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Takanori Numata, Jun Araya, Keitaro Okuda, Hanae Miyagawa, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata, Email t-numata@jikei.ac.jpBackground: Few studies on the long-term efficacy of benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, have been conducted for patients with severe eosinophilic asthma (SEA), especially regarding the improvement of pulmonary function and clinical remission in a real-world setting.Objective: To elucidate the long-term efficacy and clinical remission rate (CRR) in patients with SEA.Methods: From July 2018 to July 2022, 23 Japanese patients with SEA received benralizumab for two years or more at Jikei University Hospital. We retrospectively evaluated the patients’ characteristics, biomarkers, number of exacerbations, pulmonary function, asthma symptoms, maintenance oral corticosteroid (OCS) dose and CRR.Results: The mean observation period was 38.3 (24– 49) months. Among the 23 patients, 10 patients switched from mepolizumab to benralizumab. After administration of benralizumab, the forced expiratory volume in one second (FEV1) increased and was maintained for two years in the biologic-naïve group and in the switching group (177 ± 404 and 151 ± 236 [mL], respectively, P = 0.80). In all patients, the %FEV1 improved from 76.7 ± 22.9% to 84.3 ± 18.4% (P = 0.016), and the number of annual exacerbations decreased from 2.5 ± 3.3 to 0.74 ± 1.7 (P = 0.014). Furthermore, the Asthma Control Test score significantly improved, and the reduction in OCS dose was maintained for three years. Ultimately, five patients met the clinical remission criteria and exhibited stabilization of pulmonary function, no exacerbation, no OCS use and well-controlled symptoms. The CRR was significantly higher in patients with a blood basophil count (BBC) ≥ 22 than in those with a BBC < 22 (/μL) (38.5% vs 0%, respectively, P = 0.046).Conclusion: Long-term treatment with benralizumab significantly improved pulmonary function, alleviated asthma symptoms and decreased the number of exacerbations at two years in a real-world setting. The CRR may be associated with the BBC at baseline.Keywords: benralizumab, severe asthma, clinical remission, pulmonary function, blood basophil count

For the characterization of soil stiffness anisotropy at small strains and the calculation of soil elastic constants derived from the cross-anisotropic model, it is important to obtain stress wave phase velocities of soils in both principal and oblique directions. This study developed an original eight-prismatic shape apparatus equipped with disk-shaped shear plates to measure shear (S-) wave phase velocities (Vphase) in multiple directions, and four granular materials of various shapes were tested by this apparatus under isotropic confinement. Experimental results confirm the capability of the new apparatus and reveal that both S-wave propagation and oscillation directions are sensitive to soil inner fabric, i.e., Vs changes with the variation of either S-wave propagation or oscillation direction. Based on the experimental observations, it is suggested to keep the same S-wave oscillation direction when measuring Vs in multiple propagation directions so that the corresponding shape of the S-wave surface (polar plots of Vs in arbitrary propagation directions) is more precise to reflect the small-strain stiffness anisotropy of soils.

It is empirically known that the packing property and mechanical responses of cohesionless granular materials are influenced by grain shape. For example, the attainable range of void ratio depends on grain shape; angular materials tend to exhibit greater friction angles. Besides, shear wave velocity (Vs ) and small-strain shear modulus (G0 ) of sphere assemblies are affected by surface roughness. However, consensus has yet to be reached on the combined effect of grain shape and surface roughness on G0 and stress-strain relation. This contribution aims to evaluate the shape-roughness combined effect on the strain-dependent mechanical responses of granular materials. Three groups of glass beads having different grain shapes and a silica sand were used, and their grain surfaces were roughened through a systematic procedure using a milling machine. In total, eight materials were subjected to triaxial compression after measurement of Vs. The experimental results reveal that the stress-strain relation of angular particles is remarkably affected by the surface roughness, whereas the roughness effect on the stress-dependent variation in G0 is limited for angular particles.

