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Yuki Abe,1 Masaru Suzuki,1 Hiroshi Shima,2 Yusuke Shiraishi,2 Naoya Tanabe,2 Susumu Sato,2 Kaoruko Shimizu,1 Hirokazu Kimura,1 Hironi Makita,1,3 Toyohiro Hirai,2 Satoshi Konno,1 Masaharu Nishimura1,3 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo, 060-8638, Japan; 2Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan; 3Hokkaido Medical Research Institute for Respiratory Diseases, Chuo-ku, Sapporo, 060-0063, JapanCorrespondence: Masaru SuzukiDepartment of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email suzumasa@med.hokudai.ac.jpPurpose: Low body mass index (BMI) has been reported to be associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). In contrast, a detailed analysis of the association between body weight change over time and prognosis is not sufficient, particularly in Japanese patients with COPD who have been reported to be much thinner compared to Westerners. This study aimed to investigate the relationship between annual body weight change and long-term prognosis in Japanese patients with COPD in two independent cohorts.Patients and Methods: We analyzed 279 patients with COPD who participated in the Hokkaido COPD cohort study as a discovery cohort. We divided participants into three groups according to quartiles of annual body weight change calculated by the data from the first 5 years: weight loss group ( 0.20 kg/year). The association between annual body weight change and prognosis was replicated in the Kyoto University cohort (n = 247).Results: In the Hokkaido COPD cohort study, the weight loss group had significantly worse mortality than the other groups, whereas there was no difference in BMI at baseline. In the multivariate analysis, annual body weight change was an independent risk factor for all-cause mortality, which was confirmed in the Kyoto University cohort.Conclusion: Annual body weight loss is associated with poor prognosis in Japanese patients with COPD, independent of baseline BMI. Longitudinal assessment of body weight is important for the management of COPD.Keywords: annual body weight change, body mass index, chronic obstructive pulmonary disease, mortality, prognosis, weight loss

Background Joubert syndrome is an autosomal recessive or X-linked genetic disease with a cerebellar vermis defect or hypoplasia, hypotonia, ocular dyskinesia, and mental retardation. In neonates, respiratory problems such as apnea and tachypnea are notable. Case report We report a patient Joubert syndrome with a homozygous NPHP1 variant, who had head titubation with irritability, including exaggerated jitteriness and a marked Morrow reflex appeared soon after birth without neonatal respiratory problems. These symptoms decreased gradually and disappeared until 1 year. Conclusion Irritability with head titubation may be an early clinical clue for the clinician to suspect Joubert syndrome.

Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a complex progression of many clinical presentations, and clinically important deterioration (CID) has been proposed in the Western studies as a composite endpoint of disease progression. The aim of this study was to investigate the relationships between 1-year CID and the following long-term clinical outcomes in Japanese patients with COPD who have been reported to have different characteristics compared to the Westerners. Methods Among Japanese patients with COPD enrolled in the Hokkaido COPD cohort study, 259 patients who did not drop out within the first year were analyzed in this study. Two definitions of CID were used. Definition 1 comprised ≥ 100 mL decrease in forced expiratory volume in 1 s (FEV1), ≥ 4-unit increase in St George’s Respiratory Questionnaire (SGRQ) score from baseline, or moderate or severe exacerbation. For Definition 2, the thresholds for the FEV1 and SGRQ score components were doubled. The presence of CID was evaluated within the first year from enrollment, and analyzed the association of the presence of CID with following 4-year risk of exacerbations and 9-year mortality. Results Patients with CID using Definition 1, but not any single CID component, during the first year had a significantly worse mortality compared with those without CID. Patients with CID using Definition 2 showed a similar trend on mortality, and had a shorter exacerbation-free survival compared with those without CID. Conclusions Adoption of CID is a beneficial and useful way for the assessment of long-term disease progression and clinical outcomes even in Japanese population with COPD. The definition of CID might be optimized according to the characteristics of COPD population and the observation period for CID.

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein–coupled receptor 20 (GPR20) as a novel non–tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and Japan). We studied GPR20 expression stratified by treatment line, KIT expression, GIST molecular subtype, and primary tumor location. We produced DS-6157a, an anti-GPR20 antibody–drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). DS-6157a exhibited GPR20 expression–dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Preclinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients who are refractory or have resistance or intolerance to approved TKIs. Significance: GPR20 is selectively expressed in GIST across all treatment lines, regardless of KIT/PDGFRA genotypes. We generated DS-6157a, a DXd-based antibody–drug conjugate that exhibited antitumor activity in GIST models by a different mode of action than currently approved TKIs, showing favorable pharmacokinetics and safety profiles. This article is highlighted in the In This Issue feature, p. 1307

A 72-year-old man diagnosed with stage 4 lung adenocarcinoma developed asymptomatic pneumatosis intestinalis while undergoing treatment with first-line chemotherapy, which included carboplatin, paclitaxel, and bevacizumab (BEV). He was treated conservatively. The pneumatosis recurred while the patient was undergoing treatment with the third-line chemotherapy, which included pemetrexed (PEM). His condition resolved after 4 weeks of supportive therapy. To our knowledge, this is the first case in which pneumatosis intestinalis was induced twice by two drugs in a patient with lung cancer. BEV and PEM are often administered to patients with lung cancer; thus, it should be noted that pneumatosis intestinalis may occur as an adverse event in patients treated with these drugs.

