Estimation of the rupture point of the craniovertebral junction intradural arteriovenous fistula with vessel wall magnetic resonance image and its pathological findings: A case report.

Background: Arteriovenous fistulas (AVFs) of the craniocervical junction (CCJ) and intradural AVFs are often associated with aneurysms and varics, and it is sometimes difficult to identify the ruptured point on radiological images. We report a case in which vessel wall magnetic resonance image (VW-MRI) was useful for identifying the ruptured point at the CCJ AVF. Case Description: A 70-year-old man presented with a sudden onset of headache. He had Glasgow Coma Scale E4V5M6, world federation of neurosurgical societies (WFNS) Grade I. Fisher group 3 subarachnoid hemorrhage and hydrocephalus were found on head computed tomography. Cerebral angiography showed a spinal AVF at the C1 level of the cervical spine. Magnetic resonance image-enhanced motion sensitized driven equilibrium (MSDE-method showed an enhancing effect in part of the AVF draining vein, but the vascular architecture of this lesion was indeterminate. We performed continuous ventricular drainage for acute hydrocephalus and antihypertensive treatment. Cerebral angiography was performed 30days after the onset of the disease, and was revealed an aneurysmal structure in a portion of the AVF draining vein, which VW-MRI initially enhanced. On the 38th day after onset, he underwent direct surgery to occlude the AV fistula and dissect the aneurysmal structure. Histopathology showed that the aneurysmal structure was varices with lymphocytic infiltration, and hemosiderin deposition was observed near the varices. Conclusion: Recently, VW-MRI has been reported to show an association between the enhancement of varices in dural AVF and rupture cases. VW-MRI, especially the enhanced MSDE method, may be useful in estimating the ruptured point in arteriovenous shunt disease.

Effective and stable gene transduction in rhesus macaque iPSCs capable of T-lineage differentiation utilizing the piggyBac system.

Introduction: Genetically modified human induced pluripotent stem cell (iPSC)-based regenerative medicine has substantial potential in the treatment of refractory human diseases. Thus, preclinical studies on the safety and efficacy of these products are essential. Non-human primate (NHP) models such as the rhesus macaque are highly similar to humans in terms of size, lifespan, and immune system, rendering them superior models. However, effective gene transduction in rhesus macaque iPSCs (Rh-iPSCs) remains challenging. In this study, we investigated the effective gene transduction into Rh-iPSCs and its effect on differentiation efficiency. Methods: We established a gene transduction method using the piggyBac transposon vector system. Gene transduced Rh-iPSCs were analyzed for undifferentiated markers. We did teratoma assay to check pluripotency. Gene transduced Rh-iPSCs were differentiated into hematopoietic stem and progenitor cells (HSPCs) and T-cell lineage cells. Additionally, gene transduced Rh-iPSCs were compared the differentiation efficiency with parental Rh-iPSCs. Results: We could establish a gene transduction method using the piggyBac transposon vector system, demonstrating high efficiency and stable transgene expression in Rh-iPSCs. These Rh-iPSCs maintained long-term gene expression while expressing undifferentiated markers. Teratoma assay indicated that these Rh-iPSCs had pluripotency. These Rh-iPSCs could differentiate into HPSCs and T cells that express transgenes. These Rh-iPSCs can differentiate into hematopoietic stem cells and T cells that express transgenes. No significant differences in efficiency of differentiation were observed between parental Rh-iPSCs and these Rh-iPSCs. Conclusions: These results indicate that the piggyBac transposon vector is an excellent gene transfer tool for rhesus macaque iPSCs and could contribute to the advancement of preclinical studies using rhesus macaque iPSCs.

Production of Mn-Ga Magnets.

Mn-based magnets are known to be a candidate for use as rare-earth-free magnets. In this study, Mn-Ga bulk magnets were successfully produced by hot pressing using the spark plasma sintering method on Mn-Ga powder prepared from rapidly solidified Mn-Ga melt-spun ribbons. When consolidated at 773 K and 873 K, the Mn-Ga bulk magnets had fine grains and exhibited high coercivity values. The origin of the high coercivity of the Mn-Ga bulk magnets was the existence of the D022 phase. The Mn-Ga bulk magnet consolidated at 873 K exhibited the highest coercivity of 6.40 kOe.