Pumices with high pore voids of volcanic origin are distributed throughout Japan and are the causal layer of slope failures. In many cases of surface failures, it is difficult to assume that the resulting layers are fully saturated. The high waterholding capacity of the pumice suggests that they were deposited in an unsaturated state with a high degree of saturation. In this study, saturated triaxial compression tests and fully undrained unsaturated triaxial compression tests were conducted on artificially produced pumice and natural pumice while measuring the amount of crushing. This is to clarify the relationship between the crushing and mechanical properties of pumice with porous particles, which are often the cause of such disasters, and their behaviour under unsaturated conditions. The results showed that the pumice stones have an ultra-high pore structure. Moreover, pumice with porous particles reached a steady state under both saturated and highly saturated unsaturated conditions, and the amount of crushing increased under highly saturated unsaturated conditions.

Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Department of Respiratory Diseases, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata, Department of Respiratory Diseases, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku Tokyo, 105-8461, Japan, Tel +81-3-3433-1111 (ext. 3271), Fax +81-3-3433-1020, Email t-numata@Jikei.ac.jpBackground: Treatment with dupilumab, an anti-interleukin (IL)-4 receptor α monoclonal antibody that blocks both the IL-4 and IL-13 pathways, has demonstrated efficacy for the treatment of severe asthma (SA) with type 2 inflammation. However, few studies have focused on the efficacy of this biologic for the treatment of SA in a real-world setting.Methods: From April 2019 to December 2021, 26 Japanese patients with SA received dupilumab at Jikei University Hospital. We retrospectively evaluated the number of moderate-to-severe exacerbations, pulmonary function, maintenance dose of corticosteroids, biomarkers, and adverse events.Results: During a mean follow-up period of 12.6 months, 10 patients received dupilumab as the first biologic, and 16 switched to dupilumab from other biologics. Dupilumab treatment significantly reduced the number of annual exacerbations from 3.4 ± 4.1 to 1.6 ± 2.7 (/person-year, p < 0.01) at the last follow-up regardless of previous biologic use. The Asthma Control Test score significantly improved in all patients by six months after administration but tended to worsen by 24 months in patients with previous biologic use. On the other hand, blood eosinophil counts (BECs) transiently increased and peaked three to six months after administration. The peak timing can be affected by previous biologic use. Adverse events included wheezing immediately after injection, hypereosinophilia, mild conjunctivitis, and relapse of chronic eosinophilic pneumonia in the patient switched from benralizumab.Conclusion: Dupilumab treatment was useful for patients with SA in a real-world setting. However, the BEC should be monitored carefully, especially in patients who previously received anti-IL-5/IL-5 receptor antibody.Keywords: dupilumab, severe asthma, exacerbation, transient eosinophilia, real-world

Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Yu Fujita, Hirofumi Utsumi, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata Tel +81-3-3433-1111 (ex 3271)Fax +81-3-3433-1020Email t-numata@jikei.ac.jpBackground: In Japan, biologic therapy was initiated for patients with severe asthma in 2009. In recent years, four biologics with different mechanisms of action have become available in the clinical setting. However, the efficacy of switching between biologics remains uncertain.Methods: To elucidate the efficacy of switching between biologics, 97 patients were enrolled who had received any biologic therapy for severe asthma at Jikei University Hospital, Tokyo, Japan, from July 2009 to December 2020. We retrospectively examined the patient characteristics, biomarkers, pulmonary function test results, selected biologics, and efficacy.Results: Thirty-one males and 66 females received any biologics. The mean age was 53.3 years at the initiation of biologic therapy. Initially, 33, 41, 15 and eight patients received omalizumab, mepolizumab, benralizumab, and dupilumab, respectively. Among three representative indicators for biologics administration, the peripheral blood eosinophil count, serum IgE levels and fractional exhaled nitric oxide, 64% of the patients had two indicators, and 28% had three indicators. Thirty-four patients (35%) switched from the initial biologic to another, and the reasons for switching included persistent asthmatic symptoms (n=22), schedule of hospital visits (n=5), and other reasons. Thus, the treatment was effective in 11 patients after switching. In addition, two patients received combination therapy with different biologics. Eighteen patients (19%) interrupted treatment for various reasons. Regardless of whether the biologic was the initial therapy, the overall efficacy of the four biologics was 60% based on the global evaluation of treatment effectiveness.Conclusion: Switching between biologics can be a promising option for severe asthma patients in whom treatment with an initial biologic is ineffective.Keywords: benralizumab, dupilumab, mepolizumab, omalizumab, switching