BACKGROUND Higher physical activity levels during hospitalization may benefit the life-space mobility, defined as the ability to move within environments that expand from one's home to the greater community, of stroke survivors following their discharge. OBJECTIVES This study aimed to evaluate the relationship between physical activity levels during rehabilitation hospitalization and life-space mobility among stroke survivors three months after their discharge. METHODS We recruited 84 stroke survivors as prospective participants from four convalescent rehabilitation hospitals. Physical activity levels during hospitalization were assessed using pedometers with a three-axis accelerometer, and their average step count over 14 consecutive days prior to discharge was used as the representative set of values. Pedometers were placed on the participant's waist or wrist on the non-paretic side. The Life-Space Assessment (LSA), a validated self-reporting measure for assessing community mobility, was implemented three months following participant discharge from rehabilitation hospitals via a mail-in survey method. To determine the relationship between the participants' level of physical activity during hospitalization and the LSA score following discharge, we performed multivariate regression analysis. RESULTS A total of 75 participants (89.3%) completed the post-discharge survey and were therefore included in the analysis. The multiple regression analysis, controlled for age, balance function, walking endurance, fear of falling, and functional status, revealed that daily step counts were significantly associated with the LSA score three months after discharge (β = 0.241, p = .026). CONCLUSIONS Physical activity levels during hospitalization were significantly associated with the life-space mobility of stroke survivors following discharge.

Streptococcus pyogenes (group A streptococcus; GAS) is an important gram-positive human pathogen capable of causing diseases ranging from mild superficial skin and pharyngeal infections to more severe invasive diseases, including streptococcal toxic shock syndrome (STSS). GAS produces a T protein, and T serotyping has considerable discriminatory power for epidemiological characterization of GAS. To clarify the relationship between STSS and pharyngitis in Japan, we examined the T serotypes of GAS strains isolated from clinical specimens of streptococcal infections (STSS, 951 isolates; pharyngitis, 16268 isolates) from 2005 to 2017. The most prevalent T serotype from pharyngitis isolates was T12, followed by T1, T4, and TB3264. The most prevalent T serotype from STSS isolates was T1, followed by TB3264. Trend of increase and decrease in the frequency of T1 or TB3264 isolation from pharyngitis was correlated with that of STSS patients. The increase of T1 or TB3264 strain-infection in pharyngitis patients may increase the probability of causing STSS, indicating that careful monitoring of GAS serotypes is essential for the prediction of rapid increase of STSS in time to develop effective management strategies.

Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10–14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.

Aim Metallic components from circular external fixators, including the Ilizarov frame, cause artefacts on X-rays and obstruct clear visualisation of bone detail. We evaluated the ability of tomosynthesis to reduce interference on radiographs caused by metal artefacts and developed an optimal image acquisition method for such cases. Materials and methods An Ilizarov frame phantom was constructed using rods placed on the bone for the purpose to evaluate the benefits of tomosynthesis. Distances between the rod and bone and the angle between the rod and X-ray tube orbit were set at three different levels. Filtered backprojection images were reconstructed using two different features of the reconstruction function: THICKNESS−− (CONTRAST4) and THICKNESS++ (METAL4); the first is suitable for improving contrast and the second is suitable for metal artefacts. The peak signal-to-noise ratio (PSNR) was used during image evaluation to determine the influence of the metallic rod on bone structure visibility. Results The PSNR increased as the angle between the metal rod and the X-ray tube orbit and the distance between the metallic rod and bone increased. The PSNR was larger when using THICKNESS−− (CONTRAST4) than when using THICKNESS++ (METAL4). Conclusion The optimal reconstruction function and image acquisition determined using the metallic rod in this study suggest that quality equal to that without the metallic rod can be obtained. Clinical significance We describe an optimised method for image acquisition without unnecessary acquisition repetition and unreasonable posture changes when the bone cannot be adequately visualised. How to cite this article Abe Y, Shimada M, Takeda Y, et al. Evaluation of Patient Positioning during Digital Tomosynthesis and Reconstruction Algorithms for Ilizarov Frames: A Phantom Study. Strategies Trauma Limb Reconstr 2020;15(1):1–6.

The goal of this pilot study was to develop an age-estimation formula and assess its effectiveness after evaluating individual intraoral findings. A total of 198 Japanese adults were included, and intraoral findings were collected from the corpses. To analyze the condition of each tooth, 20 items were established for intraoral findings, and seven tooth states were established. Logistic regression analysis was used to estimate the impact of age on each intraoral finding. Sequentially, linear regression was applied to verify the correlation between age and type of tooth, and multiple regression was used to correlate age-dependent factors. The intraoral findings with age dependency were tooth stump, edentulous jaw, attrition, no caries, dental prostheses, partial dentures, and complete dentures. Tooth stump, attrition, and dental prostheses showed positive multicollinearity. Missing tooth, extant tooth, normal teeth, and untreated lost teeth were age-correlated. Multiple regression analysis included age as the response variable and five factors as the explanatory variables in a new age-estimation formula, resulting in ± 10 years for 86.96% of cases (60–69 years old), 76.47% (70–79 years old), and 61.05% of all cases. The multiple correlation was 0.551, and the contribution rate of the multiple regression formula was 0.304. The accuracy of the proposed age-estimation formula was within ± 10 years for 61.05% of all subjects. However, the accuracy of age estimation in subjects aged 60–79 years was excellent (76.47–86.96%), which showed that this age-estimation formula would be effective for estimating the age of middle-aged to older subjects.

