An analog-AI chip for energy-efficient speech recognition and transcription.

Models of artificial intelligence (AI) that have billions of parameters can achieve high accuracy across a range of tasks1,2, but they exacerbate the poor energy efficiency of conventional general-purpose processors, such as graphics processing units or central processing units. Analog in-memory computing (analog-AI)3-7 can provide better energy efficiency by performing matrix-vector multiplications in parallel on 'memory tiles'. However, analog-AI has yet to demonstrate software-equivalent (SWeq) accuracy on models that require many such tiles and efficient communication of neural-network activations between the tiles. Here we present an analog-AI chip that combines 35 million phase-change memory devices across 34 tiles, massively parallel inter-tile communication and analog, low-power peripheral circuitry that can achieve up to 12.4 tera-operations per second per watt (TOPS/W) chip-sustained performance. We demonstrate fully end-to-end SWeq accuracy for a small keyword-spotting network and near-SWeq accuracy on the much larger MLPerf8 recurrent neural-network transducer (RNNT), with more than 45 million weights mapped onto more than 140 million phase-change memory devices across five chips.

Search for Periodic Time Variations of the Solar

We report a search for time variations of the solar ^{8}B neutrino flux using 5804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a dataset comprising five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this dataset to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53±0.35)%, and a perihelion shift of (-1.5±13.5) days.

Search for the Majorana Nature of Neutrinos in the Inverted Mass Ordering Region with KamLAND-Zen.

The KamLAND-Zen experiment has provided stringent constraints on the neutrinoless double-beta (0νßß) decay half-life in ^{136}Xe using a xenon-loaded liquid scintillator. We report an improved search using an upgraded detector with almost double the amount of xenon and an ultralow radioactivity container, corresponding to an exposure of 970 kg yr of ^{136}Xe. These new data provide valuable insight into backgrounds, especially from cosmic muon spallation of xenon, and have required the use of novel background rejection techniques. We obtain a lower limit for the 0νßß decay half-life of T_{1/2}^{0ν}>2.3×10^{26} yr at 90% C.L., corresponding to upper limits on the effective Majorana neutrino mass of 36-156 meV using commonly adopted nuclear matrix element calculations.

Precision Analysis of the

We present a precision analysis of the ^{136}Xe two-neutrino ßß electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ßß rate allows us to measure the ratio of the leading and subleading 2νßß nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ßß decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ßß NMEs.

Role of red blood cells in the anemia-associated bleeding under high shear conditions.

BACKGROUND: Red blood cells (RBCs) contribute to hemostasis under blood-flow, and anemia might contribute to a hemorrhagic diathesis. The majority of current laboratory techniques to assess hemostasis do not consider the effects of RBCs. An assay to determine the role of RBCs in hemostasis could be beneficial for clinical management. OBJECTIVES: To investigate the influence of RBCs in hemostasis. METHODS: Hemostasis was investigated using a novel microchip flow-chamber system (T-TAS® ) in an anemic patient with von Willebrand disease. Subsequently, the effects of RBCs in total thrombus analysis system (T-TAS) were examined using reconstituted whole blood at various hematocrit levels. RESULTS: In vivo: When the patient was anemic and demonstrated persisted hemorrhagic symptoms despite the maintained adequate von Willebrand factor ristocetin cofactor activity levels, thrombus formation determined by T-TAS was delayed. However, transfusions of RBCs resolved bleeding symptom and, accordingly, the thrombus formation in T-TAS improved. In vitro: Thrombus formation determined by T-TAS at 1000 s-1 was dose-dependent on hematocrit (the time to reach 10 kPa (T10 ): 10.0 ± 0, 9.5 ± 1.4, 6.7 ± 2.4, 2.8 ± 1.6 min at hematocrits of 0%, 12.5%, 25% and 50%, respectively). Markedly defective thrombus formation (T10 >10 min) was confirmed at a hematocrit <25% at 2000 s-1 . CONCLUSION: Red blood cells play an essential role in hemostasis under high shear, and RBC transfusions could be effective for refractory bleeding in patients with anemia. T-TAS measurements appear to reflect the hemostatic consequences of diminished red cell numbers under blood-flow, and could provide a valuable means for monitoring patients.

