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PURPOSE Ionoacoustics is one of the promising approaches to verify the beam range in proton therapy. However, the weakness of the wave signal remains a main hindrance to its application in clinics. Here we studied the potential use of a fixed-field alternating gradient accelerator (FFA), one of the accelerator candidates for future proton therapy. For such end, magnitude of the pressure wave and range accuracy achieved by the short-pulsed beam of FFA were assessed, using both simulation and experimental procedure. METHODS A 100 MeV proton beam from the FFA was applied on a water phantom, through the acrylic wall. The beam range measured by the Bragg peak (BP)-ionization chamber (BPC) was 77.6 mm, while the maximum dose at BP was estimated to be 0.35 Gy/pulse. A hydrophone was placed 20 mm downstream of the BP, and signals were amplified and stored by a digital oscilloscope, averaged, and low-pass filtered. Time-of-flight (TOF) and two relative TOF values were analyzed in order to determine the beam range. Furthermore, an acoustic wave transport simulation was conducted to estimate the amplitude of the pressure waves. RESULTS The range calculated when using two relative TOF was 78.16 ± 0.01 and 78.14 ± 0.01 mm, respectively, both values being coherent with the range measured by the BPC (the difference was 0.5-0.6 mm). In contrast, utilizing the direct TOF resulted in a range error of 1.8 mm. Fivefold and 50-fold averaging were required to suppress the range variation to below 1 mm for TOF and relative TOF measures, respectively. The simulation suggested the magnitude of pressure wave at the detector exceeded 7 Pascal. CONCLUSION A submillimeter range accuracy was attained with a pulsed beam of about 21 ns from an FFA, at a clinical energy using relative TOF. To precisely quantify the range with a single TOF measurement, subsequent improvement in the measuring system is required.

Objectives Early detection of pancreatic cancer is notoriously difficult. A novel cancer diagnostic method using the ability of nematodes to detect odor of urine samples has been developed (N-NOSE). This method has a high sensitivity and specificity for various cancers; however, it has not yet been verified in pancreatic cancer. We examined the usefulness of this method to aid early diagnosis of pancreatic cancer in a cancer center. Methods We collected urine samples and clinical data from patients hospitalized in our division, between July 2017 and February 2019. We excluded patients with a known current or past history of other cancers. We investigated the relationship between the results of N-NOSE and the presence of pancreatic cancer. Results There were 95 noncancer cases and 104 pancreatic cancer cases. The sensitivity and specificity of N-NOSE for pancreatic cancer were 84.6% (88/104) and 60% (57/95), respectively. N-NOSE was able to detect stages 0 to I pancreatic cancer and had a higher correlation with early-stage pancreatic cancer than advanced stage. Conclusions N-NOSE has sufficient sensitivity and specificity for use in clinical practice, and it holds great potential as a diagnostic aid for pancreatic cancer, especially for early-stage pancreatic cancer.

Viral hemorrhagic fevers caused by members of the order Bunyavirales comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.

Tolerance towards fetal alloantigens in the maternal immune system is essential for maintaining pregnancy. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells characterized by their ability to suppress immune activity and maintain maternal-fetal immune tolerance. However, the mechanisms underlying MDSC induction have not been elucidated. Herein, we investigated the myeloid-derived suppressor cells (MDSCs) in the peripheral blood of pregnant canines and its induction mechanism. By analyzing the concentration of MDSCs in the peripheral blood of pregnant canines, elevation of MDSCs has been observed during pregnancy. In addition, MDSCs from pregnant canines inhibit T cell activation. These results suggest that the elevated MDSCs in canine pregnancy may contribute to reduces maternal immune activity. To clarify the cause of MDSCs elevation in canine pregnancy, we analyzed the relationship between pregnancy-related hormones (estradiol, progesterone, and relaxin) and MDSCs. Serum relaxin levels, but not estradiol and progesterone, were correlated with the ratio of monocyte MDSCs. Additionally, relaxin induced monocytic MDSCs as well as inhibited T cell activation in vitro. Therefore, relaxin contributes to the elevation of monocytic MDSCs in the peripheral blood of pregnant canines. Our findings highlight the novel role of relaxin in pregnancy and contribute to a better understanding of maternal-fetal immune tolerance.

A 52-year-old female had cholecystoduodenostomy for biliary atresia of type I cyst at 120 days of age. The patient's surgery recovery was uneventful;however, the patient had recurring cholangitis at the age of 27. The patient had high hepatobiliary enzymes in the outpatient clinic and was diagnosed with cholangitis. In general, the Kasai method is the mainstream for biliary atresia, since it has a much-reduced incidence of both early and late postoperative problems. However, this patient had biliary atresia of type I cyst and had undergone cholecystoduodenostomy. We suspected that the obstructive cholangitis was caused by the relatively wide anastomosis opening into the duodenal bulb, where the stomach contents pass through the most, and the poor clearance owing to the convoluted cystic duct;therefore, we chose to place a stent endoscopically. However, to our surprise, Class V was detected in the bile cytology performed as a precaution. Although no tumor was seen on imaging such as contrast-enhanced CT, EUS, and PET/CT, mapping biopsy results showed the presence of cancer at the bifurcation of the cystic duct. The patient had cholangiocarcinoma confined to the extrahepatic bile ducts only;thus, extrahepatic bile duct resection was conducted. The patient was discovered to have biliary intraepithelial neoplasia-3, and the tumor was entirely respectable. The patient had a good postoperative course, with normalization of liver function and no recurrence of cholangitis. In this case, cholangiocarcinoma was detected at an early stage by cytological examination performed as a precaution during endoscopic therapy for recurrent cholangitis. In addition to the fact that the long-term pathogenesis of biliary atresia is still unknown, it is important to note the presence of malignancy, which has the greatest effect on the patient prognosis, considering that the course of the disease varies depending on the operation carried out. Because cholecystoduodenostomy for biliary atresia is a rare approach, and there has been no previous report of related cholangiocarcinoma, we report this case for the benefit of gastroenterologists who may encounter similar cases in the future.

