Evidence of a Hardening in the Cosmic Ray Proton Spectrum at around 166 TeV Observed by the GRAPES-3 Experiment.

We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January 2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).

Mass, Spectroscopy, and Two-Neutron Decay of

The structure and decay of the most neutron-rich beryllium isotope, ^{16}Be, has been investigated following proton knockout from a high-energy ^{17}B beam. Two relatively narrow resonances were observed for the first time, with energies of 0.84(3) and 2.15(5) MeV above the two-neutron decay threshold and widths of 0.32(8) and 0.95(15) MeV, respectively. These were assigned to be the ground (J^{π}=0^{+}) and first excited (2^{+}) state, with E_{x}=1.31(6) MeV. The mass excess of ^{16}Be was thus deduced to be 56.93(13) MeV, some 0.5 MeV more bound than the only previous measurement. Both states were observed to decay by direct two-neutron emission. Calculations incorporating the evolution of the wave function during the decay as a genuine three-body process reproduced the principal characteristics of the neutron-neutron energy spectra for both levels, indicating that the ground state exhibits a strong spatially compact dineutron component, while the 2^{+} level presents a far more diffuse neutron-neutron distribution.

Quasifree Neutron Knockout Reaction Reveals a Small s-Orbital Component in the Borromean Nucleus

A kinematically complete quasifree (p,pn) experiment in inverse kinematics was performed to study the structure of the Borromean nucleus ^{17}B, which had long been considered to have a neutron halo. By analyzing the momentum distributions and exclusive cross sections, we obtained the spectroscopic factors for 1s_{1/2} and 0d_{5/2} orbitals, and a surprisingly small percentage of 9(2)% was determined for 1s_{1/2}. Our finding of such a small 1s_{1/2} component and the halo features reported in prior experiments can be explained by the deformed relativistic Hartree-Bogoliubov theory in continuum, revealing a definite but not dominant neutron halo in ^{17}B. The present work gives the smallest s- or p-orbital component among known nuclei exhibiting halo features and implies that the dominant occupation of s or p orbitals is not a prerequisite for the occurrence of a neutron halo.

Surface Localization of the Dineutron in

The formation of a dineutron in the ^{11}Li nucleus is found to be localized to the surface region. The experiment measured the intrinsic momentum of the struck neutron in ^{11}Li via the (p,pn) knockout reaction at 246 MeV/nucleon. The correlation angle between the two neutrons is, for the first time, measured as a function of the intrinsic neutron momentum. A comparison with reaction calculations reveals the localization of the dineutron at r∼3.6 fm. The results also support the density dependence of dineutron formation as deduced from Hartree-Fock-Bogoliubov calculations for nuclear matter.

Measurement of the Electrical Properties of a Thundercloud Through Muon Imaging by the GRAPES-3 Experiment.

The GRAPES-3 muon telescope located in Ooty, India records rapid (∼10 min) variations in the muon intensity during major thunderstorms. Out of a total of 184 thunderstorms recorded during the interval of April 2011-December 2014, the one on December 1, 2014 produced a massive potential of 1.3 GV. The electric field measured by four well-separated (up to 6 km) monitors on the ground was used to help estimate some of the properties of this thundercloud, including its altitude and area that were found to be 11.4 km above mean sea level and ≥380 km^{2}, respectively. A charging time of 6 min to reach 1.3 GV implied the delivery of a power of ≥2 GW by this thundercloud that was moving at a speed of ∼60 km h^{-1}. This work possibly provides the first direct evidence for the generation of gigavolt potentials in thunderclouds that could also possibly explain the production of highest-energy (100 MeV) gamma rays in the terrestrial gamma-ray flashes.

Common and separate origins of the left and right inferior phrenic artery with a review of the literature.