Usefulness of the Total Thrombus-Formation Analysis System (T-TAS) in the diagnosis and characterization of von Willebrand disease.

INTRODUCTION: The heterogeneity of von Willebrand disease (VWD) makes its diagnosis a difficult task. METHODS: We report here on the usefulness of a microchip-based flow-chamber system, the total thrombus-formation analysis system (T-TAS), in the identification and characterization of VWD. Thirty VWD patients and 20 healthy subjects were studied with the T-TAS platelet (PL) and atherome (AR) microchips developed for the in vitro assessment of platelet thrombus formation and fibrin-rich platelet thrombus formation respectively. RESULTS: Samples from severe type 1 VWD, characterized by von Willebrand factor (VWF) levels below 10 U dL-1 , failed to occlude either the PL or the AR chip capillaries, while the occlusion times were normal in patients with mild type 1 VWD (VWF above 25 U dL-1 ). PL and/or AR chip occlusion occurred, but took longer than normal, for samples from type Vicenza and type 1 VWD patients, whose VWF levels ranged between 10 and 25 U dL-1 . No PL or AR chip capillary occlusion was seen for samples from patients with type 2A or 2B VWD featuring the absence of large VWF multimers, whereas no abnormalities emerged for type 2B patients with normal multimer patterns. CONCLUSION: The T-TAS appears to be sensitive mainly to plasma VWF concentration and the presence of large multimers. Failure of the PL and AR chips to become occluded points to a lack of large VWF multimers, or type 1 VWD with VWF levels below 10 U dL-1 . Although the T-TAS does not assure a precise VWD diagnosis, it does point us in the right direction, and thus seems a useful global preliminary test.

Comprehensive evaluation of haemostatic function in von Willebrand disease patients using a microchip-based flow chamber system.

The diagnosis of von Willebrand disease (VWD) is difficult due to the wide spectrum of clinical phenotypes associated with this disorder. We have analysed and characterized haemostatic function in VWD patients using a microchip-based flow chamber system. Microchips coated with either collagen [platelet (PL)-chip] or collagen/thromboplastin [atherome (AR)-chip] were used to evaluate platelet thrombus formation at 1000 s(-1) and fibrin-rich platelet thrombus formation at 240 s(-1) respectively. Blood samples from an asymptomatic patient with VWD type 1 [von Willebrand factor (VWF): RCo 3.2%; bleeding score (BS 2] displayed normal thrombus formation in both PL- and AR-chips, whereas blood from a symptomatic type 1 patient (VWF: RCo 14%, BS 9) had significantly delayed capillary occlusion. Nearly complete suppression of the flow pressure increase was observed in symptomatic patients with VWD type 2A (BS 13) and 2N (BS 27), whereas no flow pressure was found for the type 3 patient (BS 6). Fibrin-rich platelet thrombus formation was only weakly increased by the in vitro addition of factor VIII (FVIII) to blood samples from the type 3 patient, but was normalized by the addition of VWF/FVIII. The in vivo effects of treatment with desmopressin or VWF/FVIII for the symptomatic patients were analysed using two types of microchips. The PL-chip was highly sensitive for patients' VWF-mediated platelet functions, whereas the AR-chip allowed assessment of overall haemostatic ability, including sensitivity to both VWF and FVIII. The combined analysis with PL- and AR-chips may be potentially useful for the diagnosis of VWD based on clinical phenotypes, and for monitoring drug effects.

Search for bosonic superweakly interacting massive dark matter particles with the XMASS-I detector.

Bosonic superweakly interacting massive particles (super-WIMPs) are a candidate for warm dark matter. With the absorption of such a boson by a xenon atom, these dark matter candidates would deposit an energy equivalent to their rest mass in the detector. This is the first direct detection experiment exploring the vector super-WIMPs in the mass range between 40 and 120 keV. With the use of 165.9 day of data, no significant excess above background was observed in the fiducial mass of 41 kg. The present limit for the vector super-WIMPs excludes the possibility that such particles constitute all of dark matter. The absence of a signal also provides the most stringent direct constraint on the coupling constant of pseudoscalar super-WIMPs to electrons. The unprecedented sensitivity was achieved exploiting the low background at a level 10(-4) kg-1 keVee-1 day-1 in the detector.