Excellent firm bonding between the biomaterials and bone tissue (osseointegration and osteo-conductivity) has been desired for the stability in vivo of dental implants and artificial joints. Much has been learned about this concept, which has led to significant improvements in the design and surface modification of implants in the field of implant dentistry, orthopedic surgery. We have already reported that low-intensity pulsed ultrasound (LIPUS) irradiation can accelerate the bone bonding ability of the bio-conductive materials such as bioactive titanium and hydroxyapatite implant. However, it is still unclear whether the LIPUS could have same effect to different types of the bioactive-materials. Therefore, in this study, the differences of bone-like hydroxyapatite formation on some kind of hydroxyapatite surface in simulated body fluid (SBF) under the LIPUS irradiation were investigated. Two kinds of hydroxyapatite samples immersed in SBF was exposed to ultrasound waves, the bone-like apatite on the surface was analyzed by Scanning electron microscopy and X-ray diffraction. As a result, the enhancement of hydroxyapatite formation on the surface by LIPUS was confirmed, the initial epitaxial nucleation and crystal growth of apatite depended on crystal structure of the surface of matrix materials.

A 70-year-old dextral woman was admitted to a hospital with agraphia for kanji (Japanese morphograms). She had a history of severe constipation, nightmares, and visual hallucinations. Neurological examinations revealed no obvious Parkinson's disease symptoms. She showed poor skills in writing the kanji for looking at picture objects, [e.g., writing the Japanese word “inu” (which means dog) when she saw a drawing of a dog] or dictated words. A reduced striatal uptake of [123I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT) on single-photon-emission computed tomography and reduced meta-iodobenzylguanidine (MIBG) cardiac uptake on myocardial scintigraphy were detected. The accumulation of amyloid beta in the bilateral cerebral cortices was observed on amyloid-positron emission tomography. We herein report a case of Lewy body dementia with pure agraphia for kanji with underlying Alzheimer's disease pathology.

Breast cancer is the most common malignancy in women and has a risk of late recurrence. We report a case of metastasis to the stomach and colon 23 years after surgery, with characteristic findings. A 74-year-old woman underwent breast cancer resection at the age of 51. At the time, no additional therapy was performed despite the histological diagnosis of invasive lobular carcinoma with lymph node metastasis. Upper gastrointestinal endoscopy, which was performed as a follow-up for her chronic gastritis, revealed multiple erosions. Histology revealed diffuse proliferation of signet ring cell-like atypical cells, that were positive for cytokeratin CAM5.2 and estrogen receptor. These findings suggested metastasis from the invasive lobular breast carcinoma. Positron-emission tomography revealed sternal and vertebral metastases. Colonoscopy also performed to screen for intestinal metastasis revealed several lesions that resembled hyperplastic polyps. Although these lesions were not strongly suspected of metastasis, histology surprisingly revealed the same findings as the gastric metastasis. This case involved gastric and colorectal superficial metastases that were synchronously detected 23 years after primary treatment. We report that early-stage colorectal metastasis may resemble hyperplastic polyps, and biopsy should always be considered in patients with a history of breast cancer, regardless of years elapsed since treatment.

Excellent osseointegration of biomaterial is very important for the stability of dental implants in clinical field. Much has been learned about this concept and significant improvements on the design and surface modification of implants have been done in the implant dentistry.

Beyond the snow line of protoplanetary discs and inside the dense core of molecular clouds, the temperature of gas is low enough for water vapour to condense into amorphous ices on the surface of preexisting refractory dust particles. Recent numerical simulations and laboratory experiments suggest that condensation of the vapour promotes dust coagulation in such a cold region. However, in the numerical simulations, cohesion of refractory materials is often underestimated, while in the laboratory experiments, water vapour collides with surfaces at more frequent intervals compared to the real conditions. Therefore, to re-examine the role of water ice in dust coagulation, we carry out systematic investigation of available data on coagulation of water ice particles by making full use of appropriate theories in contact mechanics and tribology. We find that the majority of experimental data are reasonably well explained by lubrication theories, owing to the presence of a quasi-liquid layer (QLL). Only exceptions are the results of dynamic collisions between particles at low temperatures, which are, instead, consistent with the JKR theory, because QLLs are too thin to dissipate their kinetic energies. By considering the vacuum conditions in protoplanetary discs and molecular clouds, the formation of amorphous water ice on the surface of refractory particles does not necessarily aid their collisional growth as currently expected. While crystallisation of water ice around but outside the snow line eases coagulation of ice-coated particles, sublimation of water ice inside the snow line is deemed to facilitate coagulation of bare refractory particles., Comment: 18 pages, 14 figures, published in Monthly Notices of the Royal Astronomical Society