A 40-year-old man suffered from short bowel syndrome. Since a large amount of intestinal output and watery diarrhea hampered his quality of life, we tried to control the intestinal output by reducing the secretion of gastric acid with lansoprazole. Because the small intestine was only 10 cm in length and effective absorption of oral lansoprazole was doubtful, we monitored his intragastric pH for 24 hours and confirmed that the holding time above pH 3.0 was 14.5 hours (60.4%). He spent his home life eating porridge during the day, and receiving total parenteral nutrition of 1,100 mL/day at night while taking lansoprazole as an oral tablet (30 mg) once a day.

Neutrophils are involved in the first stage of acute inflammation. After injury, they are mobilized and recruited to the injured tissue. In diabetes, wound healing is delayed and aberrant, leading to excessive recruitment and retention of neutrophils that fail to promote angiogenesis and prolong inflammation. However, the exact pathological mechanisms of diabetic-derived neutrophils in chronic inflammation remain unclear. Here, miRNA profiling of neutrophils from bone marrow in type 2 diabetic mice was performed using a microarray. miRNAs regulate the posttranscriptional expression of target mRNAs and are important in countering inflammation-related diseases. Our study revealed that miRNAs exhibit differential expression in diabetic-derived neutrophils compared with non?diabetic-derived neutrophils, especially miR-129 family members. miR-129-2-3p directly regulated the translation of Casp6 and Ccr2, which are involved in inflammatory responses and apoptosis.Furthermore, miR-129-2-3p overexpression at the wound site of type 2 diabetic mice accelerated wound healing. These results suggest possible involvement of miR-129-2-3p in diabetic-derived neutrophil dysfunction and that retention kinetics of neutrophils and chronic inflammation may be initiated through miR-129-2-3p?regulated genes. This study characterizes changes in global miRNA expression in diabetic-derived neutrophils and systematically identifies critical target genes involved in certain biological processes related to the pathology of diabetic wound healing., Diabetes, 68(3), pp.617-630; 2019

In this study, we propose a method to remotely change the friction of a three-dimensional surface made of polystyrene foam. In a previous study, a system that projects an image onto a two-dimensional polystyrene foam surface and irradiates ultrasound according to a finger’s position in contact with the surface to change the friction has been proposed. In this study, we extended it to a three-dimensional shape and quantitatively evaluated the change in friction. It was confirmed that the frictional change could be obtained even when extended to three dimensions but that the frictional change was less likely to occur depending on how the polystyrene foam was fabricated. This technology can be applied for adding the tactile feel to a simple 3D mockup model made of polystyrene foam.

Yuki Abe, Masaru Suzuki, Hirokazu Kimura, Kaoruko Shimizu, Hironi Makita, Masaharu Nishimura, Satoshi Konno Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, JapanCorrespondence: Masaru SuzukiDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email suzumasa@med.hokudai.ac.jpPurpose: Fractional exhaled nitric oxide (FENO) reflects eosinophilic inflammation of the airways. However, the significance of longitudinal assessment of FENO, including its variability, in the clinical course of severe asthma remains unclear. The aim of this study is to examine the association between long-term changes in FENO and the development of exacerbations in severe asthma.Patients and Methods: Among the severe asthma patients enrolled in the Hokkaido Severe Asthma Cohort Study, 100 patients with severe asthma who completed a 3-year follow-up in which FENO was measured annually were included. According to the FENO level at baseline, 1 year, and 2 years, the patients were classified into three groups: the sustained high group (≥ 50 ppb at all three visits), the sustained low group (< 25 ppb at all three visits), and the intermediate group (other). Subjects in the intermediate group were further classified into two groups based on the median value of the coefficient of variation (CV) of FENO during the 3 years (high CV and low CV intermediate groups).Results: The sustained high group experienced shorter exacerbation-free survival and more frequent exacerbations than the sustained low group (median number of exacerbation events, 3 vs 0, p = 0.01). In the intermediate group, the high CV group experienced shorter exacerbation-free survival than the low CV group, and the CV of FENO was an independent contributing factor to the development of exacerbations.Conclusion: Persistence of FENO above 50 ppb over the years as well as the presence of large variations in FENO levels was associated with the development of exacerbations in patients with severe asthma.Keywords: asthma, coefficient of variation, exacerbation, fractional exhaled nitric oxide, longitudinal assessment, variability

We propose a film device that can be attached to flat surfaces, including touch panels, to remotely reduce surface friction by irradiating airborne ultrasound. In this article, we present a film-air resonance structure that produces large-amplitude surface vibrations excited by airborne ultrasound. We confirmed via simulation that the surface amplitude increases to a level sufficient to reduce friction at the designed frequency. It was also observed in an experiment using a prototype that the friction between a finger and film surface is sharply reduced, and the surface vibrates with sufficient amplitude when touched with a finger.

We aimed to evaluate the relationship between the daily wheelchair self-propulsion distance and functional recovery in subacute stroke survivors.Seventy-four patients with stroke were prospectively recruited from four convalescent rehabilitation hospitals. All participants were unable to walk independently and required manual wheelchairs for locomotion on admission. The daily wheelchair self-propulsion distance was measured using a cycle computer that was connected to a touch switch to exclude the assistance-propulsion distance. The outcome measures were represented as the relative gain of the Functional Independence Measure (FIM) effectiveness during hospitalization. Moreover, a better functional recovery was defined as a FIM effectiveness50%. Participants were categorized into three groups according to tertiles of the average daily wheelchair self-propulsion distance: lowest tertile (T1, ≤0.59 km/day); middle tertile (T2, 0.60-1.23 km/day); and highest tertile (T3, ≥1.24 km/day).Multivariate logistic regression analysis adjusted for baseline characteristics showed that the T2 and T3 groups had a significant association with better FIM effectiveness, and their odds ratios (95% confidence interval, p) were 7.26 (1.13-45.85,The daily wheelchair self-propulsion distance was significantly associated with functional recovery in subacute stroke survivors.IMPLICATIONS FOR REHABILITATIONNon-ambulatory stroke survivors can obtain extra independent physical activity by using wheelchair self-propulsion, when they do not have someone to assist them with walking.This multicenter observational study revealed that the self-propulsion distance of a manual-wheelchair was significantly associated with functional recovery in subacute stroke survivors.