The economic loss caused by herbivore browsing in forest plantations is a concerning problem in many areas around the world. Information on the spatial distribution of browsing damage is important for forest owners when selecting locations for new plantations, because planting trees in areas of high browsing pressure increases economic losses. Although it is difficult to survey browsing damage across large areas, sporadic sampling data on browsing damage are often collected by foresters, governments, and researchers. Thus, in this study, we applied a generalized additive model (GAM) for analysis of sporadic data to reveal large-scale spatial variation in deer (Cervus nippon) browsing damage. A map of browsing pressure produced by a GAM that used years after planting (plantation age) and location as independent factors showed a few areas of high browsing pressure. In addition, browsing damage increased with increasing plantation age, and plantation stands aged 2+ years showed more browsing damage. Areas with high browsing damage estimated based on plantation stands aged 2+ years generally coincided with areas of high deer abundance, with some exceptions. Thus, this model reflects large-scale browsing damage relatively well and will help forest owners to avoid locating new plantations in areas of high browsing pressure.

The Iwate-Miyagi Nairiku Earthquake (M7.2) that occurred on June 14, 2008, caused a slope failure in Dozo-zawa River near the summit of Mt. Higashi-Kurikoma. The debris flow caused by the slope failure flowed for about 10 km and took the lives of 7 people. The mechanisms of the slope failure and long-distance debris flow have not yet been well understood. In this study, a series of triaxial compression tests was conducted using a highly crushable pumice soil collected from the collapsed area, and shear behavior and particle breakage were discussed. Both reconstituted specimens and intact specimens showed contractancy and reached critical states that implies high flow potential. However, intact specimens preserved looser structure during consolidation and showed stronger contractancy during shearing than the reconstituted specimens, due to their natural soil structure. Significant particle breakage was observed in the tests with reconstituted specimens.

The presence of soil solids, water, and air complicates understanding unsaturated soil dynamics. A thorough understanding of unsaturated soil behavior is essential for the fruitful design of slopes, embankments, and retaining structures. A series of constant void ratio and constant confining pressure triaxial compression tests were carried out under constant water content conditions (pore air pressure drained and pore water pressure undrained) to study the shear strength and deformation characteristics of a partially saturated silty soil. Test specimens were prepared with a water content of 15%, 20% (Optimum water content), and 25%, with the corresponding degree of saturation of 37, 49, and 62.5%. The degree of compaction of all specimens was kept at 83% while the dry density was 1.29 g/cm3, and the void ratio was around 1.045. All the samples were isotropically consolidated under 500kPa by keeping deviatoric stress at 0kPa. The constant void ratio test results showed that the deviatoric stress reached a peak value followed by a sudden decrease within the axial strain of 0-1.5%. In contrast, the deviatoric stress increased continuously until reaching the critical state without depicting any peak for constant confining pressure tests. However, in both cases, the lower the water content at the time of specimen preparation, the higher the shear resistance.

