IL-10) gene product and to reveal the DNA sequence which best activates antisense effects.The design of potent AS-S-oligo was performed by using melting temperature (Tm) value of a DNA/RNA hybrid calculated by the nearest neighbor method and a secondary structure of human IL-10 mRNA suggested by RNA folding algorithms. U937 cells were used to estimate the antisense effect of the AS-S-oligos.Of the eight candidates selected as potent AS-S-oligos on the basis of having higher Tm values and favorable secondary structures of the IL-10 mRNA, AS-S-oligos directed against the translated (AS367-S-oligo) and 3'-untranslated (AS637-S-oligo) region of IL-10 mRNA showed the strongest inhibitory effects on IL-10 production and this inhibition was dose- and time-dependent. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that the antisense effects of AS-S-oligos originated from a specific reduction of target IL-10 mRNA by hybridization with AS367- and AS637-S-oligos. In addition, these AS-S-oligos did not affect human tumor necrosis factor-alpha (TNF-alpha) production in the cells stimulated by lipopolysaccharide (LPS). Strong positive correlations between the inhibitory effect of AS-S-oligos on the IL-10 production and not only Tm values calculated by nearest neighbor method but also Tm values determined by absorbance versus temperature profiles were demonstrated except for AS25-S-oligo and AS1249-S-oligo.These findings suggest AS367- and AS637-S-oligos powerfully inhibit IL-10 production in U937 cells via an antisense mechanism. In addition, it is suggested efficiency of AS-S-oligo directed against the sequence of the target gene product can be explained by these Tm values and the proposed secondary structures of the target gene product.

We have determined the structure of an Shc-derived phosphotyrosine-containing peptide complexed with Grb2 SH2 based on intra- and intermolecular NOE correlations observed by a series of isotope-filtered NMR experiments using a PFG z-filter. In contrast to an extended conformation of phosphotyrosine-containing peptides bound to Src, Syp and PLC gamma SH2s, the Shc-derived peptide formed a turn at the +1 and +2 positions next to the phosphotyrosine residue. Trp121, located at the EF1 site of Grb2 SH2, blocked the peptide binding in an extended conformation. The present study confirms that each phosphotyrosine-containing peptide binds to the cognate SH2 with a specific conformation, which gives the structural basis for the binding specificity between SH2s and target proteins.

The effects of liposomes on nitric oxide (NO) production from mouse peritoneal macrophages following intraperitoneal injection of liposomes were investigated.Mouse peritoneal macrophages were collected following intraperitoneal injection of liposomes and cultured with and without lipopolysaccharide (LPS). Peritoneal washing fluid was also collected from the mice injected with liposomes. NO production was evaluated by measuring the concentration of nitrite in the macrophage culture supernatant by Griess reagent.NO production stimulated by LPS was observed in peritoneal macrophages obtained from the liposome-treated mice, but liposomes did not active macrophages directly to induce NO in response to LPS. NO production was higher in the liposomes composed of phosphatidylcholine than that of negatively charged liposomes composed of phosphatidylserine. Peritoneal washing fluid obtained from mice injected with liposomes has a capacity to induce NO production in the macrophages from naive mice. This capacity was not diminished by heat-treatment at 100 degrees C for 5 min.Peritoneal macrophages were activated to produce NO in response to LPS following intraperitoneal injection of liposomes. They did not activate macrophages directly, and the induction of heat-stable macrophage priming factor, but not cytokines, is suggested.

Uptake of the nonabsorbable marker 6-carboxyfluorescein was investigated both free and encapsulated in liposomes as a function of their surface charge and hydrodynamic diameter in rat Peyer's patch and nonpatch tissue. Significant uptake of the marker occurred only when encapsulated in liposomes consisting of at least 25 mol% phosphatidylserine and was highest in Peyer's patches. 6-Carboxyfluorescein encapsulated in liposomes equal to or greater than 374 nm was preferentially taken up by Peyer's patches. There was a trend to higher uptake in lower intestinal segments. These findings were supported by fluorescence microscopic observations. Uptake by Peyer's patches was specific for negatively charged liposomes as judged from competition studies.