We present preliminary results on generation of energetic α-particles driven by lasers. The experiment was performed at the Institute of Laser Engineering in Osaka using the short-pulse, high-intensity, high-energy, PW-class laser. The laser pulse was focused onto a thin plastic foil (pitcher) to generate a proton beam by the well-known TNSA mechanism which, in turn, was impinging onto a boron-nitride (BN) target (catcher) to generated alpha-particles as a result of proton-boron nuclear fusion events. Our results demonstrate generation of α-particles with energies in the range 8–10 MeV and with a flux around 5 × 10^9 sr^−1.

To explore the underlying mechanism of rapid liver hypertrophy by liver partition in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), liver partition at different sites was investigated. Increased inflammatory cytokines owing to the liver partition have been reportedly responsible. If this were true, rapid liver hypertrophy should be achieved regardless of where the liver was split. A male Sprague-Dawley rat model was created, in which a liver split was placed inside the portal vein ligated lobe (PiLL), in addition to the ALPPS and portal vein ligation (PVL) models. Liver regeneration rate, inflammatory cytokine levels, activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and expressions of regenerating islet-derived (Reg)3&alpha, and Reg3&beta, were investigated. The liver regeneration rate was significantly higher in the ALPPS group than in the PiLL group, whereas inflammatory cytokine levels were nearly equal. Additional volume increase in ALPPS group over PVL and PiLL groups was JAK2/STAT3-dependent. Reg3&alpha, expressions were observed only in the ALPPS group. An increase in inflammatory cytokines was not enough to describe the mechanism of rapid liver hypertrophy in ALPPS. Expressions of Reg3&alpha, could play an important role in conjunction with an activation of the JAK2/STAT3 pathway.

Most metastatic lung tumors display well-defined, round, multiple nodular shadows, whereas the presence of diffuse ground-glass opacities on chest computed tomography generally suggests non-malignant conditions. Here, we report an unusual case of pulmonary metastasis from gastric cancer in which diffuse ground-glass opacities were observed in all lung segments. A 59-year-old man with a 3-month history of worsening chest pain and shortness of breath was referred to the pulmonary clinic. Chest computed tomography revealed low attenuation areas, suggesting emphysema, along with diffuse ground-glass opacities and interlobular septal thickening in both lungs. A transbronchial lung biopsy specimen revealed signet-ring cell carcinoma infiltrating the alveolar septa. Immunohistochemical staining of the cancer cells was positive for CDX-2, cytokeratin 7, and cytokeratin 20, and negative for surfactant apoprotein-A, TTF-1, and Napsin A. Gastrointestinal endoscopy revealed an ulcerative tumor in the stomach, and a biopsy from the tumor demonstrated malignant cells with similar morphology and immunophenotypes as those in the lungs. The final diagnosis was diffuse lung metastasis from gastric cancer. Our case shows that although multiple, well-defined nodules are typically considered to be the classic presentation of pulmonary metastasis, clinicians should also be aware of the possibility of pulmonary metastasis presenting as diffuse ground-glass opacities.

Women with estrogen deficiency are at the risk of suffering from neurological symptoms such as memory impairment. In the present study, we investigated the effect of garlic, Allium sativum L. (Asparagales: Amaryllidaceae), treated with subcritical water on memory impairment in ovariectomized (OVX) rats. OVX rats were administered garlic powder for 84 d. Hippocampus-dependent spatial memory was assessed using the Morris water maze test. Escape latency of the OVX rats increased compared with that of sham-operated rats. The prolonged escape latency of the OVX rats decreased to the level of that of sham-operated rats upon the administration of garlic powder (0.5% in feed). The weights of the body, uterus, and brain were not affected by the garlic powder administration. These results suggest that garlic powder treated with subcritical water mitigates memory impairment in OVX rats.

In this paper we discuss an effect of feature extraction using Incremental Learning Restricted Boltzmann Machine (IL-RBM). We trained the model on Moving MNIST and analyzed the obtained representation by visualizing hidden activities and reported some meaningful features obtained in incremental learning, similar to that of obtained in Slow Feature Analysis (SFA).

Thermal neutron (∼25 meV) beam is a powerful tool for investigating the structure and properties of materials used in science and technology. A laser-driven neutron source generating 1010 neutrons within 1 ns duration is utilized to a single shot radiography with a dual beam of thermal neutrons and X-rays. As a proof of principle, we show the non-destructive inspection of hazardous substances (Cadmium) contained in a typical battery, when the cadmium anode thickness is evaluated from the transmittance of thermal neutrons. The fact that the neutron inspection above is performed with a single laser shot, i.e. with a single bunch of neutrons leads to a safer neutron source that is optically controlled on/off, and provides a novel tool for science and engineering.