It has been established that the initiation of paroxysmal atrial fibrillation (AF) is frequently associated with ectopic beats inside the thoracic veins, including the pulmonary veins, superior vena cava, coronary sinus, and/or vein of Marshall. However, similar arrhythmogenic ectopic discharge or premature atrial contractions (PACs) originating from the inferior vena cava (IVC) have been rarely described. We present the case of a 51-year-old man with paroxysmal AF undergoing electrophysiological study. Twelve-lead electrocardiography demonstrated PACs with negative P waves in the inferior leads. Ectopic beats originating from the ostium of the IVC, which were likely to initiate AF, were observed. Furthermore, the origin of the PAC was visualized using an electroanatomical local activation timing (LAT) map and located close to the fibrotic tissue of the vasculature. Radiofrequency catheter ablation was performed at the earliest activation site, and ectopic beats were not observed after the procedure. This is the first report to demonstrate a LAT contact map of ectopic discharge arising from the IVC. If PACs with negative P waves in the inferior leads are found in a patient with AF, the IVC should be investigated for possible focal ectopic discharges. LEARNING OBJECTIVE: Non-pulmonary vein foci play a significant role in the pathogenesis of atrial fibrillation (AF). However, inferior vena cava (IVC) triggers that initiate AF have rarely been described. Premature atrial contractions with negative P waves in the inferior leads may be associated with ectopic discharges originating from the IVC, which contribute to the initiation of AF.

The asteroid (3200) Phaethon is known to be the parent body of the Geminids, although meteor showers are commonly associated with the activity of periodic comets. What is most peculiar to the asteroid is its comet-like activity in the ejection of micrometer-sized dust particles at every perihelion passage, while the activity of the asteroid has never been identified outside the near-perihelion zone at $0.14~\mathrm{au}$ from the Sun. From the theoretical point of view, we argue that the activity of the asteroid is well explained by the electrostatic lofting of micrometer-sized dust particles with the aid of mobile alkali ions at high temperatures. The mass-loss rates of micrometer-sized particles from the asteroid in our model is entirely consistent with the values inferred from visible observations of Phaethon's dust tail. For millimeter-sized particles, we predict three orders of magnitudes higher mass-loss rates, which could also account for the total mass of the Geminid meteoroid stream by the electrostatic lofting mechanism., Comment: 7 pages. 2 figures, to appear in Icarus Letters

Autobiographical memory specificity (AMS) refers to the tendency to recall events that occurred at a particular time and place. We examined the hypothesis that AMS is associated with pattern separation, which is an essential component of episodic memory that may allow us to encode and retain the unique aspects of events. In Study 1 (N = 94) and Study 2 (preregistered; N = 99), participants completed the Autobiographical Memory Test, which measures AMS, and the Mnemonic Similarity Task measuring pattern separation. We coded Autobiographical Memory Test responses conventionally and then further classified the categoric memory responses (i) that contained words indicating repetitions or regularity (e.g., always, often) and (ii) did not contain these words. The pattern separation ability correlated positively with specific memories and correlated negatively with categoric memories lacking those words. We propose to distinguish these two types of categoric memory and discuss the integrative model of autobiographical memory structure.

Human infections with the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threatens public health. The susceptibility of HPAIVs to baloxavir acid (BXA), which is a new class of inhibitor for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but has not yet been characterized fully. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants in vitro was assessed. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested to those of seasonal and other zoonotic strains. BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate; A/Hong Kong/483/1997 (H5N1) strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, followed by prevention of acute lung inflammation and improvement of mortality compared with oseltamivir phosphate (OSP). Furthermore, combination treatments with BXM and OSP, using a 48-hour delayed treatment model showed a more potent effect on viral replication in organs, accompanied by improved survival compared to BXM or OSP monotherapy. From each test, no resistant virus (e.g., I38T in the PA) emerged in any BXM-treated mouse. These results therefore support the conclusion that BXM has potent antiviral efficacy against H5 HPAIV infections.

Excellent firm bonding between the biomaterials and bone tissue (osseointegration and osteo-conductivity) is very important for the stability of dental implants and artificial joints etc. Much has been learned about this concept, which has led to significant improvements in the design and surface modification of implants in the field of implant dentistry, orthopedic surgery. For this issue, we have focused on the effects of low-intensity pulsed ultrasound (LIPUS) irradiation, investigated whether LIPUS could accelerate the osseointegration ability of bio-active material such as bioactive titanium and hydroxyapatite. As samples, Bio-active pure titanium and hydroxyapatite (HA) were prepared, in vitro simulation test and animal experiment have performed. In simulation test, the bone-like hydroxyapatite formation on material surface in simulated body fluid (SBF) under the LIPUS were assessed. In animal test, the bio-active samples implanted to the rabbits femur, undertaken the irradiation of LIPUS were investigated by using Scanning Electron Microscope (SEM), X-ray diffraction (XRD) etc. and histological observation. As a result, LIPUS irradiation showed the excellent enhancement of bone-material attachment by means of the crystal growth of bone-like apatite on sample materials surface, which suggested the application of LIPUS has clinical potential to improve the osseointegration (osteointegration), bone-bonding ability of bio-active materials.