In a 94-year-old male cadaver, upon which routine dissection was being conducted, a rare variation was found in the gastrophrenic trunk (GPT), the common trunk of the left gastric artery (LGA), right inferior phrenic artery (RIPA), and left inferior phrenic artery (LIPA); the GPT arises from the abdominal aorta. A hepatosplenic trunk accompanied the variation. In this variation, the RIPA first branched from the GPT and then to the LIPA and LGA. Variations in the common trunk of the LIPA and RIPA in the GPT are common, but to our knowledge, a variation (separate inferior phrenic artery in the GPT) similar to our findings has not been previously reported. We discuss the incidence and developmental and clinical significance of this variation with a detailed review of the literature. Knowledge of such a case has important clinical significance for invasive and non-invasive arterial procedures. Therefore, different variations concerning the LGA and inferior phrenic artery should be considered during surgical and non-surgical evaluations.

Transient Weakening of Earth's Magnetic Shield Probed by a Cosmic Ray Burst.

The GRAPES-3 tracking muon telescope in Ooty, India measures muon intensity at high cutoff rigidities (15-24 GV) along nine independent directions covering 2.3 sr. The arrival of a coronal mass ejection on 22 June 2015 18:40 UT had triggered a severe G4-class geomagnetic storm (storm). Starting 19:00 UT, the GRAPES-3 muon telescope recorded a 2 h high-energy (∼20 GeV) burst of galactic cosmic rays (GCRs) that was strongly correlated with a 40 nT surge in the interplanetary magnetic field (IMF). Simulations have shown that a large (17×) compression of the IMF to 680 nT, followed by reconnection with the geomagnetic field (GMF) leading to lower cutoff rigidities could generate this burst. Here, 680 nT represents a short-term change in GMF around Earth, averaged over 7 times its volume. The GCRs, due to lowering of cutoff rigidities, were deflected from Earth's day side by ∼210° in longitude, offering a natural explanation of its night-time detection by the GRAPES-3. The simultaneous occurrence of the burst in all nine directions suggests its origin close to Earth. It also indicates a transient weakening of Earth's magnetic shield, and may hold clues for a better understanding of future superstorms that could cripple modern technological infrastructure on Earth, and endanger the lives of the astronauts in space.

Influenza 2014-2015 among pregnant Japanese women: primiparous vs multiparous women.

This study was performed to determine whether multiparous pregnant women are prone to influenza. A questionnaire survey was conducted at 19 centres located throughout Japan, targeting all 6,694 postpartum women within 7 days after birth before leaving the hospital. All women gave birth during the study period between March 1, 2015, and July 31, 2015. Data regarding vaccination and influenza infection in or after October 2014, age, previous experience of childbirth, and number and ages of cohabitants were collected. Seventy-eight percent (n = 51,97) of women given questionnaires responded. Of these, 2,661 (51 %) and 364 (7.0 %) women reported having been vaccinated and having contracted influenza respectively. Multiparous women had a higher risk of influenza regardless of vaccination status (8.9 % [121/1362] vs 5.7 % [74/1299], relative risk [95 % confidence interval], 1.80 [1.36 to 2.38] for vaccinated and 9.3 % [112/1198] vs 4.3 % [57/1328], 2.18 [1.60 to 2.97] for unvaccinated women) compared to primiparous women. The risk of influenza increased with increasing number of cohabitants: 4.8 % (100/2089), 7.5 %, (121/1618), 9.0 %, (71/785), and 10.4 % (58/557) for women with 1, 2, 3, and ≥4 cohabitants respectively. Family size is a risk factor for influenza infection in pregnancy.

Does Internet-based cognitive behavioral therapy (iCBT) prevent major depressive episode for workers? A 12-month follow-up of a randomized controlled trial.