Pneumomediastinum is defined as the presence of extraluminal gas within the mediastinum. Hamman described a diabetic ketoacidosis (DKA) patient with subcutaneous emphysema and spontaneous pneumomediastinum, a case known in current times as Hamman's syndrome and now pneumomediastinum is known to be one of the accompanying findings of DKA. We describe two cases with diabetes mellitus in which postmortem computed tomography (CT) could detect pneumomediastinum prior to autopsy. One was a woman in her 40 s, who had type II diabetes mellitus with bronchopneumonia in the middle and lower lobes of the right lung (Case 1) and the other also aged in her 40 s with type I diabetes mellitus (Case 2). In these cases with diabetic mellitus, the finding of pneumomediastinum at postmortem CT gave differential diagnostic considerations of DKA in addition to common cause such as decomposition or cardiopulmonary resuscitation. Autopsy with histopathological and biochemical examination suggested the cause of death in both cases were fatal DKA. The main cause of pneumomediastinum in Case 1 was pulmonary emphysema, and DKA was an exacerbation factor of pneumomediastinum. In contrast, DKA could have caused pneumomediastinum in Case 2, so called Hamman's syndrome. Pneumomediastinum is an obvious morphological abnormality, and thus we should pay attention to the information of pneumomediastinum from postmortem CT scanning.

[abstFig src='/00290002/07.jpg' width='210' text='The motion detection system' ] Fall accident prevention is one of the most important issues in elderly care settings. To prevent an accident, it is necessary to notify caregivers if the elderly person is getting out of bed. We have previously developed a posture discrimination system based on body motions. Herein, we propose a discrimination method by using machine learning to improve the performance of the system. A purpose of this study is to evaluate the proposed method. Elderly people in a nursing home were chosen as subjects in this study. We analyzed the body motion data during bed rest and bed exit of the subjects using the proposed method. These results suggest that it is effective.

Medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder caused by the mutation of the RET proto-oncogene, that shows nearly complete penetration. The American Thyroid Association guidelines recommend prophylactic thyroidectomy for patients with high-risk RET mutations. However, in Japan, ethical and medical issues may preclude prophylactic treatment in young patients. Hence, an early diagnosis of MTC is necessary to ensure a favorable outcome. Here, we report the case of a young Japanese girl with a high-risk RET mutation, diagnosed with very early stage MTC using serum calcitonin (Ctn) values measured using an electro chemiluminescence immuno-assay (ECLIA). The Japanese girl with a family history of MEN2 had been followed at our hospital since she was 5-mo-old. RET analysis revealed that she displayed a Cys634Gly mutation. The patient underwent annual neck ultrasonography and calcium infusion testing. When she was 8-yr-old, the Ctn level, measured using ECLIA, dramatically increased with calcium stimulation, from a baseline of 11.3 pg/mL to 333 pg/mL. She subsequently underwent total thyroidectomy and was diagnosed with stage I MTC. Detecting early stage MTC by monitoring serum Ctn measured by ECLIA, may represent a useful strategy for patients with high-risk RET mutations.

We propose a system that can remotely change the friction feel of the polystyrene foam surface using an Airborne Ultrasound Tactile Display (AUTD). In previous studies, the superficial friction of an object is mainly controlled by ultrasonic vibration of an object to reduce the friction using the squeeze film effect or by static electricity to increase superficial friction. In contrast to these studies, our approach changes the friction remotely, thus no device is needed on the target surface. This allows the tactile display to be a large screen or disposable, which can be used as an intuitive touch panel in applications where hygiene is important, such as during surgery. Furthermore, changing the surface friction of three-dimensional objects of any shape is also considered as another application. In this system, the position of the fingertip is detected by a device (Xperia Touch) equipped with a projector and a fingertip detection sensor, and the ultrasound focus is changed according to the fingertip position in real time using AUTD. As a result, the feel of friction on the polystyrene foam is altered by the focused ultrasound. Various friction patterns can be presented according to the image of the projector.

Antibody–drug conjugates (ADCs) represent a promising class of drugs with a wider therapeutic index (TI) than conventional chemotherapeutic agents due to their efficient and specific drug delivery. ADC payload is attached to antibody by chemical linkage. Two classes of cytotoxins – DNA damaging agents and microtubule inhibitors – have been validated as ADC payloads in clinical trials and four ADCs, MYLOTARG®, ADCETRIS®, KADCYLA®, and BESPONSA®, have been approved so far. There are many different ADCs in clinical development stage. Novel linker-payload technologies are evaluated and a new class of payload DNA topoisomerase I inhibitor is emerging. This review will focus on introduction of the four approved ADC drugs and promising novel ADCs with DNA topoisomerase I inhibitors, Sacituzumab Govitecan and [fam-] Trastuzumab Deruxtecan, in late stages of clinical development.