Mineral aerosols (i.e., dust) can affect climate and weather by absorbing and scattering shortwave and longwave radiation in the Earth's atmosphere, the direct radiative effect. Yet understanding of the direct effect is so poor that the sign of the net direct effect at top of the atmosphere (TOA) is unconstrained, and thus it is unknown if dust cools or warms Earth's climate. Here we develop methods to estimate the instantaneous shortwave direct effect via observations of aerosols and radiation made over a 3-year period in a desert region of the southwestern US, obtaining a direct effect of -14±1 and -9±6 W m−2 at the surface and TOA, respectively. We also generate region-specific dust optical properties via a novel dataset of soil mineralogy from the Airborne Visible/Infrared Imaging Spectrometer (AVIRIS), which are then used to model the dust direct radiative effect in the shortwave and longwave. Using this modeling method, we obtain an instantaneous shortwave direct effect of -21±7 and -1±7 W m−2. The discrepancy between the model and observational direct effect is due to stronger absorption in the model, which we interpret as an AVIRIS soil iron oxide content that is too large. Combining the shortwave observational direct effect with a modeled longwave TOA direct effect of 1±1 W m−2, we obtain an instantaneous TOA net effect of -8±6 W m−2, implying a cooling effect of dust. These findings provide a useful constraint on the dust direct effect in the southwestern United States.

Kenichiro Shimizu,1 Yutaka Yoshii,1 Miyuki Morozumi,2 Naoko Chiba,2 Kimiko Ubukata,2 Hironori Uruga,3 Shigeo Hanada,3 Nayuta Saito,1 Tsukasa Kadota,1 Saburo Ito,1 Hiroshi Wakui,1 Naoki Takasaka,1 Shunsuke Minagawa,1 Jun Kojima,1 Hiromichi Hara,1 Takanori Numata,1 Makoto Kawaishi,1 Keisuke Saito,4 Jun Araya,1 Yumi Kaneko,1 Katsutoshi Nakayama,1 Kazuma Kishi,3 Kazuyoshi Kuwano1 1Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, 2Department of Infectious Diseases, Keio University School of Medicine, 3Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, 4Department of Respiratory Medicine, The Jikei University Daisan Hospital, Tokyo, Japan Abstract: Respiratory infection is a major cause of exacerbation in chronic obstructive pulmonary disease (COPD). Infectious contributions to exacerbations remain incompletely described. We therefore analyzed respiratory tract samples by comprehensive real-time polymerase chain reaction (PCR) in combination with conventional methods. We evaluated multiple risk factors for prolonged hospitalization to manage COPD exacerbations, including infectious agents. Over 19 months, we prospectively studied 46 patients with 50 COPD exacerbations, collecting nasopharyngeal swab and sputum samples from each. We carried out real-time PCR designed to detect six bacterial species and eleven viruses, together with conventional procedures, including sputum culture. Infectious etiologies of COPD exacerbations were identified in 44 of 50 exacerbations (88%). Infections were viral in 17 of 50 exacerbations (34%). COPD exacerbations caused by Gram-negative bacilli, including enteric and nonfermenting organisms, were significantly associated with prolonged hospitalization for COPD exacerbations. Our results support the use of a combination of real-time PCR and conventional methods for determining both infectious etiologies and risk of extended hospitalization. Keywords: COPD, exacerbation, etiology, real-time PCR, prolonged hospitalization, risk factor

Abstract Charcot-Marie-Tooth disease type 2Z is caused by MORC2 mutations and presents with axonal neuropathy. MORC2 mutations can also manifest as developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN). We report a patient exhibiting an intermediate phenotype between these diseases associated with a novel MORC2 variant. A literature review revealed that the genotype‒phenotype correlation in MORC2-related disorders is complex and that the same mutation can cause a variety of phenotypes.