BACKGROUND: In this study we investigated whether an Internet-based computerized cognitive behavioral therapy (iCBT) program can decrease the risk of DSM-IV-TR major depressive episodes (MDE) during a 12-month follow-up of a randomized controlled trial of Japanese workers. METHOD: Participants were recruited from one company and three departments of another company. Those participants who did not experience MDE in the past month were randomly allocated to intervention or control groups (n = 381 for each). A 6-week, six-lesson iCBT program was provided to the intervention group. While the control group only received the usual preventive mental health service for the first 6 months, the control group was given a chance to undertake the iCBT program after a 6-month follow-up. The primary outcome was a new onset of DSM-IV-TR MDE during the 12-month follow-up, as assessed by means of the web version of the WHO Composite International Diagnostic Interview (CIDI), version 3.0 depression section. RESULTS: The intervention group had a significantly lower incidence of MDE at the 12-month follow-up than the control group (Log-rank χ2 = 7.04, p < 0.01). The hazard ratio for the intervention group was 0.22 (95% confidence interval 0.06-0.75), when estimated by the Cox proportional hazard model. CONCLUSIONS: The present study demonstrates that an iCBT program is effective in preventing MDE in the working population. However, it should be noted that MDE was measured by self-report, while the CIDI can measure the episodes more strictly following DSM-IV criteria.

Development of a speech-discriminating electromyogram system for routine ambulatory recordings for the low-level masseter muscle activity.

Previous work suggests a relationship between sustained low-level tooth clenching and the aetiology of myogenous temporomandibular disorder (TMD) pain. This study aimed to establish a reliable system with which to evaluate low-level electromyographic (EMG) activity related to low-level tooth clenching while discriminating speech activity, which is one of the most common facial muscle activities to be discriminated from low-level clenching. This device should facilitate the clinical evaluation of awake muscle activity in TMD patients. Eight female and eight male subjects (38.9 ± 11.3 years) participated in the study to evaluate the validity of estimation of speech duration. Actual speech duration was defined by one examiner by pointing out the timing of beginning and end point of each speech on wave-editing software. Speech duration, as detected by a voice sensor system, which was activated by a voice loudness of 54.71 ± 5.00 dB, was significantly correlated with the above actual speech duration (P < 0.01, R(2) = 0.9935). An actual recording with the system was carried out in one TMD patient and one healthy volunteer and revealed that the duration of diurnal EMG activity higher than 5% MVC was 1649.16 s and 95.99 s, respectively. As the voice sensor system adopted in this study could define the exact onset and offset of each segment of speech, EMG activity during speech could be precisely discriminated. The results of this study demonstrate that the EMG system with voice sensor system would be an effective tool for the evaluation of low-level masticatory muscle activity.

Antiplatelet drugs may increase the risk for checkpoint inhibitor-related pneumonitis in advanced cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are indicated for various cancers and are the mainstay of cancer immunotherapy. They are often associated with ICI-related pneumonitis (CIP), however, hindering a favorable clinical course. Recently, non-oncology concomitant drugs have been reported to affect the efficacy and toxicity of ICIs; however, the association between these drugs and the risk for CIP is uncertain. The aim of this study was to assess the impact of baseline concomitant drugs on CIP incidence in ICI-treated advanced cancer patients. PATIENTS AND METHODS: This was a single-center retrospective study that included a cohort of 511 patients with advanced cancer (melanoma and non-small-cell lung, head and neck, genitourinary, and other types of cancer) treated with ICIs. Univariable analysis was conducted to identify baseline co-medications associated with CIP incidence. A propensity score matching analysis was used to adjust for potential CIP risk factors, and multivariable analysis was carried out to assess the impact of the identified co-medications on CIP risk. RESULTS: Forty-seven (9.2%) patients developed CIP. In these patients, the organizing pneumonia pattern was the dominant radiological phenotype, and 42.6% had grade ≥3 CIP, including one patient with grade 5. Of the investigated baseline co-medications, the proportion of antiplatelet drugs (n = 50, 9.8%) was higher in patients with CIP (23.4% versus 8.4%). After propensity score matching, the CIP incidence was higher in patients with baseline antiplatelet drugs (22% versus 6%). Finally, baseline antiplatelet drug use was demonstrated to increase the risk for CIP incidence regardless of cancer type (hazard ratio, 3.46; 95% confidence interval 1.21-9.86). CONCLUSIONS: An association between concomitant antiplatelet drug use at baseline and an increased risk for CIP was seen in our database. This implies the importance of assessing concomitant medications for CIP risk management.