Successful hyperbaric oxygen therapy for refractory BK virus-associated hemorrhagic cystitis after cord blood transplantation.

BK virus-associated hemorrhagic cystitis (BKV-HC) is a common and major cause of morbidity in recipients of allogeneic hematopoietic stem cell transplantation. A 32-year-old woman developed severe BKV-HC on day 24 after cord blood transplantation (CBT). Despite supportive therapies - such as hyperhydration, forced diuresis, and urinary catheterization - macroscopic hematuria and bladder irritation persisted for over a month. Hyperbaric oxygen (HBO) therapy at 2.1 atmospheres for 90 min per day was started on day 64 after CBT. Macroscopic hematuria resolved within a week, and microscopic hematuria was no longer detectable within 2 weeks. Hematuria did not recur after 11 sessions of HBO therapy, and no significant side effects were observed during or after treatment. HBO therapy could thus be useful in controlling refractory BKV-HC after CBT.

Relative incidences and outcomes of Clostridium difficile infection following transplantation of unrelated cord blood, unrelated bone marrow, and related peripheral blood in adult patients: a single institute study.

BACKGROUND: Clostridium difficile is a major cause of nosocomial diarrhea. The incidence and prognosis of C. difficile-associated diarrhea (CDAD) has not yet been assessed in adult patients after unrelated cord blood transplantation (uCBT). METHODS: The medical records of 135 adult unrelated cord blood transplant recipients were reviewed retrospectively to investigate the clinical features of CDAD after uCBT. These data were compared to medical records of 39 unrelated bone marrow transplant recipients and 27 related peripheral blood stem cell transplant recipients as controls. RESULTS: A total of 17 recipients developed CDAD, with onset occurring at a median of 22 days (range, 0-56 days) after transplantation. Among the unrelated cord blood transplant recipients, 11 (9%) developed CDAD. These results were comparable with those of CDAD after unrelated bone marrow transplantation (uBMT) (2/39, 6%) and related peripheral blood stem cell transplantation (rPBSCT) (4/27, 16%) (P=0.37). Fifteen of the infected recipients were successfully treated with oral metronidazole, vancomycin, or cessation of antibiotics. The remaining 2 recipients who developed CDAD after uCBT died of other causes. The development of CDAD did not negatively affect overall survival after uCBT. CONCLUSIONS: These data indicate that the incidence and prognosis of CDAD after uCBT are comparable with those after uBMT and rPBSCT.

Carcinoma of the external auditory canal: histological and treatment groups.

OBJECTIVE: Evaluation of the clinical and pathological factors associated with the treatment and outcomes of external auditory canal (EAC) carcinomas. METHODOLOGY: A retrospective review of clinical and pathological analysis was performed on 23 patients who were histologically diagnosed with EAC carcinomas and treated at Hamamatsu University hospital. We evaluated the clinical staging, treatment methods, pathological diagnosis (particularly squamous cell carcinoma, SCC), and patient outcomes. Main outcome measures include staging, treatment procedures, pathological features, and estimated survival rates. RESULTS: The 5-year overall survival (OS) of study participants was 75.2% and the 10-year OS was 60.2% using the Kaplan-Meier method. The prognosis for SCC was poor compared with other carcinomas (p= 0.0462). The prognoses for SCC patients after treatment with surgery alone and after postoperative radiotherapy or chemoradiotherapy were significantly better than for patients with unresectable tumours (p = 0.0004 and p = 0.0001, respectively). There was no significant difference among the four tumour stage groups. Information about patients' survival status was obtained after a median follow-up period of 57.5 months (range, 7-151 months). CONCLUSION: Our survival analysis data for carcinoma of the EAC demonstrates that SCC and unresectable cases are associated with poor outcomes. Outcomes for patients with operable disease more closely parallel the survival curves of patients with advanced stage T4 disease. Patients with SCC should be strictly categorized as cases with severe disease.