For the accurate design of structures subjected to both static and dynamic loadings, elastic wave velocity and small strain stiffness are essential parameters. Numerous techniques have been developed to estimate wave velocities of geomaterials. Bender elements which are widely adopted for wave velocity measurements are invasive in nature and are not suitable for coarse-grained materials. In the present study, new design configuration of disk transducer has been introduced to measure both vertical and horizontal wave velocities for coarse granular soils considering multidirectional oscillation of propagating waves. An innovative arrangement of both compression and shear type elements has been installed in a large-sized triaxial apparatus having rectangular specimens of size 236×236×500 mm to assess the wave velocities. The materials described are Toyoura sand (D50 = 0.24 mm) and Oiso gravel (D50 = 11.8 mm). This arrangement enables measurements of nine types of wave velocities, and thus the stiffness anisotropy to be quantified. For Oiso gravel, horizontal wave velocities are greater than vertical wave velocities for both shear and compression waves. For Toyoura sand, shear wave velocities are higher in horizontal direction of propagation, whereas similar compression wave velocities are observed from both horizontal and vertical directions.

Natural slopes and embankments are generally unsaturated in nature with negative pore water pressure adding to the shear strength and hence the stability of the slopes. During the event of rainfall, pore water pressure becomes less negative or even positive as a result the shear strength of soil decreases and failure occur. Therefore, the strength and deformation characteristics for unsaturated soil become important when analysing the stability of these types of slopes. In this study, a triaxial test apparatus was used to study the effect of water infiltration on the mechanical behaviour of unsaturated soil. The test results show that water infiltration decreased with increase in net confining stress and the stress paths were independent of the matric suction, the net confining stress and the shearing conditions for the present experimental study.

In this study, the effect of environmental exposure conditions on the long term mechanical property of surplus soils improved by lime and cement was investigated by conducting unconfined compression tests on the specimens cured under different conditions. As the result of the experiments after about 1 year (336 days) from specimen preparation, the unconfined compressive strengths of the soaked specimens were found to be the smallest, while those of the sealed specimens were the largest. Effect of soaking on the strengths appeared obviously in the cement treated soil, while the effect decreased when the duration of initial sealed curing increased. It was inferred that these differences in the strengths were caused by the changes in physical properties such as degree of saturation, and chemical properties due possibly to the leaching of hydration products during soaked curing.

This study investigated the progression of deterioration in cement treated surplus soils with cement contents of 1.7, 3.5 and 5.3 % under soaked condition by conducting needle penetration test and measuring calcium ion distribution within soil specimens. It was found that deterioration has progressed throughout the specimen after 336 days soaking in all the cases. From the measurement of calcium ion distribution, it was identified that calcium has leached out from the centre to the surface of the specimens though that distribution did not follow a good correlation with localized strength distribution. It was understood that the progression of deterioration of improved surplus soils with lower cement contents cannot be explained only with the remaining amount of calcium.

This study aims to develop a fundamental understanding of the role of fine particles on the small-strain stiffness of gap-graded granular soils. Stiffness was measured using cyclic triaxial probes, which give a measure of static stiffness, and dynamic wave propagation data, from which the dynamic stiffness can be measured. Assemblies of loosely packed spherical particles were considered. In the laboratory, local deformation transducers were used to measure the static stiffness, while the dynamic stiffness was calculated from stress wave velocities, measured using planar piezoelectric elements. To relate the particle-scale responses to the overall soil stiffness, complementary discrete element method (DEM) simulations were performed in which both static and dynamic stiffnesses were measured. Both the laboratory and the DEM data indicate that at low fines contents (< 30%) the stiffness decreases with increasing fines content. When the fines content increases from 30% to 35% there is a sharp increase in stiffness with increasing fines content; this is understood to mark the transition point at which the fines start to contribute significantly to the overall behaviour. Analyses of the frequency domain response of shear wave signals revealed that the lowpass frequency increases significantly at this transition point. This observation can be used to develop experimental interpretation protocols to assess to what extent fines are contributing to the overall soil stiffness.