Pandemic-Induced Occupational Disruption and Association With Health in Japanese Community-Dwelling Older Adults.

The COVID-19 pandemic caused occupational disruption and adverse health outcomes in community-dwelling older adults. This study aimed to investigate the extent of occupational disruption in older adults and its relationship to health-related quality of life (QOL), depression, and frailty. In this cross-sectional study, retention rates in four activity domains and relationships with health outcomes were examined in Japanese older adults aged ≥65 years (n=163) using canonical correlation analysis (CCA) and mixed linear models. More than 25% of activities were restricted compared with the pre-pandemic period. CCA demonstrated correlations between four retention rates and health outcomes (canonical correlation = .42, p = .0003). Retention in instrumental and social activities independently predicted QOL and depression (p < .05). This study highlights that different activities may have different effects on health outcomes and can provide community occupational therapy practitioners with a perspective to assess occupational disruption and identify activities for intervention.

Pandemic-Induced Changes of Daily Routine and Its Association with Health for Japanese Older AdultsWe investigated the changes in daily activity due to the COVID-19 pandemic among community-dwelling older adults in Japan and examined their association with health outcomes. The results showed that more than 25% of activity was reduced due to the pandemic. There was a moderate association between changes in activity and physical, mental, and subjective health. Especially, instrumental and social activities were strongly associated with mental and subjective health. This study highlights the possibility that different types of activities may have different effects on health. Our study can provide occupational therapy practitioners supporting community-dwelling older adults with a perspective to assess changes in daily activities due to the pandemic and identify activities to target for future intervention. As this study was conducted at a single point in time, future studies should be conducted at multiple points in time.

Dynamic assessment for low back-support exoskeletons during manual handling tasks.

Exoskeletons can protect users' lumbar spine and reduce the risk of low back injury during manual lifting tasks. Although many exoskeletons have been developed, their adoptability is limited by their task- and movement-specific effects on reducing burden. Many studies have evaluated the safety and effectiveness of an exoskeleton using the peak/mean values of biomechanical variables, whereas the performance of the exoskeleton at other time points of the movement has not been investigated in detail. A functional analysis, which presents discrete time-series data as continuous functions, makes it possible to highlight the features of the movement waveform and determine the difference in each variable at each time point. This study investigated an assessment method for exoskeletons based on functional ANOVA, which made it possible to quantify the differences in the biomechanical variables throughout the movement when using an exoskeleton. Additionally, we developed a method based on the interpolation technique to estimate the assistive torque of an exoskeleton. Ten men lifted a 10-kg box under symmetric and asymmetric conditions five times each. Lumbar load was significantly reduced during all phases (flexion, lifting, and laying) under both conditions. Additionally, reductions in kinematic variables were observed, indicating the exoskeleton's impact on motion restrictions. Moreover, the overlap F-ratio curves of the lumbar load and kinematic variables imply that exoskeletons reduce the lumbar load by restricting the kinematic variables. The results suggested that at smaller trunk angles (<25°), an exoskeleton neither significantly reduces the lumbar load nor restricts trunk movement. Our findings will help increasing exoskeleton safety and designing effective products for reducing lumbar injury risks.

Trends and Characteristics of Suicide-Related Behaviors Before and After the COVID-19 Epidemic in Tottori, Japan: A Retrospective Study.