Development of a nomogram incorporating serum C-reactive protein level to predict overall survival of patients with advanced urothelial carcinoma and its evaluation by decision curve analysis.

BACKGROUND: The purpose of this study is to investigate the prognostic impact of C-reactive protein (CRP) on patients with advanced urothelial carcinoma and to develop a novel nomogram predicting survival. METHODS: A total of 223 consecutive patients were treated at Tokyo Medical and Dental Hospital. A nomogram incorporating V was developed based on the result of a Cox proportional hazards model. Its efficacy and clinical usefulness was evaluated by concordance index (c-index) and decision curve analysis. RESULTS: Of the 223 patients, 184 (83%) died of cancer. Median follow-up periods of patients who died and those who remained alive were 5 and 11 months, respectively. We developed a novel nomogram incorporating Eastern Cooperative Oncology Group Performance Status, presence of visceral metastasis, haemoglobin and age. The c-index of the nomogram predicting survival probability 6 and 12 months after diagnosis was 0.788 and 0.765, respectively. Decision curve analyses revealed that the novel nomogram incorporating CRP had a superior net benefit than that without CRP for most of the examined probabilities. CONCLUSION: We demonstrated the prognostic impact of CRP that improved the predictive accuracy of a nomogram for survival probability in patients with advanced urothelial carcinoma.

Enhancement of gene expression by transcriptional activation using doxorubicin-loaded liposome/pDNA complexes.

Gene therapy is a promising treatment option for cancers generated by mutation of oncogenes or tumor suppressor genes. The transcriptional process is activated by doxorubicin (DXR), and gene expression efficiency followed by gene transfection can be enhanced by the combination-use of DXR. Therefore, co-encapsulation of plasmid DNA (pDNA) and DXR into non-viral gene carriers can enhance gene expression. Here, we prepared DXR-loaded liposome/pDNA complexes (DXR-loaded PEGylated lipoplexes) by co-encapsulating pDNA and DXR into liposomes. Gene expression was enhanced by DXR encapsulation into lipoplexes in colon-26 cells and cultured mouse macrophages, and this gene expression level was significantly higher than that obtained by the combination of PEGylated lipoplexes and free DXR. Moreover, the activation profiles of transcriptional factors induced by DXR-loaded lipoplexes were different from those induced by free DXR; therefore, co-encapsulation of pDNA and DXR into gene carriers might be contributed to effective enhancement of gene expression. These findings provide a new approach for achieving effective gene transfection using PEGylated lipoplexes.

A phase II trial of stereotactic body radiotherapy in 4 fractions for patients with localized prostate cancer.

PURPOSE/OBJECTIVE(S): To report results from our phase II study of stereotactic body radiotherapy (SBRT) delivering 36 Gy in 4 fractions for patients with localized prostate cancer. MATERIALS/METHODS: We enrolled 55 patients treated with SBRT delivering 36 Gy in 4 fractions between 2015 to 2018. All patients were categorized as low-risk (n = 4), intermediate-risk (n = 31) or high-risk (n = 20) according to National Comprehensive Cancer Network criteria. Median age was 73 years (range 54-86 years). Two-thirds of patients (n = 37) had received androgen-deprivation therapy for 3-46 months (median, 31 months). Median duration of follow-up was 36 months (range 1-54 months). We used Radiation Therapy Oncology Group and National Cancer Institute-Common Toxicity Criteria version 4 for toxicity assessments. Quality of life (QOL) outcomes were also evaluated using the Expanded Prostate Cancer Index Composite (EPIC). RESULTS: Protocol treatments were completed for all patients. Six patients experienced biochemical failures. Among these six patients, three patients experienced clinical failure. One patient showed bone metastasis before biochemical failure. One patient died of gastric cancer. The 3-year biochemical control rate was 89.8%. Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were observed in 5 patients (9%) and 6 patients (11%), respectively. No grade 3 or higher acute toxicities were observed. Late grade 2 GU and GI toxicities were observed in 7 patients (13%) and 4 patients (7%), respectively. Late grade 3 GU and GI toxicities were observed in 1 patient (1.8%) each. EPIC scores decreased slightly during the acute phase and recovered within 3 months after treatment. CONCLUSION: Our phase II study showed that SBRT delivering 36 Gy in 4 fractions was safe and effective with favorable QOL outcomes, although this regimen showed slightly more severe toxicities compared to current standards.