Autophagy is an intracellular process that regulates the degradation of cytosolic proteins and organelles. Dying cells often accumulate autophagosomes. However, the mechanisms by which necroptotic stimulation induces autophagosomes are not defined. Here, we demonstrate that the activation of necroptosis with TNF-α plus the cell-permeable pan-caspase inhibitor Z-VAD induces LC3-II and LC3 puncta, markers of autophagosomes, via the receptor-interacting protein kinase 3 (RIPK3) in intestinal epithelial cells. Surprisingly, necroptotic stimulation reduces autophagic activity, as evidenced by enlarged puncta of the autophagic substrate SQSTM1/p62 and its increased colocalization with LC3. However, necroptotic stimulation does not induce the lysosomal-associated membrane protein 1 (LAMP1) nor syntaxin 17, which mediates autophagosome-lysosome fusion, to colocalize with LC3. These data indicate that necroptosis attenuates autophagic flux before the lysosome fusion step. Our findings may provide insights into human diseases involving necroptosis.

Obstructive sleep apnea (OSA) is associated with the occurrence of various kinds of bradyarrhythmia and tachyarrhythmia. The activation of the autonomic nerve system is an important causative factor of the pathogenesis of the arrhythmia in OSA patients. Previous studies have shown that the R-R interval is an effective parameter for evaluating autonomic nerve activities. However, whether or not OSA can induce variations in the R-R interval and whether or not continuous positive airway pressure (CPAP) therapy can improve these variations in OSA patients are unclear. The present study explored whether or not CPAP therapy could improve the regularity of the R-R interval.

Human infections with avian-origin influenza A(H7N9) virus represent a serious threat to global health; however, treatment options are limited. Here, we show the inhibitory effects of baloxavir acid (BXA) and its prodrug baloxavir marboxil (BXM), a first-in-class cap-dependent endonuclease inhibitor, against A(H7N9), in vitro and in vivo. In cell culture, BXA at four nanomolar concentration achieved a 1.5–2.8 log reduction in virus titers of A(H7N9), including the NA-R292K mutant virus and highly pathogenic avian influenza viruses, whereas NA inhibitors or favipiravir required approximately 20-fold or higher concentrations to achieve the same levels of reduction. A(H7N9)-specific amino acid polymorphism at position 37, implicated in BXA binding to the PA endonuclease domain, did not impact on BXA susceptibility. In mice, oral administration of BXM at 5 and 50 mg/kg twice a day for 5 days completely protected from a lethal A/Anhui/1/2013 (H7N9) challenge, and reduced virus titers more than 2–3 log in the lungs. Furthermore, the potent therapeutic effects of BXM in mice were still observed when a higher virus dose was administered or treatment was delayed up to 48 hours post infection. These findings support further investigation of BXM for A(H7N9) treatment in humans.

The response of the lead zirconate titanate (PZT) element to an irradiated 20 MeV electron beam was studied. Both the resonant and antiresonant frequencies of the PZT element were measured under irradiation, and then the variation of the electromechanical coupling factor was investigated. It was found that the coupling factor linearly decreased with increasing beam energy absorbed in the PZT element, whereas the surface temperature remained constant. We propose a dosimeter based on piezoelectric PZT.

Dust Astronomy investigates the nature and the origin of dust particles in space. The particle size distribution ranges from nanodust to approximately 100 micrometer. The study of the elemental and/or chemical composition of the particles together with the knowledge about their origin provides insights into many disciplines. Dust Astronomy is an interdisciplinary working field, which includes Solar System Science, Interstellar Medium studies and Astrobiology. A basic tool for these studies are Dust Telescopes. Dust Telescopes are in-situ instruments to characterize individual dust particles by their velocity vector, size and composition. They are based on impact ionization used for time-of-flight compositional analysis and on charge induction for particle speed and size measurements. In this sense, already the Cassini Cosmic Dust Analyzer (CDA) was a simple Dust Telescope, which successfully characterized the dust environment at Saturn. Now, future missions go even further. In the next years the missions DESTINY+, EUROPA and IMAP will launch. In this talk, a summary is given about the capabilities of Dust Telescopes with a focus on the DESTINY+ Dust Analyser (DDA). DDA is a medium size instrument with a target diameter of 26 cm. A two-axis articulation allows to track dust RAM directions. Larger Telescopes like the record breaking LAMA instrument, developed especially for the measurement of low interstellar dust fluxes, and the instruments for the probes IMAP and EUROPA are compared with DDA. The paper will address questions about the detection of nanodust or, what is a good instrument approach for a Dust Observatory? What are the instrumental challenges for an Interstellar Probe?