Background: In Japan, the number of suicides has increased since the coronavirus disease (COVID-19) epidemic. However, only a few studies have examined the trends among individuals who attempted suicide. In this study, we examined the background characteristics and motives of individuals who attempted suicide and visited the emergency room because of suicide-related behavior before and after the spread of COVID-19. Methods: This single-center retrospective observational study collected information from electronic medical records. We included patients who presented to the emergency department of Tottori University Hospital with suicide-related behaviors between May 1, 2017, to August 31, 2022. The period from May 1, 2017, through December 31, 2019, was designated as 'the period before COVID-19" (before-period), and that from January 1, 2020, through August 31, 2022, was designated as "the period after COVID-19" (after-period). We compared the total number of cases, their background, and motives for suicide-related behaviors between the before- and after-periods. Results: The total number of suicide events was 304. Of these, 182 and 122 occurred during the before-period and after-period, respectively. The incidence of the F3 category of the International Classification of Diseases, 10th Revision, increased, while that of the F4 and F6 categories decreased during the after-period. The proportion of suicide attempts due to health problems decreased and that of work problems increased during the after-period. Conclusion: The total number of suicide-related behaviors decreased after the COVID-19 pandemic. This may be because patients with psychiatric disorders other than depression and schizophrenia often engage in suicidal behavior through non-fatal methods, such as drug overdose and wrist-cutting, which may have led them to refrain from seeing a doctor. The proportion of suicidal motivation due to work-related fatigue has increased, perhaps because the quality and quantity of work changed significantly due to COVID-19.

Late-onset aqueductal membranous occlusion treated neuroendoscopic procedure and consideration of its pathological findings: A case report.

Background: Aqueduct of Sylvius stenosis/obstruction interferes with cerebrospinal fluid (CSF) flow and leads to the non-communicating hydrocephalus. Acquired non-neoplastic causes of aqueduct of Sylvius stenosis/ obstruction include simple stenosis, gliosis, slit-like stenosis, and septal formation, but the detailed mechanisms are not clear. In the present study, we experienced a case of late-onset aqueductal membranous occlusion (LAMO) successfully treated by neuroendoscopic procedure, which allowed us to examine the pathology of the membranous structures of the aqueduct of Sylvius occlusion. Case Description: A 66-year-old woman presented with gradually progressive gait disturbance, cognitive dysfunction, and urinary incontinenc. Brain magnetic resonance imaging (MRI) showed enlargement of the bilateral lateral ventricles and the third ventricle without dilatation of fourth ventricle, and heavily T2-weighted images showed an enlarged aqueduct of Sylvius and a membranous structure at its caudal end. Gadolinium contrast-enhanced T1-weighted images showed no neoplastic lesions. We diagnosed this case that the hydrocephalus due to late-onset idiopathic aqueductal stenosis or LAMO and the patient underwent endoscopic third ventriculostomy and endoscopic aqueduct oplasty. Membranous tissue specimens were obtained from the occluded aqueduct of Sylvius at the time of treatment. Histopathological examination revealed gliosis, and inside the gliosis, there were cell clusters that appeared to be ependymal cells and were corpora amylacea. We confirmed CSF flow at the site of obstruction of the aqueduct of Sylvius and the stoma of the third ventricle floor by MRI images. Her symptoms were improved immediately. Conclusion: We experienced a case of LAMO successfully treated by neuroendoscopic procedure, which allowed us to examine the pathology of the membranous structure of the aqueduct of Sylvius. The pathological study of LAMO is rare, and we report it, including a review of the literature.

Changes in Community-Dwelling Elderly's Activity and Participation Affecting Depression during COVID-19 Pandemic: A Cross-Sectional Study.

We determined the changes in the activity or participation of the community-dwelling elderly in Japan during the COVID-19 pandemic and identified the activities leading to depression. This will allow us to evaluate rehabilitation interventions that can be used to minimize or eliminate the negative impact of COVID-19 on today's community-dwelling elderly. Herein, demographics, activity or participation (Activity Card Sort-Japan version: ACS-JPN), the number of social networks (Lubben Social Network Scale: LSNS), and depression (Geriatric Depression Scale: GDS) were examined in 74 community-dwelling elderly in Japan from August to October 2020. A statistical analysis was conducted to determine the effect of demographics on GDS, LSNS, and ACS-JPN, to compare the activity retention rates of the four domains using ACS-JPN, and to extract the activities that might affect depression using a generalized linear model. The results show that the retention of leisure activity with a high physical demand (H-leisure) and sociocultural activities was significantly lower than instrumental activities of daily living and leisure activity with a low physical demand (L-leisure). L-leisure and the number of social networks were possible risk factors for depression during the pandemic. This study highlighted the importance of maintaining the number of L-leisure and social networks at home to prevent depression in community-dwelling elderly when they could not perform outdoor activities and direct interpersonal interaction.

