We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. ...There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non–germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.
•We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.•ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.
Abstract
Background
Coronavirus infections are spreading rapidly worldwide, and primary and middle schools are closed in many countries. After the state of emergency was lifted in Japan, schools have ...reopened, and teachers are conducting face-to-face classes while maintaining safety precautions. This study aimed to assess the factors contributing to infection-related anxiety and educational anxiety among teachers conducting face-to-face classes during the COVID-19 pandemic after schools reopened.
Methods
This questionnaire-based cross-sectional study was conducted with 263 primary and middle school teachers in the Shinagawa area of Tokyo (October 10–30, 2020). The questionnaire assessed the type of school (primary or middle school), sex, age, and factors contributing to infection-related anxiety and educational anxiety that arose from the pandemic. The levels of anxiety and the factors contributing to anxiety were assessed using a 5-point Likert scale ranging from 1 (not at all) to 5 (very anxious).
Results
In an analysis of the data of 237 participants excluding the missing data, many teachers reported feeling infection- and education-related anxiety. A majority of the participants were women (
n
= 152, 64.1%), and the mean age of the participants was 39.8 ± 11.3 years. A stepwise multiple regression analysis identified six factors for infection-related anxiety as significant (
R
2
= 0.61,
p
< 0.001). Among these variables, the largest partial regression coefficient value was reported for the following reason: “I feel anxious because we cannot ensure the safety of teachers themselves or of their families” (β = 0.37,
p
< 0.001). For educational anxiety, four of six reasons were identified as significant (
R
2
= 0.64,
p
< 0.001). Among these, “anxiety about the students’ home situations” (β = 0.41,
p
< 0.001) and “delay in education (students’ side)” (β = 0.27,
p <
0.001) had stronger associations with anxiety compared to the others.
Conclusion
In-person education during the COVID-19 pandemic has caused teachers to experience anxiety. This report provides useful information by highlighting the reasons for infection-related anxiety and educational anxiety that teachers experience in face-to-face classes during a pandemic. Even if the coverage of a COVID-19 vaccine becomes widespread worldwide, we will still be combating COVID-19 infections for at least a few years. Given concerns regarding such infections, to ensure students’ right to education, it is essential to understand why teachers feel anxious and to determine appropriate measures to decrease such anxiety.
The impact of the irradiation side on the cross sections of single-event upsets (SEUs) induced by neutrons was investigated by performing neutron irradiation measurements and simulations. A test ...board equipped with 65-nm bulk 6-T CMOS static random access memories was irradiated by quasi-monoenergetic neutrons, and the number of SEUs was counted. The number of SEUs obtained by the board-side irradiation was approximately 20% to 30% smaller than that obtained by irradiation on the plastic package side. We also investigated the impact of irradiation side on the soft error rates (SERs) obtained with by the terrestrial neutron energy spectrum via a Monte Carlo simulation. The SER obtained from the plastic package side irradiation was approximately twice that obtained for the board side irradiation, indicating that SERs can be reduced by equipping the device with the package side facing downward. Additionally, based on the simulation, the atomic composition of the material placed in front of the memory chip has a considerable influence on the SER because production yields and angular distributions of secondary H and He ions (the main causes of SEUs) depend on the composition. In particular, the existence of hydrides, such as plastic, considerably increases the SER because of the higher production yields of secondary H ions that are generated via elastic scattering of neutrons with hydrogen atoms.
Objectives
Pulmonary endarterectomy (PEA) is an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but postoperative residual hypertension leads to in-hospital mortality. ...Inhaled epoprostenol sodium (PGI
2
) and NO are administered for pulmonary hypertension after cardiothoracic surgery. This prospective study provides the first comparative evaluation of the effects of inhaled PGI
2
and NO on pulmonary hemodynamics, systemic hemodynamics, and gas exchange in patients developing residual pulmonary hypertension after PEA.
Methods
Thirteen patients were randomized to receive either NO (
n
= 6) or PGI2 (
n
= 7) inhalation when pulmonary hypertension persisted after weaning from cardiopulmonary bypass. Hemodynamic and respiratory variables were measured before inhalation of the agent (T0); 30 min (T1), 3 h (T2), and 6 h after inhalation (T3); and the next morning (T4). The NO dose was started at 20 ppm and gradually tapered until extubation, and PGI
2
was administered at a dose of 10 ng kg
−1
min
−1
.