We report the results of a search for the inelastic scattering of weakly interacting massive particles (WIMPs) in the XENON1T dark matter experiment. Scattering off $^{129}$Xe is the most sensitive probe of inelastic WIMP interactions, with a signature of a 39.6 keV de-excitation photon detected simultaneously with the nuclear recoil. Using an exposure of 0.89 tonne-years, we find no evidence of inelastic WIMP scattering with a significance of more than 2$\sigma$. A profile-likelihood ratio analysis is used to set upper limits on the cross-section of WIMP-nucleus interactions. We exclude new parameter space for WIMPs heavier than 100 GeV/c${}^2$, with the strongest upper limit of $3.3 \times 10^{-39}$ cm${}^2$ for 130 GeV/c${}^2$ WIMPs at 90\% confidence level., Comment: 9 pages, 4 figures

The Cosmic Dust Analyzer (CDA) onboard Cassini characterized successfully the dust environment at Saturn from 2004 to 2017. Besides the study of Saturn’s E ring and its interaction with the embedded moons, CDA detected nanoparticles in the outer Saturn system moving on unbound orbits and originating primarily from Saturn’s E-ring. Although the instrument was built to detect micron and sub-micron sized particles, nano-sized grains were detected during the flyby at early Jupiter and in the outer environment at Saturn. Fast dust particles with sizes below 10 nm were measured by in-situ impact ionization and mass spectra were recorded. What are the limits of in-situ hypervelocity impact detection and what can be expected with current high-resolution mass spectrometers as flown onboard the missions DESTINY+ or EUROPA? Is the sensitivity of Dust Telescopes sufficient to detect nano-diamonds in interstellar space? This presentation summarizes the current experience of in-situ dust detectors and gives a prediction for future missions. In summary, current Dust Telescopes with integrated high-resolution mass spectrometers are more sensitive than the CASSINI Cosmic Dust Analyzer.

We report on a search for nuclear recoil signals from solar $^8$B neutrinos elastically scattering off xenon nuclei in XENON1T data, lowering the energy threshold from 2.6 keV to 1.6 keV. We develop a variety of novel techniques to limit the resulting increase in backgrounds near the threshold. No significant $^8$B neutrino-like excess is found in an exposure of 0.6 t $\times$ y. For the first time, we use the non-detection of solar neutrinos to constrain the light yield from 1-2 keV nuclear recoils in liquid xenon, as well as non-standard neutrino-quark interactions. Finally, we improve upon world-leading constraints on dark matter-nucleus interactions for dark matter masses between 3 GeV/c$^2$ and 11 GeV/c$^2$ by as much as an order of magnitude.

We reported the development of an effective cancer treatment using a multidisciplinary treatment, including photodynamic therapy (PDT) with indocyanine green (ICG) liposomes and a combination of Lentinula edodes mycelia (LEM) and hydrogen gas inhalation therapy. ICG liposomes were prepared by adding 5 mg of ICG to 50 mL liposomes. Later, 25 mL of ICG liposomes were diluted with 250 mL of 5% glucose solution and administered intravenously to the patient. We selected the multi-laser delivery system (MLDS), a laser irradiator for performing PDT. Further, the patients received a combination of LEM and hydrogen gas inhalation therapy throughout the treatment. We reported two cases of PDT therapy, one with middle intrathoracic esophagus carcinoma and the other with hypopharyngeal cancer. In the first case, the MLDS laser was directly attached to the endoscope and directed to the cancer area with wavelengths of 810 nm. After the treatment, a biopsy demonstrated no tumor recurrence. In the second case, the patient was treated with endovascular PDT using ICG liposomes and MLDS fiber optics. Later, tumor shrinkage was demonstrated after the first round and disappeared after six months. In conclusion, the present findings suggest that the effect of PDT using ICG liposomes with LEM and hydrogen gas may eradicate cancer without burdening patients by enhancing tumor immunity.

To identify prognostic factors for TAFRO syndrome, a rare inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. Data of patients with TAFRO syndrome were extracted from a Japanese patient registry. Patients were divided into groups according to the clinical and laboratory parameters at initial presentation. Cut-off values for the laboratory parameters were determined using receiver operating characteristic curve analysis and by clinical relevance. Patient survival was analyzed by the Kaplan–Meier method. Univariable analysis was performed using log-rank tests. Multivariable analyses were performed with the logistic regression model and the Cox-proportional hazards model. We extracted the data of 83 patients with TAFRO syndrome from the registry. Univariable analysis identified several potential prognostic factors. Of these factors, age ≥ 60 years and D-dimer ≥ 18 μg/dL remained significant predictors of poor overall survival in the multivariable Cox-proportional hazards model. Based on these results, we developed a simple prognostic scoring system for TAFRO syndrome (TS-PSS). Patients in our cohort were stratified into low, intermediate, and high-risk groups by the TS-PSS. This system should be verified with independent patient cohorts in future studies. Supplementary Information The online version contains supplementary material available at 10.1007/s12185-021-03159-x.

The Japanese fisheries, aquaculture, and seafood sectors have been undergoing continuous transformation affected by economic downturns due to the new coronavirus (COVID-19) pandemic. Analyses of the COVID-19 impacts on fishery, aquaculture and seafood sectors in six sites in different parts of Japan exhibit that the impacts of the economic recession due to the pandemic differ between sectors, species, and local communities. The impacts of the COVID-19 pandemic were multiplied by other national and international policy changes as well as other factors such as fish stock depletion and the possible relocation of fish stocks due to sea water temperature change. Stagnating demand for fisheries may give incentives to reinforce conservation and introduce new schemes aimed at seafood sustainability. There can be, however, a possible driver for a vicious cycle that induces overfishing and fish price deterioration. Stakeholder ingenuity and policy innovation are required to achieve sustainable fisheries.