Time-lapse observation of the dedifferentiation process in mouse chondrocytes using chondrocyte-specific reporters.

OBJECTIVE: When chondrocytes prepared from cartilage are expanded in monolayer culture, fibroblast-like cells gradually prevail. Although these prevailing fibroblast-like cells are believed to emerge because of the dedifferentiation of chondrocytes, the definite origin of the prevailing fibroblast-like cells has not been determined. We herein examined whether the prevailing non-chondrocytic cells observed after monolayer expansion culture arise from dedifferentiating chondrocytes or are the result of the overgrowth of fibroblasts that are present at the start of the culture. We also evaluated whether chondrocytes dedifferentiate because they proliferate or because they are cultured in monolayers. METHODS: Chondrocytes were prepared from Col11a2-EGFP transgenic mice and Col11a2-Cre; R26-stop(flox)-EYFP transgenic mice, which respectively express enhanced green fluorescent protein (EGFP) and Cre specifically in chondrocytes under the control of Col11a2 promoter/enhancer sequences. Col11a2-Cre; R26-stop(flox)-EYFP mice express enhanced yellow fluorescent protein (EYFP) only in cells which express or used to express Cre. We performed a time-lapse observation of the chondrocytes during monolayer expansion culture, and also observed the chondrocytes after treatment with mitomycin C. RESULTS: A time-lapse observation showed that Col11a2-EGFP chondrocytes underwent cell divisions, lost GFP fluorescence, increased cell numbers, and prevailed during the expansion culture. The observation of the Col11a2-Cre; R26-stop(flox)-EYFP chondrocytes confirmed that most of the cells after expansion in monolayer culture had been chondrocytes. Mitotically inactive chondrocytes generated by treatment with mitomycin C still underwent dedifferentiation, thus suggesting that chondrocyte dedifferentiation is not associated with cell division. CONCLUSION: The non-chondrocytic cells that prevail after the monolayer expansion culture of chondrocytes originate from chondrocytes, and are not generated by the overgrowth of fibroblasts that are present at the start of the culture. Chondrocyte dedifferentiation does not appear to be associated with cell division.

Haemodilution-induced changes in coagulation and effects of haemostatic components under flow conditions.

BACKGROUND: Blood flow patterns are important modifiers of platelet interactions with plasma coagulation factors. However, it is not feasible to evaluate rheological effects of haemodilution on coagulation using conventional coagulation testing. METHODS: We evaluated thrombus formation with a microchip-based flow-chamber system using whole blood from 12 healthy volunteers (with/without 40% dilution with saline), and 15 cardiac patients [before/after cardiopulmonary bypass (CPB)] in parallel with thromboelastometry. The in vitro additions of von Willebrand factor (vWF, 1.5 U ml(-1)), prothrombin complex concentrate (PCC, 0.3 U ml(-1)), fibrinogen (2 g litre(-1)), or combined PCC (0.3 U ml(-1)) and fibrinogen (1 g litre(-1)) were examined. Recalcified whole-blood samples were perfused over the microchip coated with collagen and tissue thromboplastin at flow rates of 10 and 3 µl min(-1). RESULTS: Dilution of whole blood led to delayed onset of thrombus formation (Ton), and thrombus growth (T80). Changes relative to baseline values were more extensive at 10 µl min(-1) (≥85% prolongation for Ton and T80) than at 3 µl min(-1) (≥40% prolongation for Ton and T80). Adding vWF accelerated thrombus formation only at 10 µl min(-1), while PCC increased thrombin generation in the thrombus at both flow rates. Fibrinogen increased mural thrombus formation at 3 µl min(-1). Decreased clot strength after dilution was restored by fibrinogen, but not by vWF or PCC on thromboelastometry. Additive effects of fibrinogen and PCC in post-CPB blood were demonstrated by both flow chamber and thromboelastometry. CONCLUSIONS: Blood flow affects thrombus formation after haemodilution and subsequent haemostatic component interventions, with differential effects at low and high flow.