Identification of Subgroups of Activity Participation in Group of Community-Dwelling Older Adults.

Occupational therapy in public health is advancing for groups of older adults, but few studies have focused on measuring population-based activity engagement. This study aimed to identify subgroups based on the daily activity pattern of community-dwelling older adults. Japanese older adults aged ≥65 years responded to a 128-activity-item questionnaire. Sparse principal component analysis was applied to summarize the activities, and k-means clustering was used to identify subgroups. Respondents were divided into three subgroups (subgroup 1: n = 39, high instrumental/leisure and social/cognitive activity; subgroup 2: n = 51, high instrumental/leisure and low social/cognitive activity; subgroup 3: n = 44, low instrumental/leisure and social/cognitive activity). The three subgroups were associated with sociodemographics (sex, area, education, and activity level) (p < .05). This study highlighted the activity-based subgroups of older adults and provided a novel viewpoint regarding occupation-based community assessments in addition to previous community occupational therapy practice.

Optimal threshold of a control parameter for tomotherapy respiratory tracking: A phantom study.

BACKGROUND: Radixact Synchrony® , a real-time motion tracking and compensating modality, is used for helical tomotherapy. Control parameters are used for the accurate application of irradiation. Radixact Synchrony® uses the potential difference, which is an index of the accuracy of the prediction model of target motion and is represented by a statistical prediction of the 3D distance error. Although there are several reports on Radixact Synchrony® , few have reported the appropriate settings of the potential difference threshold. PURPOSE: This study aims to determine the optimal threshold of the potential difference of Radixact Synchrony® during respiratory tumor-motion-tracking irradiation. METHODS: The relationship among the dosimetric accuracy, motion tracking accuracy, and control parameter was evaluated using a moving platform, a phantom with a basic respiratory model (the fourth power of a sinusoidal wave), and several irregular respiratory model waveforms. The dosimetric accuracy was evaluated by gamma analysis (3%, 1 mm, 10% dose threshold). The tracking accuracy was measured by the distance error of the difference between the tracked and driven positions of the phantom. The largest potential difference for 95% of treatment time was evaluated, and its correlation with the gamma-pass ratio and distance error was investigated. The optimal threshold of the potential difference was determined by receiver operating characteristic (ROC) analysis. RESULTS: A linear correlation was identified between the potential difference and the gamma-pass ratio (R = -0.704). A linear correlation was also identified between the potential difference and distance error (R = 0.827). However, as the potential difference increased, it tended to underestimate the distance error. The ROC analysis revealed that the appropriate cutoff value of the potential difference was 3.05 mm. CONCLUSION: The irradiation accuracy with motion tracking by Radixact Synchrony® could be predicted from the potential difference, and the threshold of the potential difference should be set to ∼3 mm.

Low Radiation Protocol for Intraoperative Robotic C-Arm Can Enhance Adolescent Idiopathic Scoliosis Deformity Correction Accuracy and Safety.