The dual spacecraft mission BepiColombo is the first joint mission between the European Space Agency (ESA) and the Japanese Aerospace Exploration Agency (JAXA) to explore the planet Mercury. BepiColombo was launched from Kourou (French Guiana) on October 20th, 2018, in its packed configuration including two spacecraft, a transfer module, and a sunshield. BepiColombo cruise trajectory is a long journey into the inner heliosphere, and it includes one flyby of the Earth (in April 2020), two of Venus (in October 2020 and August 2021), and six of Mercury (starting from 2021), before orbit insertion in December 2025. A big part of the mission instruments will be fully operational during the mission cruise phase, allowing unprecedented investigation of the different environments that will encounter during the 7-years long cruise. The present paper reviews all the planetary flybys and some interesting cruise configurations. Additional scientific research that will emerge in the coming years is also discussed, including the instruments that can contribute. Open Access funding provided by Istituto Nazionale di Astrofisica within the CRUI-CARE Agreement. Peerreview

Oxidative stress owing to an imbalance between reactive oxygen species and antioxidants, such as coenzyme Q10 (CoQ10), is a major contributor to male infertility. We investigated the effects of the reduced form of CoQ10 (ubiquinol) supplementation on semen quality in dogs with poor semen quality. Three dogs received 100 mg of ubiquinol orally once daily for 12 weeks. Semen quality, serum testosterone, and seminal plasma superoxide dismutase (SOD) activity were examined at 2-week intervals from 2 weeks before ubiquinol supplementation to 4 weeks after the treatment. Ubiquinol improved sperm motility, reduced morphologically abnormal sperm, and increased seminal plasma SOD activity; however, it had no effect on testosterone level, semen volume, and sperm number. Ubiquinol supplementation could be used as a non-endocrine therapy for infertile dogs.

An in-situ cosmic-dust instrument called the Mercury Dust Monitor (MDM) had been developed as a part of the science payload for the Mio (Mercury Magnetospheric Orbiter, MMO) stage of the joint European Space Agency (ESA)–JAXA Mercury-exploration mission. The BepiColombo spacecraft was successfully launched by an Ariane 5 rocket on October 20, 2018, and commissioning tests of the science payload were successfully completed in near-earth orbit before injection into a long journey to Mercury. MDM has a sensor consisting of four plates of piezoelectric lead zirconate titanate (PZT), which converts the mechanical stress (or strain) induced by dust-particle impacts into electrical signals. After the commencement of scientific operations, MDM will measure the impact momentum at which dust particles in orbit around the Sun collide with the sensor and record the arrival direction. This paper provides basic information concerning the MDM instrument and its predicted scientific operation as a future reference for scientific articles concerning the MDM’s observational data.

Chronic kidney disease is a prognostic factor for cardiovascular disease. Worsening renal function (WRF), specifically, is an important predictor of mortality in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI). We evaluate the prognostic impact of mid-term WRF after PCI on future cardiovascular events. We examined the renal function data of 1086 patients in the first year after PCI using the SHINANO 5-year registry. Patients were divided into two groups, mid-term WRF and non-mid-term WRF, and primary outcomes were major adverse cardiovascular events (MACE) and death. Mid-term WRF was defined as an increase in creatinine (≥ 0.3 mg/dL) in the first year after PCI. Mid-term WRF was found in 101 patients (9.3%), and compared to non-mid-term WRF, it significantly increased the incidence of MACE (p p p = 0.001). Furthermore, mid-term WRF patients had higher incidence of future heart failure (p p = 0.01). Patients with both mid-term WRF and chronic kidney disease had increased MACE compared to patients with either condition alone (p p p

XENONnT is a dark matter direct detection experiment, utilizing 5.9 t of instrumented liquid xenon, located at the INFN Laboratori Nazionali del Gran Sasso. In this work, we predict the experimental background and project the sensitivity of XENONnT to the detection of weakly interacting massive particles (WIMPs). The expected average differential background rate in the energy region of interest, corresponding to (1, 13) keV and (4, 50) keV for electronic and nuclear recoils, amounts to 12.3 ± 0.6 (keV t y)-1 and (2.2± 0.5)× 10−3 (keV t y)-1, respectively, in a 4 t fiducial mass. We compute unified confidence intervals using the profile construction method, in order to ensure proper coverage. With the exposure goal of 20 t y, the expected sensitivity to spin-independent WIMP-nucleon interactions reaches a cross-section of 1.4×10−48 cm2 for a 50 GeV/c2 mass WIMP at 90% confidence level, more than one order of magnitude beyond the current best limit, set by XENON1T . In addition, we show that for a 50 GeV/c2 WIMP with cross-sections above 2.6×10−48 cm2 (5.0×10−48 cm2) the median XENONnT discovery significance exceeds 3σ (5σ). The expected sensitivity to the spin-dependent WIMP coupling to neutrons (protons) reaches 2.2×10−43 cm2 (6.0×10−42 cm2).