Evaluation of a novel flow chamber system to assess clot formation in factor VIII-deficient mouse and anti-factor IXa-treated human blood.

Blood flow properties play important roles in the regulation and formation of thrombus. To evaluate the influence of blood flow on thrombus formation in haemophilia, whole blood samples were obtained from FVIII-deficient (FVIII(-/-) ) and wild-type (FVIII(+/+) ) mice (n = 6 respectively), and from six human volunteers. Anti-FIXa aptamer was added to human blood to model acquired haemophilia B. Recalcified whole blood samples containing corn trypsin inhibitor and danaproid were perfused over the microchip coated with collagen and tissue thromboplastin at shear rates of 1100 and 110 s(-1) . Thrombus formation in the capillary was quantified by monitoring flow pressure changes. The intervals to 5 kPa (T(5) ) and 40 k Pa (T(40) ) reflect the onset and growth of thrombus formation respectively. Furthermore, fibrin and platelets in thrombi were quantified by immunostaining. T(5) at both shear rates were similar in FVIII(-/-) and FVIII(+/+) mice. T(40) of FVIII(-/-) mice (1569 ± 565 s) was significantly delayed compared with FVIII(+/+) mice (339 ± 78 s) at 110 s(-1) (P < 0.05), but not at 1100 s(-1) . The delay was normalized by adding human FVIII (2 IU mL(-1) ). Similarly, adding anti-FIXa aptamer to human blood prolonged T(40) at 110 s(-1) (P < 0.01), but not at 1100 s(-1) . Impaired production of fibrin due to anti-FIXa aptamer at 110 s(-1) was shown in the immunostained thrombus. Our perfusion experiments demonstrated that shear rates influence thrombus formation patterns in haemophilia, and that reduced activity of intrinsic tenase (FIXa-FVIIIa) becomes evident under venous shear rates.

Effects of renal function on the pharmacokinetics and pharmacodynamics of prophylactic cefazolin in cardiothoracic surgery.

The purpose of this investigation was to study the effects of renal function on the pharmacokinetics and pharmacodynamics (PK-PD) of free cefazolin administered prophylactically in cardiothoracic surgery. Patients received an initial 2-g dose of cefazolin, followed by 1-g doses 6, 12, 18 and 24 h after the first dose. In patients who underwent cardiopulmonary bypass, 1 g was added to the priming solution. In 35 patients with a normal estimated creatinine clearance (CLcr) ≥50 ml/min, a free cefazolin concentration <4 µg/ml was observed in 11.4, 5.7 and 54.3% of patients before the second dose, at the end and 24 h after operation, respectively. In contrast, only 7.4% of 27 patients with CLcr <49 ml/min had a free cefazolin concentration <4 µg/ml 24 h after the operation. There was a high negative correlation between CLcr and time above the target minimal inhibitory concentration (MIC) when the CLcr was <50 ml/min (r(2) = 0.807), and no correlation when the CLcr was ≥50 ml/min. Renal function has a significant impact on the PK-PD of prophylactic cefazolin in cardiothoracic surgery. The postoperative drug dosing intervals should be <6 h in order to achieve a 100% time above the MIC in patients with CLcr ≥ 50 ml/min.

Safety of pre-engraftment prophylactic foscarnet administration after allogeneic stem cell transplantation.

Human herpesvirus-6 (HHV-6) is a major cause of limbic encephalitis with a dismal prognosis after allogeneic hematopoietic stem cell transplantation (SCT). Because our previous trial of preemptive therapy with foscarnet sodium (phosphonoformic acid; PFA) failed to prevent HHV-6 encephalitis, we conducted a prospective study to examine the safety of prophylactic PFA administration and elucidate the changes in the plasma HHV-6 DNA levels in the early post-SCT period. Plasma HHV-6 DNA was measured thrice weekly from day 6. PFA, 90 mg/kg/day, was administered from days 7 to 21 after bone marrow or peripheral blood SCT and to day 25 after umbilical cord blood transplantation. Of the 10 patients enrolled, 2 dropped out of the study, 1 because of early death, and 1 with a low glomerular filtration rate. Grade 3 or greater adverse events occurred in 9 of the 10 prophylactic PFA patients and in 7 of the 10 control patients who had clinical backgrounds similar to the study subjects and underwent SCT during the same period. Neurological disorders developed in none of the study subjects but in 4 of the 10 control patients, including 2 with HHV-6 encephalitis. HHV-6 reactivation occurred in 3 of the 10 study subjects. The prophylactic PFA regimen was thus safe and it may reduce the risk of limbic encephalitis, but is not considered to be potent enough to prevent HHV-6 reactivation.