Manifestation of preferred chewing side for hard food on TMJ disc displacement side.

The purpose of this study was to reveal the relationship between chewing-side preference and anterior disc displacement (ADD) of the TMJ. Thirty-two healthy subjects with ages ranging from 26 to 34 years were selected from volunteer students at the Okayama University Dental School. Subjects were asked to chew freely with two kinds of test foods, beef jerky (hard food) and chiffon cake (soft food), thus expecting different amounts of mechanical loading on the TMJ. One, 4, and 7 s after starting the mastication, subjects were asked to open their mouth momentarily to have a digital image of their mouth taken. The bolus placement area was measured by processing the digital images, calculated as the number of pixel of bolus area. Area asymmetry index was used for the determination of preferred chewing side (PCS). Oblique sagittal MRI scanning in the closed mouth position was taken to evaluate the articular disc position. In asymptomatic subjects with ADD, a significant predominance of the PCS on the ipsilateral side of ADD was observed during the mastication of hard food. On the contrary, no correlation was found between unilateral ADD and PCS for the soft food. From the results of this study, it is suggested that ADD is the associating factor of PCS for hard food. Therefore, it would be necessary to break down the concept of PCS into at least two categories, one for hard food and one for soft food, considering the mechanical loading on the TMJ.

Activity patterns of the suprahyoid muscles during swallowing of different fluid volumes.

Influences of bolus volumes on activity patterns of the suprahyoid muscles during swallowing were examined using the T(P) technique (which quantitatively evaluates muscle activity patterns and indicates a negatively skewed pattern at lower T(P) values) in healthy young adults (eight men and four women). One of six volumes of tea ranging from 10 to 32 mL was delivered randomly to each subject while recording an electromyogram of the suprahyoid muscles and a laryngeal mechanogram with a piezoelectric sensor. Each subject was asked to swallow the full volume of liquid in a gulp if possible. T(P) values were calculated as deciles from T(0) to T(100) during intervals that were defined by the trajectory of the laryngeal mechanogram recorded during swallowing. Seven significant differences were detected in the average T(P) values from T(30) to T(60): between 16 mL (e.g., 0.448 in T(30)) and 25 mL (0.408 in T(30)) and between 20 mL (0.453 in T(30)) and 25 mL. There were significant differences among the 12 subjects for all of the nine average T(P) values (Ps < 0.001), suggesting a notable intersubject variation in the suprahyoid (SH) activity patterns. The average peak amplitudes of the integrated suprahyoid activity differed significantly among the six volumes (P < 0.001), while the average durations measured by the laryngeal mechanogram did not. The present results suggest that the swallowing volume mainly affects SH activity patterns, which were evaluated by the T(P) technique, during the early period of each swallow.

Central airway stenosis in a patient with autoimmune pancreatitis.

Autoimmune pancreatitis is a unique form of chronic pancreatitis characterised by a high-serum immunoglobulin (Ig)G4 concentration involving various extra pancreatic lesions. A 63-yr-old female with autoimmune pancreatitis complained of cough. Chest computed tomography revealed an irregular stenosis of the central airway, lung hilar and mediastinal lymph node swelling, and a marked thickness of the bronchovascular bundle. Bronchoscopic examination revealed an irregular tracheobronchial stenosis accompanied with an oedematous mucosa and engorged vessels. Lung hilar and mediastinal lymph node swelling, central airway stenosis and bronchoscopic findings remarkably resembled those of sarcoidosis. Bronchial biopsy specimens demonstrated diffuse infiltrations of plasma cells, lymphocytes and eosinophils with fibrosis. Immunostaining showed infiltration of several IgG4-positive plasma cells. The patient was treated with oral prednisolone at 1 mg x kg(-1) x day(-1) for pancreatic lesions. A month later, the lung lesions, including central airway stenosis, lung hilar and mediastinal lymph node swelling, and bronchovascular bundle thickness, had dramatically improved along with improvement of pancreatitis, thus indicating a close association between the two conditions. This is the first report of a patient with autoimmune pancreatitis showing central airway stenosis similar to that of sarcoidosis.