More than 85% of GISTs are driven by activating mutations in KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Currently, the only approved treatments for GIST are KIT directed tyrosine kinase inhibitors (TKIs). However, treatment with approved TKIs eventually results in disease progression most often due to the development of secondary resistance mutations in KIT. In addition, these agents have limited activity in PDGFRA mutant GIST and KIT/PDGFRA wild type (WT) GIST as primary therapy. Therefore, it is essential to develop novel therapeutic strategies with different modes of action in advanced GIST. G protein-coupled receptor 20 (GPR20) is an orphan GPCR selectively and abundantly expressed in GIST. GPR20 expression is regulated by FOXF1 and ETV1, transcription factors that play critical roles in KIT-driven GIST initiation, proliferation, and survival. We hypothesize that GPR20 is a potential therapeutic target for ADC development for the treatment of GIST. In this study, 1) GPR20 and KIT protein expression was assessed by IHC staining on GIST samples from DFCI (n=144) and NCCHE (n=100) as well as on normal and malignant tissue microarrays obtained commercially, and 2) an anti-GPR20 ADC (DS-6157a) was generated to evaluate antitumor activity in GIST models and to assess safety. GPR20 was expressed in more than 88% of the GIST samples analyzed, with higher expression levels in samples that: (I) received multiple treatment lines compared to naïve/early treated samples, (II) expressed higher KIT levels, (III) were small intestinal GIST, and/or (IV) had no KIT mutation, including succinate dehydrogenase (SDH) deficient GIST and neurofibromatosis type 1 (NF1)-associated GIST. The interstitial cells of Cajal were the only normal cells positive for GPR20. Normal mast cells expressed KIT but not GPR20. DS-6157a is an ADC composed of a humanized anti-GPR20 antibody, a Gly-Gly-Phe-Gly tetra-peptide-based linker, and a DNA topoisomerase I (TOP1) inhibitor Dxd. DS-6157a exhibited GPR20 expression-dependent cell growth-inhibitory activity and induced tumor regression with dosing at 3 to 10 mg/kg in multiple GIST xenograft models. In addition, DS-6157a showed antitumor activity in a GIST patient-derived xenograft model that was resistant to imatinib, sunitinib, and regorafenib. In vitro, DS-6157a induced TOP1 inhibitor-associated markers of DNA damage (phosphorylation of Chk1) and apoptosis (cleaved PARP) in GPR20 expressing cells. In preclinical toxicology studies using rats and cynomolgus monkeys, the pharmacokinetics and safety profile of DS-6157a were favorable at up to 200 mg/kg and 30 mg/kg, respectively. These data support the clinical development of DS-6157a as a potential novel GIST therapy with activity in patients that are resistant, refractory, or intolerant to approved TKIs. Citation Format: Kenji Iida, Amr H. Abdelhamid, Akiko Kawano Nagatsuma, Tomoko Shibutani, Satoru Yasuda, Michiko Kitamura, Chiharu Hattori, Manabu Abe, Jun Hasegawa, Takuma Iguchi, Tsuyoshi Karibe, Takashi Nakada, Koichiro Inaki, Reiko Kamei, Yuki Abe, Jessica L. Andersen, Sandro Santagata, Matthew L. Hemming, Suzanne George, Toshihiko Doi, Atsushi Ochiai, George D. Demetri, Toshinori Agatsuma. Therapeutic targeting of GPR20, selectively expressed in gastrointestinal stromal tumor (GIST), with DS-6157a, an antibody-drug conjugate (ADC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5181.

Squamous cell carcinoma of the endometrium is extremely rare, accounting for approximately 1% of uterine body malignancies. The present report describes a case of squamous cell carcinoma of the uterine body arising from ichthyosis due to persistent pyometra. A 68-year-old Japanese woman, gravida 1 para 1, was referred to the Gynecological Department of Tokyo Women's Medical University, due to watery brown vaginal discharge which had persisted for 10 days. Pelvic magnetic resonance (MRI) imaging revealed a tumorous lesion occupying the cervical uteri, measuring 3 cm in diameter, and pyometra. The endometrial biopsy specimen obtained after drainage of the purulent fluid in the uterus was insufficient for obtaining a definitive pathological diagnosis. Under a clinical diagnosis of cervical tumor and pyometra, total transabdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathologically, two primary cancers were diagnosed, i.e., cervical endometrioid carcinoma and squamous cell carcinoma of the endometrium. The patient was treated with additional chemotherapy with carboplatin (area under the curve, 6) and paclitaxel (175 mg/m2). The patient has remained alive, without recurrence, for 1 year to date. In this case, preexisting cervical endometrioid carcinoma caused stenosis of the uterine orifice and also resulted in pyometra. The uterine body squamous cell carcinoma appeared to have been caused by persistent inflammatory stimuli to the endometrium. One must be cautious regarding cancer in elderly postmenopausal females presenting with pyometra. The findings in this case report suggest that chronic inflammation of the endometrium may be associated with primary squamous cell carcinoma of the endometrium.

The nuclear burn history provides critical information about the dynamics of the hot-spot formation and high-density fuel-shell assembly of an Inertial Confinement Fusion (ICF) implosion, as well as information on the impact of alpha heating, and a multitude of implosion failure mechanisms. Having this information is critical for assessing the energy-confinement time τE and performance of an implosion. As the confinement time of an ICF implosion is a few tens of picoseconds, less than 10-ps time resolution is required for an accurate measurement of the nuclear burn history. In this study, we propose a novel 1-ps time-resolution detection scheme based on the Pockels effect. In particular, a conceptual design for the experiment on the National Ignition Facility and OMEGA are elaborated upon herein. A small organic Pockels crystal "DAST" is designed to be positioned ∼5 mm from the ICF implosion, which is scanned by a chirped pulse generated by a femto-second laser transmitted through a polarization-maintained optical fiber. The originally linearly polarized laser is changed to an elliptically polarized laser by the Pockels crystal when exposed to neutrons, and the modulation of the polarization will be analyzed. Our study using 35-MeV electrons showed that the system impulse response is 0.6 ps. The response time is orders of magnitude shorter than current systems. Through measurements of the nuclear burn history with unprecedented time resolution, this system will help for a better understanding of the dynamics of the hot-spot formation, high-density fuel-shell assembly, and the physics of thermonuclear burn wave propagation.