STUDY DESIGN: Retrospective case-series study. OBJECTIVES: To assess (1) low cone beam CT (CBCT) mediated intraoperative navigation to limit radiation exposure without compromising surgical accuracy, and (2) the potential of intraoperative C-arm CBCT navigation to augment pedicle screw (PS) placement accuracy in AIS surgery compared to pre-surgery CT-based planning. METHODS: The first part involved a prospective phantom study, comparing radiation doses for conventional CT, and standard (6sDCT) and a low dose (5sDCT) Artis Zeego®-imaging. Next, 5sDCT- and 6sDCT-navigation were compared on PS accuracy and radiation exposure during AIS correction. The final part compared surgical AIS deformity correction through intraoperative 5sDCT navigation to a matched cohort treated using conventional pre-surgery CT-scans for navigation. Outcome parameters included operation time, skin dose (SD), dose area product (DAP), intraoperative blood loss, postoperative complications, and PS deviation rates. RESULTS: The phantom study demonstrated a reduction in radiation for the 5sDCT protocol. Moreover, 5sDCT-imaged patients (n = 15) showed a significantly lower SD (-27.41%) and DAP (-30.92%), without compromising PS accuracy compared with 6sDCT-settings (n = 15). Finally, AIS correction through intraoperative CBCT C-arm navigation (n = 27) significantly reduced screw deviation rates (6.83% versus 10.75%, P = .016) without increasing operation times, compared with conventional CT (n = 37). CONCLUSIONS: Intraoperative navigation using a CBCT C-arm system improved the accuracy of PS insertion and reduced surgery time. Moreover, it reduced radiation exposure compared with conventional CT, which was further curtailed by adapting the low-dose 5sDCT protocol. In short, our study highlights the benefits of intraoperative CBCT navigation for PS placement in AIS surgery.

Somnolence and Dizziness During Mirogabalin Treatment in Patients With Neuropathic Pain Related to Lumbar Disease Who Switched From Pregabalin: A Retrospective Study.

STUDY DESIGN: Multicenter retrospective study. OBJECTIVES: To investigate adverse events (AEs) in patients with neuropathic pain related to lumbar disease who switched to mirogabalin from pregabalin. METHODS: This study surveyed the records of 82 patients with peripheral neuropathic leg pain related to lumbar disease who switched to mirogabalin from pregabalin. We evaluated AEs associated with pregabalin and mirogabalin, the continuation rate of mirogabalin, and the pain-relieving effect at 4 weeks after switching from pregabalin to mirogabalin. We compared patients who switched due to lack of efficacy (LoE group) and patients who switched due to AEs (AE group). RESULTS: The incidence rates of somnolence and dizziness with pregabalin were 12.2% and 14.6%, respectively, while the incidence rates with mirogabalin were reduced to 7.3% for somnolence and 4.9% for dizziness. The incidence of AEs with pregabalin was significantly higher in the AE group (LoE group: 11.1%, AE group 100%), especially for somnolence (LoE group: 3.2%, AE group: 47.1%) and dizziness (LoE group: 4.8%, AE: 52.9%). After switching, the incidences of AEs with mirogabalin were not significantly different between the 2 groups (LoE group: 15.9%, AE group: 23.5%), including for somnolence (LoE group: 7.9%, AE group: 5.9%) and dizziness (LoE group: 4.8%, AE group: 5.9%). There were no significant differences in continuation rate of mirogabalin or the pain-relieving effect between groups. CONCLUSIONS: The patients who experience somnolence and dizziness with pregabalin might be able to continue safely receiving treatment for their pain by switching to mirogabalin.

TRITIUM CONCENTRATION IN MONTHLY PRECIPITATION NEAR THE FUSION TEST FACILITY IN JAPAN BEFORE AND AFTER THE DEUTERIUM PLASMA EXPERIMENT.

In Japan, the deuterium plasma experiment using the Large Helical Device was started at the National Institute for Fusion Science (NIFS) in March 2017 to investigate high-temperature plasma physics and hydrogen isotope effects in research leading towards the realisation of fusion energy. The deuterium plasma experiment produces small amount of tritium by fusion reactions. To understand any impacts by the experiment to the surrounding environment, monthly precipitation samples have been collected at the NIFS site since November 2013 to assess the relationship between isotope composition and chemical species in precipitation including tritium. By comparing data before and after the deuterium plasma experiment start, it was found that tritium released from the main stack of the fusion test facility had no impact on the environment surrounding NIFS.

LEVELS OF ATMOSPHERIC TRITIUM IN THE SITE OF FUSION TEST FACILITY.