Pulmonary involvement of autoimmune pancreatitis.

BACKGROUND: A wide variety of systemic lesions have been seen in patients with autoimmune pancreatitis. The pulmonary involvement of autoimmune pancreatitis was analysed to clarify the clinicopathological features of pulmonary lesions in comparison with pulmonary sarcoidosis. MATERIALS AND METHODS: Nineteen patients had autoimmune pancreatitis and eight had pulmonary sarcoidosis. The symptoms, laboratory data, chest computed tomography, Gallium-67 scintigraphy, pulmonary function testing and bronchoscopy findings, including the histological IgG4-immunostaining and IgG subclasses in the bronchoalveolar lavage in autoimmune pancreatitis, were collected to compare them with pulmonary sarcoidosis. RESULTS: The serum total protein, IgG and IgG4 levels were found to be significantly elevated in comparison with pulmonary sarcoidosis. In autoimmune pancreatitis, 17 patients showed bilateral hilar lymphadenopathy, while eight showed pulmonary nodules on chest computed tomography. Eighteen of 19 patients on Gallium-67 scintigraphy showed accumulation spots in either the hilar or mediastinal lymph nodes. Six patients with pulmonary nodules demonstrated accumulation spots in the corresponding lesions on chest computed tomography. All eight patients with pulmonary sarcoidosis showed accumulation spots in either the hilar or mediastinal lymph nodes. Bronchoalveolar lavage IgG4 in autoimmune pancreatitis showed a significant increase in comparison with pulmonary sarcoidosis. The histological findings obtained by a transbronchial lung biopsy showed the infiltration of lymphocytes and plasma cells in the thickened interstitum and alveoli with IgG4-positive plasma cell infiltration in patients with autoimmune pancreatitis. CONCLUSION: IgG4 in the bronchoalveolar lavage was seen at remarkably increased levels and IgG4-positive plasma cells were identified in the pulmonary lesions of patients with autoimmune pancreatitis.

The roles of PGF(2alpha) and PGE(2) in regression of the corpus luteum after intrauterine infusion of Arcanobacterium pyogenes in cows.

To study the effect of bacteria in the uterus on the fate of the corpus luteum (CL), Arcanobacterium pyogenes was inoculated into the uteri of cows on Day 3 (Day 0=day of spontaneous ovulation). Plasma concentrations of 13,14-dihydro-15-keto-PGF(2alpha) (PGFM), 13,14-dihydro-15-keto-PGE(2) (PGEM) and progesterone (P(4)) were determined. In five cows, the developing CL regressed and first-wave dominant follicles, which normally become atretic, ovulated (Group OV) after bacterial inoculation. In another five cows (Group NOV) and five control cows, the developing CL did not regress and first-wave dominant follicles did not ovulate. In Group OV, PGFM concentrations increased by 126.2pg/mL (from 36.8+/-7.8pg/mL on Day 3 to 163+/-37.2pg/mL on Day 6), with an increase ratio of 5.8-fold. Conversely, in Group NOV, PGFM had a greater increase of 198.4pg/mL (from 128.2+/-27.8pg/mL on Day 3 to 326.6+/-115.1pg/mL on Day 5), but the increase ratio was only 2.3-fold. Although PGEM tended to increase in both groups, raw increases and increase ratios were small. Bacterial inoculation into the uterus stimulated the release of prostaglandins and affected the fate of the CL; in that regard, the CL was affected more by PGF(2alpha) than by PGE(2), and the increase ratio of PGF(2alpha) was more important than the raw increase.