Transverse sinus-sigmoid sinus (TS-SS) dural arteriovenous fistula (dAVF) is common type of dAVF, on the other hand, anterior condylar confluence (ACC) dAVF is relatively rare. There has been no report presenting patients with TS-SS dAVF and ACC dAVF identified simultaneously yet. We present a case of TS-SS dAVF and ACC dAVF that developed subcortical hemorrhage of left temporal lobe. A 66-year-old woman with no past history was transferred to our hospital for sudden-onset consciousness disturbance, and was urgently admitted after the detection of a subcortical hemorrhage in the left temporal lobe. We suspected a dAVF based on magnetic resonance angiography and performed digital subtraction angiography (DSA). DSA revealed that the left occipital artery, left ascending pharyngeal artery, left middle meningeal artery, left tentorial artery, and posterior meningeal artery flowed into the TS-SS and ACC. DSA also showed outflow from the TS-SS to the brain surface through the vein of Labbe and the vein of Trolard. We performed transvenous embolization to prevent re-bleeding, she was then discharged from our hospital and her remaining sensory aphasia gradually improved. In the present study, the active investigation to determine the cause of subcortical hemorrhage led to a definitive diagnosis. The combination of ACC dAVF and TS-SS dAVF has not been reported thus far and this is considered a valuable case.

A large-aperture high-sensitivity image intensifier panel that consists of an avalanche photodiode array and a light-emitting diode array is presented. The device has 40% quantum efficiency, over 104 optical gain, and 80-ns time resolution. The aperture size of the device is 20 cm, and with the current manufacturing process, it can be scaled to arbitrarily larger sizes. The device can intensify the light from a single particle scintillation emission to an eye-visible bright flash. The image resolution of the device is currently limited by the size of the avalanche photodiode that is 2 mm, although it can be scaled to smaller sizes in the near future. The image intensifier is operated at a small voltage, typically +57 V. The device can be applied to various applications, such as scintillation imaging, night vision cameras, and an image converter from non-visible light (such as infrared or ultraviolet) to visible light.

BackgroundTreatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients.MethodsThe registration data including hemoglobin A1c(HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort).ResultsThe proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p1cvalues between the two cohorts.ConclusionsThe popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.

Increasing the laser energy absorption into energetic particle beams represents a longstanding quest in intense laser-plasma physics. During the interaction with matter, part of the laser energy is converted into relativistic electron beams, which are the origin of secondary sources of energetic ions, γ-rays and neutrons. Here we experimentally demonstrate that using multiple coherent laser beamlets spatially and temporally overlapped, thus producing an interference pattern in the laser focus, significantly improves the laser energy conversion efficiency into hot electrons, compared to one beam with the same energy and nominal intensity as the four beamlets combined. Two-dimensional particle-in-cell simulations support the experimental results, suggesting that beamlet interference pattern induces a periodical shaping of the critical density, ultimately playing a key-role in enhancing the laser-to-electron energy conversion efficiency. This method is rather insensitive to laser pulse contrast and duration, making this approach robust and suitable to many existing facilities., Enhanced coupling of laser energy to the target particles is a fundamental issue in laser-plasma interactions. Here the authors demonstrate increased photon absorption leading into higher laser to electron and proton energy transfer through the interference of multiple coherent beamlets.

Diagnosis of fatal hypothermia is considered to be difficult in forensic practice and even if findings due to cold exposure are evident, cold exposure is not necessarily a direct cause of death. Identification of useful molecular markers for the diagnosis of fatal hypothermia has not been successful. In this study, to identify novel molecular markers that inform the diagnosis of fatal hypothermia, we focused on skeletal muscle, which plays a role in cold-induced thermogenesis in mammals. We made rat models of mild, moderate, and severe hypothermia and performed body temperature-dependent gene expression analysis in the iliopsoas muscle using next-generation sequencing (NGS). NGS showed that after severe hypothermia, the expression levels of 91 mRNAs were more than double those in mild and moderate hypothermia and control animals. Gene ontology (GO) analysis indicated that these mRNAs are involved in a number of biological processes, including response to stress and lipids, and cellular response to hypoxia. The expression of four genes [connective tissue growth factor (Ctgf), JunB proto-oncogene, AP-1 transcription factor subunit (Junb), nuclear receptor subfamily 4, group A, member 1 (Nr4a1), and Syndecan 4 (Sdc4)] and the level of one protein (CTGF) were induced only by severe hypothermia. These genes and protein are involved in muscle regeneration, tissue repair, and lipid metabolism. These results indicate that heat production to maintain body temperature in a process leading to fatal hypothermia might be performed by the iliopsoas muscle, and that Ctgf, Junb, Nr4a1, and Sdc4 genes are potential diagnostic markers for fatal hypothermia.

A relativistic laser pulse, confined in a cylindrical-like target, under specific conditions may perform multiple scattering along the internal target surface. This results in the confinement of the laser light, leading to a very efficient interaction. The demonstrated propagation of the laser pulse along the curved surface is just yet another example of the “whispering gallery” effect, although nonideal due to laser–plasma coupling. In the relativistic domain its important feature is a gradual intensity decrease, leading to changes in the interaction conditions. The process may pronounce itself in plenty of physical phenomena, including very efficient electron acceleration and generation of relativistic magnetized plasma structures.