We have studied proximity effect-induced superconductivity of micro wire networks in a magnetic field for investigating topological effects of the superconducting order parameter through Little-Parks oscillation. We prepared a regular honeycomb network, which has Pb-Au bilayer structure, by standard electron beam lithography and measured variation of superconducting transition temperature (Tc) in a magnetic field. We also fabricated a honeycomb network made of Pb monolayer and measured it in the same way. In the experimental results of the monolayer network, 2.06 ± 0.02 Gauss of periodic variation of Tc in a magnetic field was observed at around 7.2 K. The area estimated from this period is 10.04 μm2 and correspond to unit honeycomb enclosed by center of the wire. While, in the results of the bilayer network, 2.66 ± 0.04 Gauss of periodic variation of Tc in a magnetic field was observed at around 4.3 K because of the proximity effect. The area estimated from this period is 7.78 μm2 and correspond to unit honeycomb enclosed by edge of the wire. In the latter case, the superconducting current flows through edge of the wire since the order parameter can be considered to be more developed and inhomogeneous on the wire cross-section at around 4.3 K less than 7.2 K. Consequently, a novel network of paths flowing through the superconducting current, which consists of loops enclosed by edge of the wire, can be realized by controlling the proximity effect.

The effect of dextran sulfate of three molecular weights (1000, 5000, and 90,000) on the accumulation of gentamicin in rat kidney was investigated using a continuous infusion technique. During the infusions of both gentamicin and gentamicin-dextran sulfate mixtures, the gentamicin plasma concentration was maintained at 10 microgram/ml. The renal cortical accumulation of gentamicin was significantly lower when dextran sulfate (1000, 5000) was coadministered. The inhibition of cortical gentamicin accumulation increased with increasing dextran sulfate dose, and it was proportional to the amount of dextran sulfate excreted into the urine. Analysis by electrophoresis on cellulose acetate membrane indicated that gentamicin binds to dextran sulfate in rat urine. Therefore, gentamicin-dextran sulfate binding within the lumen of the proximal tubules may reduce the renal reabsorption and possibly the renal toxicity of gentamicin.

Thermally-reacted poly(methacrylamide) degrades under high-energy irradiation. It has a sensitivity of 2-3 × 10−7 C/cm2 when exposed to 10 KV electrons. The resist is thermally stable to 330°C and has a high glass transition temperature, 180 200°C. It may be used for the lift-off process and ion-milling.

Using the attenuation and cross-polarization discrimination (XPD) statistics measured in the CS (20/30 GHz) and BSE (12/14 GHz) centimeter wave propagation experiments performed for over four and three years, the worst month statistics of attenuation and those of XPD on earth-space path at 11.7 and 19.5 GHz are derived. The probability relation between the annual and worst month statistics is approximated by a power-law relation, and the constants for the relation are derived by a least squares procedure. It is found that the relation is independent of both frequency and polarization. The cumulative probability ratios of the worst month to annual statistics at the same attenuation or XPD values are derived as a function of annual cumulative probability. The ratios are well described by the Brussaard model of the worst month statistics. Attenuation ratio and XPD difference among the annual and worst month statistics are also derived and compared with the predicted results.

A case of multiple trichilemmal cysts is presented. After trauma, a large tumor developed on one of the cysts. The histologic features of this tumor were similar to those of proliferating trichilemmal cyst, but some of the tumor cells showed definite nuclear atypicality. The malignant potential of this tumor was confirmed by later development of metastases to the regional lymph nodes.

A broad-band Smith-diagram display unit has been developed by using a new waveguide circuit called a phase-directional coupler. Among the interesting features of this new display unit are its broad-band capabilities, high precision and simple construction. A "vibrating-dummy method" has been developed as a perfect termination in contrast with the well-known "sliding-load method." The Smith-diagram display unit of small reflection coefficients was achieved by combining this new method with the above display unit. Included in this paper are the experimental results obtained at 6 Gc and 11 Gc.