Results
In both groups, mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) significantly decreased over time until T4 (mean PAP:
p
< 0.0001; PVR:
p
= 0.003), while mean systemic arterial blood pressure significantly increased (
p
= 0.028). There were no significant between-group differences in patient characteristics, cardiac index, left atrial pressure, or ratio of arterial oxygen tension to fraction of inspired oxygen. There were no in-hospital deaths.
Conclusions
Both inhaled PGI
2
and NO significantly reduced PAP and PVR without adverse effects on systemic hemodynamics in patients who developed residual pulmonary hypertension after PEA. Inhaled PGI
2
can be offered as alternative treatment option for residual pulmonary hypertension.
Purpose
Very few studies have investigated the efficacy of ganglionated plexus ablation during the conventional maze procedure. In this study, we sought to evaluate its additive effect in reducing ...recurrent atrial fibrillation after concomitant maze surgery.
Methods
A retrospective study was conducted of 79 patients who underwent Cox maze IV concomitantly with open-heart surgery with (GP group) or without (Maze group) ganglionated plexus mapping. All active ganglionated plexuses were ablated. The two groups were compared and their follow-up data were analyzed.
Results
Active ganglionated plexuses were found in 81% of patients who underwent ganglionated plexus mapping. The rates of freedom from atrial fibrillation at 1 year in the GP and Maze groups were 77 and 75%, respectively. The cumulative freedom from atrial fibrillation at follow-up (27.7 ± 17.3 months) was comparable in the two groups (
p
= 0.427). A multivariate analysis revealed that persistent atrial fibrillation for more than 90 months was an independent predictor of recurrent atrial fibrillation.
Conclusion
Ganglionated plexus ablation with Cox maze IV did not reduce the incidence of recurrent atrial fibrillation in comparison to Maze alone.
The standard procedure for aortic aneurysm is still total arch replacement even stentgraft or frozen elephant trunk procedure becomming common. However, the distal anastomosis in the total arch ...replacement, is often difficult with limited surgical view. And bleeding from it requires sugical hemostasis with cardiopulmonary bypass and left thoracotomy, resulting in severe invasive. We report a case of 82-year-old woman, who had an distal anastomotic bleeding, successfully treated by endovascular aortic repair with antegrade stent-graft insertion via the branch of total arch graft. It is rare to report that hemostasis was performed with stent graft for bleeding at the anastomotic site during sugery, and this could be alternative technique.
The authors report a 71-year-old male with descending thoracic aortic aneurysm and multiple risk factors (aortoiliac occlusive disease, obesity, ascending aorta dilatation, and history of left ...ventriculoperitoneal shunt for hydrocephalus) who was treated with thoracic endovascular aortic repair (TEVAR) via left common carotid artery (LCCA) access and left axillary–carotid artery (Ax–CA) bypass; this approach shortened the LCCA clamp time during the procedure. The patient was discharged without any complications. TEVAR via LCCA access with left Ax–CA bypass is a useful and safe procedure for patients in whom conventional femoral artery access is not feasible.
Zonation has been a major focus of intertidal ecology. In general, sandy beaches are thought to have three zones (supralittoral, littoral, and sublittoral zones). In the present study, 41 areas of ...sandy beaches were surveyed along the Japan Sea coast of Honshu (from Aomori to Yamaguchi Prefectures) characterized by a small tidal range, large seasonal fluctuations in the mean tide level, and harsh wind-driven waves in winter, and the applicability of the three-zone scheme was examined. Overall, a total of 316 beach stations were surveyed, 28 taxonomic units were identified, and the most abundant species was the amphipod Haustorioides japonicus. The taxonomic units were grouped using multivariate techniques into a total of 7 assemblages, and the relationship of these assemblages to zonation was examined. Investigation of the indicator species of the 7 assemblages and their vertical position on the beaches showed that one assemblage corresponded to the supralittoral zone (indicators were talitrid amphipods and the isopod Tylos granuliferus). Another assemblage corresponded to the sublittoral zone, and the other five assemblages to the littoral zone. The assemblage of the sublittoral zone tended to disappear on the northern beaches, while one of the littoral assemblages whose indicators included a mysid species, Archaeomysis kokuboi, tended to occur on the northern beaches. Thus, the three-zone scheme can be applied to sandy beaches of the Japan Sea, but there are large variations among the beaches.
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