Cardiac implantable electronic devices (CIEDs) offer heart failure (HF) diagnostic information, including intrathoracic impedance (ITI) or physical activity (PA). However, few studies have evaluated the utility of these parameters measured by CIEDs with CorVue algorithm. The purpose of this study was to investigate the relationship between ITI alerts triggered by the CorVue algorithm and HF development. We also examined the association between device-measured PA and ITI alerts associated with HF development. We retrospectively studied consecutive patients with CIEDs equipped with CorVue algorithm, which were implanted between June 1, 2011 and August 31, 2019. These patients were divided into two groups: patients with decreased ITI followed by the ITI alerts (ITI alert group) and those without the alerts (non-ITI alert group). There were 35 and 14 patients in the ITI and non-ITI alert groups, respectively. A total of 96 ITI alerts were observed. ITI alerts associated with HF development were observed in 21% (20/96); whereas, ITI alerts not associated with HF development were observed in 79% (76/96). Accurate device-measured PA was confirmed in 76 ITI alerts, which consisted of 30 alerts with lower PA and 46 alerts without lower PA. ITI alerts associated with HF development were observed in 30% (9/30) of the alerts with lower PA, whereas observed only in 6.5% (3/46) of the alerts without lower PA. In conclusion, the CorVue ITI alerts indicated a high false-positive rate. However, device-measured PA may be useful to determine whether ITI alerts are associated with HF development or not, which was attributed to the high negative predictive value.

The Destiny+ mission (Demonstration and Experiment of Space Technology for Interplanetary voyage Phaethon fLyby and dUst Science) has been selected as part of its M-class Space Science Program by the Japanese space agency JAXA/ISAS and is set to launch in 2023/2024. The mission target is the active asteroid (3200) Phaethon with a projected flyby in early 2028. The scientific payload consists of two cameras (the Telescopic Camera for Phaethon, TCAP, and the Multi-band Camera for Phaethon, MCAP), and the Destiny+ Dust Analyzer (DDA). DDA is the technological successor to the Cosmic Dust Analyzer (CDA) aboard Cassini-Huygens, which prominently investigated the dust environment of the Saturnian system. The DDA sensor is designed as a combination of impact ionization time-of-flight mass spectrometer and trajectory sensor, which will allow for the analysis of sub-micron and micron sized dust particles with respect to their composition (mass resolution m/Δm ≈ 100-150), mass, electrical charge, velocity (about 10% accuracy), and impact direction (about 10° accuracy). Besides attempting to sample the impact-generated dust cloud around Phaethon during the flyby, DDA will be actively observing the interplanetary & interstellar dust environment over the roughly four years spanning cruise phase from the Earth-Moon system through interplanetary space. After launch into a GTO-like orbit, Destiny+ will first employ its solar-electric propulsion system to spiral up to the lunar orbit within about 18 months, followed by a series of lunar swingbys and interim coasting phases in distant cislunar space, accumulating momentum to leave the Earth-Moon system at high excess velocity. The subsequent roughly 2-year interplanetary transfer to intercept Phaethon will be characterized by moderate orbital eccentricity of up to 0.1 and largely unpowered coasting phases. During these four years, the DDA sensor will benefit from a maximum pointing coverage range enabled by its dual-axis pointing mechanism and spacecraft attitude flexibility (during times of unpowered flight). This will allow for exhaustive mapping and analysis of the different interplanetary dust populations, as well as interstellar dust encountered in the region between 0.9-1.1 AU. Here, we give a progress report on the science planning efforts for the 4-year transfer phase. We present a tentative observation timeline that assigns scientific campaigns to different phases of the mission, taking into account results of various dust models, as well as operational and technical constraints.