Successful treatment of Trichosporon fungemia in a patient with refractory acute myeloid leukemia using voriconazole combined with liposomal amphotericin B.

Trichosporon fungemia is a rare and fatal fungal infection that occurs in patients with prolonged neutropenia associated with hematologic malignancies. A 21-year-old male developed Trichosporon fungemia during remission induction therapy for acute myeloid leukemia (AML). Although two courses of induction therapy failed to induce a remission of AML, combination therapy with voriconazole and liposomal amphotericin B (L-AmB) followed by monocyte colony-stimulating factor ameliorated the Trichosporon fungemia and enabled the patient to receive reduced-intensity bone marrow transplantation (BMT) from his human leukocyte antigen-A one-locus mismatched mother. The patient achieved a durable remission after BMT without exacerbation of Trichosporon fungemia. The combination therapy with voriconazole and L-AmB may therefore be useful in controlling Trichosporon fungemia associated with prolonged neutropenia after remission induction therapy for AML.

Effectiveness of the computed analysis of electroglottographic signals in muscle tension dysphonia.

OBJECTIVE: To investigate the usefulness of electroglottography (EGG) parameters in the diagnosis and estimation of efficacy of voice therapy for muscle tension dysphonia (MTD). PATIENTS AND METHODS: Nineteen MTD participants, an equivalent number of dysphonic ('organic') patients with vocal fold lesions and as many normal speakers were enrolled. Acoustic (Ac) and EGG signals during sustained phonation were recorded simultaneously. The period and amplitude perturbation quotient of both signals, the closed quotient (CQ) of EGG signals (mean CQ) and its standard deviation (CQSD) were calculated, and subsequently compared among the three groups. These parameters in the MTD group were compared before and after voice therapy. RESULTS: The perturbation measures of both signals in the MTD group were either as high as or significantly higher than those in the organic group or the control group, respectively. Both the Ac and EGG parameters after therapy significantly decreased. The CQSD, but not mean CQ, also decreased after therapy. CONCLUSION: EGG parameters related to the regularity of vocal fold vibration, but not to the degree of vocal fold contact (mean CQ), are useful for the diagnosis and estimation of voice therapy outcome in MTD.

Penetration of MeV electrons into the mesosphere accompanying pulsating aurorae.

Pulsating aurorae (PsA) are caused by the intermittent precipitations of magnetospheric electrons (energies of a few keV to a few tens of keV) through wave-particle interactions, thereby depositing most of their energy at altitudes ~ 100 km. However, the maximum energy of precipitated electrons and its impacts on the atmosphere are unknown. Herein, we report unique observations by the European Incoherent Scatter (EISCAT) radar showing electron precipitations ranging from a few hundred keV to a few MeV during a PsA associated with a weak geomagnetic storm. Simultaneously, the Arase spacecraft has observed intense whistler-mode chorus waves at the conjugate location along magnetic field lines. A computer simulation based on the EISCAT observations shows immediate catalytic ozone depletion at the mesospheric altitudes. Since PsA occurs frequently, often in daily basis, and extends its impact over large MLT areas, we anticipate that the PsA possesses a significant forcing to the mesospheric ozone chemistry in high latitudes through high energy electron precipitations. Therefore, the generation of PsA results in the depletion of mesospheric ozone through high-energy electron precipitations caused by whistler-mode chorus waves, which are similar to the well-known effect due to solar energetic protons triggered by solar flares.