View of SARA with and without cowl Held in Japan every year since 2007, the Real World Robot Challenge (RWRC) is a technical challenge for mobile robots. Every robot is given the missions of traveling a long distance and finding specific persons autonomously. The robots must also have an affinity for people and be remotely monitored. In order to complete the missions, we developed a new mobile robot, SARA, which we entered in RWRC 2014. The robot successfully completed all of the missions of the challenge. In this paper, the systems we implemented are detailed. Moreover, results of experiments and of the challenge are presented, and knowledges we gained through the experience are discussed.

This paper analyzes the debate on nuclear power after the Fukushima accident by using a text-mining approach. Texts are taken from the editorial articles of five major Japanese newspapers, Asahi Shinbun, Mainichi Shinbun, Nikkei Shinbun, Sankei Shinbun and Yomiuri Shinbun. After elucidating their different views on nuclear power policy, including general issues such as radiation risks, renewable energy and lessons from the meltdown, the paper reveals two main strands of arguments. Newspapers in favor of denuclearization appeal to "democratic values." They advocate public participation in decisions on future energy policy and criticize the closed-off administration of nuclear energy. Meanwhile, pro-nuclear newspapers adopt a "technological nationalistic" stance, claiming that denuclearization will weaken Japan's superiority in the field of nuclear power technology. In other words, the debate about the nuclear power is not merely about energy supply, but also about the choices facing Japanese society over visions for the future after the events of Fukushima.

Background The designation of some cardiac-specific proteins as prognostic biomarkers in chronic obstructive pulmonary disease (COPD) exacerbations suggest that the process of exacerbation involves cardiomyocyte injury. Among these cardiac biomarkers, heart-type fatty acid binding protein (h-FABP) is considered a very sensitive diagnostic marker for cardiomyocyte injury and a prognostic marker in chronic heart failure. However, the prognostic usefulness of h-FABP in patients with COPD remains unclear. Methods Sixty-six patients were enrolled in this study. Subjects who recovered from COPD exacerbation and were discharged without needing home oxygen therapy were defined as the improved group. Those who died of the COPD exacerbations, were discharged but needed home oxygen therapy, or were transferred to a rehabilitation hospital for respiratory failure and the remaining aftereffects of exacerbation were defined as the unimproved group. Results The improved and unimproved groups included 54 and 12 subjects, respectively. Compared with the improved group, the unimproved group had significantly higher white blood cell counts and alanine aminotransferase, lactate dehydrogenase, blood urea nitrogen (BUN), uric acid, potassium, and h-FABP levels, and significantly lower total protein and total cholesterol levels and estimated glomerular filtration rates, either at admission or during the early morning within 24h after admission. A multivariate analysis revealed that higher serum h-FABP and potassium levels were independently predictive of a poor prognosis following a COPD exacerbation, and a receiver operating characteristic curve analysis yielded a cutoff of 4.5ng/ml for predicting lack of improvement. Conclusion H-FABP may predict the outcomes of COPD exacerbation.

Background Sarcopenia is diagnosed on the basis of skeletal muscle mass and muscle strength/function. However, more simple and accurate measures for muscle mass and muscle strength/function should be explored. Objective The aim of this study was to compare the skeletal muscle characteristics at each stage of sarcopenia (normal, presarcopenia, dynapenia, and sarcopenia) via ultrasonography, multifrequency bioelectrical impedance analysis (BIA), and physical assessment batteries in community-dwelling older adults. By evaluating the relationship between muscle quality/quantity indicators and muscle mass/muscle function, we attempted to identify better muscle quantity and quality indicators for the diagnosis of sarcopenia. Setting and subjects Community-dwelling older men (n = 100, 81.6 ± 7.4 years) and women (n = 247, 79.7 ± 6.9 years) participated in this study. Measurements Skeletal muscle quantity and quality were measured by ultrasonography and multifrequency BIA. Ultrasonographic (thickness and echo intensity) and multifrequency BIA (volume and density) indicators, as well as physical assessment measures, were compared among each stage of sarcopenia. In addition, receiver-operating characteristic analysis was used to assess the sensitivity and specificity of each indicator. Results Most of the muscle quantity indicators were lower in the sarcopenia and presarcopenia groups than in the other groups, whereas most of the muscle quality indicators were lower in the sarcopenia and dynapenia groups than in the other groups. According to the receiver-operating characteristic analysis, quadriceps muscle thickness and thigh muscle volume were better indicators of muscle mass, whereas the quadriceps muscle echo intensity and thigh muscle density were more robust indicators of muscle function. Conclusions In this study, we found potential muscle quality and quantity indicators for sarcopenia diagnosis by ultrasonography and multifrequency BIA. Future longitudinal studies are warranted to define the role of these indicators for the diagnosis of sarcopenia.

Tandem mass screening has recently been started in Japan, but genetic screening has yet to be widely performed in neonates and many unexpected deaths are still being reported. We previously reported two cases of sudden infant death that may have been prevented had newborn screening been performed. In this study, we retrospectively reviewed 71 cases of sudden infant death for 66 arrhythmia- and 63 metabolic disease-related genes to identify how many cases of sudden infant death may have been prevented had mass screening been performed. Next-generation sequencing revealed that six cases had arrhythmia-related gene variants and five cases had metabolic disease-related gene variants. Had genetic screening been performed in addition to biochemical and physiological screening during the neonatal period to identify those at risk of arrhythmia or metabolic disease, these infants could have been diagnosed and treated, preventing their deaths. As such, screening of newborns may prevent sudden infant death.