Exploring the icy moons of Jupiter: The Ganymede Laser Altimeter (GALA) for ESA’s JUICE Mission Fabian Lüdicke (1), Hauke Hussmann (1), Kay Lingenauber (1), Reinald Kallenbach (1), Keigo Enya (2), Masanori Kobayashi (3), Nicolas Thomas (4), Luisa Lara (5), Kazuyuki Touhara (2) and the GALA team. (1) DLR Institute of Planetary Research, Berlin, Germany (fabian.luedicke@dlr.de), (2) ISAS/JAXA, (3) Chiba Institute of Technology, Japan, (4) Physikalisches Institut, University of Bern (UBE), (5) CSIC, Instituto de Astrofísica de Andalucía (IAA), Granada, Spain Abstract The Ganymede Laser Altimeter (GALA) is one of ten instruments selected for ESA’s Jupiter Icy Moons Explorer (JUICE) mission. We will present an overview on the scientific goals as well as on the status of the instrument development and performance analysis. Introduction ESA’s JUICE mission will explore Jupiter, its magnetosphere and satellites first in orbit around Jupiter before going finally into polar orbit around Ganymede [1]. GALA is one of ten payloads on-board the spacecraft and is developed under responsibility of the DLR Institute of Planetary Research in collaboration with industry and institutes from Germany, Japan, Switzerland and Spain. Its major objectives are to measure the surface topography and the tidal deformation of the satellite. The JUICE Mission JUICE (Jupiter Icy Moons Explorer) will be the first orbiter around a moon (other than Earth’s moon) in solar system exploration. Its launch is planned for May/June 2022 followed by an interplanetary cruise of 7.6 years. Jupiter orbit insertion will take place by the end of 2029. An orbit maneuver will bring the spacecraft into a 500-km circular orbit in which it will be staying for at least 132 days until end of nominal mission. The latter phase will be the main period for GALA taking data. In addition data will be taken at Europa, Ganymede, and Callisto at closest approaches of flybys in the Jupiter orbiting phase. GALA Science GALA has two main objectives: (1) by range measurements it shall obtain Ganymede’s topography on global, regional and local scales. This will reveal how surface features have formed and how they are connected with the shallow interior ice shell. Global shape measurements will tell us whether the satellite is in hydrostatic state with respect to rotational and tidal forces. (2) Obtaining range measurements distributed in time along the orbital cycle, tidal variations of surface elevations will be measured. The tidal amplitudes are indicative for the presence of a subsurface ocean and would (together with complementary measurements) constrain the ice-I shell thickness [2]. GALA GALA is a single-beam altimeter: a laser pulse (at 1064 nm wavelength) is emitted by using an actively Q-switched Nd:YAG laser firing at 30 Hz in nominal operation. A small fraction of the pulse is guided through fiber optics onto the detector characterizing the outgoing pulse and time of emission. After about 3 msec the Lambertian reflection of the pulse from the surface is received by a aperture telescope and transferred to the detector, an Avalanche Photo Diode. The signal is digitized at a sampling rate of 200 MHz and transferred to the range finder module, which determines (a) the time of flight between the emission and receiving of the pulse (b) the pulse shape, in particular the pulse-width, and (c) the energy of the received pulse. From the time of flight of the wave-package and the spacecraft position and attitude, the distance for each shot can be converted into height above a reference surface in post-processing of the data. (1) (2) (3) Figure 1: (1) GALA Tranceiver, (2) Electronics Unit (ELU), (3) Laser Electronics Unit (LEU) In 2019 the GALA EM (Engineering Model) was delivered to Airbus Defence and Space Toulouse and was successfully integrated into the JUICE EM and tested. The EM is used to test the functionality of GALA; it can be operated only under ambient conditions. Later it will be used as a ground reference model for checks for the Flight Model. For the GALA delivery in 2021 the different GALA flight model subsystems are currently tested and integrated at DLR, and at industries in Japan (Meisei) and Germany (Hensoldt Optronics). Flight hardware of the Power converter Module (PCM) and the Range Finder Module have been received from our partner institutes in Spain (IAA, CSIC) and Switzerland (UBE). The main units of GALA are the TRU, the LEU and the ELU, see Figure 1. The TRU consists of the laser/detector system, including an Avalanche Photo Diode. ELU includes the main CPU, Data Processing Module, Range Finder Module for the analysis of the laser pulses and the Power Converter Module which provides the power. A detailed description of GALA can be found in [3]. All parts were tested in terms of functionality and performance, here in particular the detector. Besides electrical testing a big part is the testing of the on-board software, the Application Software. Mainly it manages the commanding of the above mentioned parts, the memory management, FDIR (Fault Detection Isolation Recovery) and the interface (I/F) to the spacecraft (S/C). For I/F testing to the S/C a SIS (Spacecraft Interface Simulator) is used to check the GALA commanding and the data output. After testing at DLR the above mentioned GALA parts will be assembled to the GALA PFM at Hensoldt Optronics Oberkochen. Here additional tests will take place like thermal vacuum tests, EMC and further functional testing, especially for the laser system, but also for the complete system before it will be delivered for final integration into the JUICE spacecraft in 2021. References [1] Grasset, O. and 17 colleagues (2013), JUpiter ICy moons Explorer (JUICE): an ESA mission to orbit Ganymede and to characterise the Jupiter system, Planet. Space Sci., 78, 1-21. [2] Steinbrügge, G., A. Stark, H. Hussmann, F. Sohl, and J. Oberst (2015), Measuring tidal deformations by laser altimetry. A performance model for the Ganymede Laser Altimeter, Planet. Space Sci., 117, 184-191. [3] Hussmann, H. and 38 colleagues 2019. The Ganymede Laser Altimeter (GALA): key objectives, instrument design, and performance. CEAS Space Journal (Special Issue on Space Lidar and Space Optics) 11, 381 – 390.

We report results from searches for new physics with low-energy electronic recoil data recorded with the XENON1T detector. With an exposure of 0.65 t-y and an unprecedentedly low background rate of $76\pm2$ events/(t y keV) between 1 and 30 keV, the data enables sensitive searches for solar axions, an enhanced neutrino magnetic moment, and bosonic dark matter. An excess over known backgrounds is observed at low energies and most prominent between 2 and 3 keV. The solar axion model has a 3.4$\sigma$ significance, and a 3D 90% confidence surface is reported for axion couplings to electrons, photons, and nucleons. This surface is inscribed in the cuboid defined by $g_{ae}, Comment: 26 pages, 15 figures. v2 added Ar37 background discussion and best-fit mass of bosonic dark matter, v3 updated Ar37 discussion, tritium estimation, and solar axion energy spectrum. Data in Fig. 2, 4, and 15, including unbinned energy points in Fig. 4, are available in 10.5281/zenodo.4088778