In Japan, a multitude of slope disasters occur annually, resulting in often severe loss of human life. On occasion, disasters that occur at very gentle slopes and disasters that flow long distance, associated with destructive energy, are observed. In such cases, the trigger layer often consists of volcanic soils with extremely high void ratios and external triggers, including earthquake or heavy rainfall, increase the risk of slope disasters. These volcanic soils are often characterised by an extremely loose structure and are either retained mainly by weak cementation or are composed of crushable particles having intra voids. Although the cause of destructive long-distance flow has been explained by liquefaction, there are some observed disasters in which the trigger layer was not fully saturated, i.e. liquefaction should not be considered as a major cause. Focusing on the fact that long-distance flow or gentle slope flow, disasters are triggered by volcanic soil layers of extremely loose structure, artificial loose soil samples were prepared in the laboratory. These samples were prepared with cementation between particles and with crushable particles. In this study, deformation and strength characteristics of the extremely loose soils were investigated by conducting CD triaxial tests. It is revealed that such extremely loose soils can be vulnerable after the weakly cemented structure collapses as a result of external factors such as earthquakes.

Transmission used in automobiles is indispensable from the viewpoint of improvement of maximum speed, quietness and fuel consumption even if the power source of automobile is changed from internal combustion engine to electric motor in the future. We are studying a heat treatment process for imparting machinability to the forged material after hot forging used for a transmission of automobiles. In the past, the heat stored in the material after hot forging was merely released into the atmosphere. We succeeded in imparting machinability to the material by cooling while well controlling the heat stored in the forged material after hot forging. In the previous paper [1], we reported the progress of tool wear of this forged material in the high-speed cutting region with the cutting speed of 200 m/min or more in intermittent cutting. In this report, we conducted cutting experiments on the machinability of this developed forged material in the normal cutting speed region with the cutting speed less than 200 m/min. As a result, at the cutting speed V of V=157 m/min or less, it reached the conclusion that the built-up edges frequently occurred and the tool was chipped due to it. From the previous report and the results of this experiment, it was found that the cutting speed V of about V=213 m/min is optimum for cutting these forged materials with cemented carbide.

Tetsuro Ohno, Mitsuhiro Yanai, Hiroyuki Ando, Yoshitaka Toyomasu, Atsushi Ogawa, Hiroki Morita, Kyoichi Ogata, Erito Mochiki, Takayuki Asao, Hiroyuki KuwanoDepartment of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, JapanBackground: The aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans.Methods: The study was performed as a crossover design, and ten unresectable or relapsed gastric cancer patients were randomly divided into two groups. Group A (n = 5) was started on Rikkunshito (2.5 g three times daily, orally) from the first course of chemotherapy and followed by a second course without Rikkunshito. A treatment with reversed order was performed for Group B (n = 5). All patients received combined chemotherapy with S-1 plus cisplatin. The primary endpoint was the amount of oral intake, and the categories of scales of anorexia, nausea, and vomiting; secondary endpoints included the plasma concentration of acylated ghrelin.Results: In the Rikkunshito-on period, no decrease of the plasma concentration of acylated ghrelin induced by cisplatin was observed. The average oral intake in the Rikkunshito-on period was significantly larger than that in the Rikkunshito-off period, and the grade of anorexia was significantly lower in the Rikkunshito-on period than in the Rikkunshito-off period.Conclusion: Rikkunshito appeared to prevent anorexia induced by cisplatin, resulting in effective prophylactic administration of chemotherapy with cisplatin, and patients could continue their treatments on schedule.Keywords: Rikkunshito, cisplatin, ghrelin, anorexia, stomach cancer

In this study, a variable focusing lens with a driving mechanism was developed. The surface curvature of the lens is formed via the interaction of elastic film tension and liquid pressure generated by compression of a bellows, which enables the focal length to be changed. This paper discusses the optical characteristics of the lens system. The focal length range is 250 – 750 mm with beam diameters of 0.3 mm – 0.9 mm, respectively, when a YAG laser is irradiated. In the study, the lens system was applied to laser beam welding of mild-steel sheet with a thickness of 0.5 mm for 3,000 shots of laser irradiation at a peak power of 4.7 kW and a duration of 10 ms.