In the deuterium plasma experiment using Large Helical Device at the National Institute for Fusion Science (NIFS), a small amount of tritium is produced by the D-D fusion reaction. Then, a part of produced tritium is discharged into the environment via a stack. Thus, the atmospheric tritium in the site of NIFS has been monitored before starting the deuterium plasma experiment. The atmospheric tritium concentrations at NIFS were indicated to be background levels in Japan. To investigate the impact of tritium discharged from the stack, the correlation between the atmospheric tritium concentration and the tritium concentration observed in the stack was evaluated, and no significant correlation was found. In addition, the atmospheric tritium concentration at NIFS ranged within the background levels in Japan. Therefore, the impact of discharged tritium from the stack would be negligible in the environment at NIFS.

Effect of Roasting Degree on Major Coffee Compounds: A Comparative Study between Coffee Beans with and without Supercritical CO2 Decaffeination Treatment.

Coffee is a beverage that is consumed worldwide, and the demand for decaffeinated coffee has increased in recent years. This study aimed to investigate the effect of roasting conditions on the concentration of physiologically active compounds in coffee beans with and without supercritical CO2 decaffeination treatment. Decaffeination treatment markedly reduced caffeine concentration and slightly reduced trigonelline concentration in the coffee beans, whereas the concentrations of chlorogenic acids (chlorogenic acid, cryptochlorogenic acid, and neochlorogenic acid) were largely unchanged. Roasting was performed using a hot-air coffee roaster machine and the coffee beans were treated at different peak temperatures (125-250℃), different hold times at the peak temperature (120-240 s), and different temperature increase times to reach the peak temperature (60-180 s). Roasting conditions such as long hold and long temperature rise times at high temperatures (≥ 225℃) significantly degraded coffee compounds except for caffeine, with similar degradation rates between non-decaffeinated and decaffeinated coffee beans. In contrast, the L* value of decaffeinated coffee decreased with less thermal history compared to that of non-decaffeinated coffee. This allowed for the complete roasting of decaffeinated coffee with a lower thermal history compared to those of non-decaffeinated counterparts, suppressing the degradation of several coffee compounds. For example, comparing the similar L* values between coffee beans with and without decaffeination treatment, it was found that the former tended to contain more chlorogenic acid. Generally, decaffeination results in the loss of physiologically active compounds along with caffeine, which is a major concern. However, this study showed that appropriate control of decaffeination and roasting conditions can limit the degradation of several valuable coffee compounds, such as trigonelline and chlorogenic acid.

Chromatographic Purification of Lithium, Vanadium, and Uranium from Seawater Using Organic Composite Adsorbents Composed of Benzo-18-Crown-6 and Benzo-15-Crown-5 Embedded in Highly Porous Silica Beads.

The use of the composite adsorbents composed of benzo-15-crown-5 (abbreviated as BC15) and benzo-18-crown-6 (BC18) for the simultaneous recovery of vanadium (V), uranium (U), and lithium (Li) from seawater has been proposed for industrial applications. The adsorption and desorption behavior of these elements on BC15 and BC18 has been examined in various types of aqueous solutions over a wide temperature range. As a result, it was shown that BC15 and BC18 have sufficient adsorption ability for the simultaneous recovery of V, U, and Li from seawater. Moreover, it was seen that the distribution coefficients (K d) of V decrease with an increase in [HCl]T (subscript T: total concentration), indicating that the anionic V species such as H2V4O13 4- are exponentially changed into the cationic V species such as V3+, VO2+, and VO2 + under the condition [HCl]T = 1.0 M, and the complexation reactions between BC15 (or BC18) and the initial V structures are inhibited. Besides, it was reasonably shown that the adsorption mechanism is the path through the electrostatic interaction between the anionic V species such as H2V4O13 4-, and the -C-O-C- single bond that the electron density is eccentrically located in ether functional groups in crown ether rings in BC15 and BC18 (or the -C-OH single bond that the electron density is eccentrically located in bisphenol A in BC15 and BC18). Then, the chromatography experiment of V, U, and Li on BC15 (or BC18) at 298 K was carried out by flowing seawater, 1.0 × 10-2 M HCl, and 1.0 M HCl in sequence. The first peak of V can be separated from the plateau of Li and the first and second peaks of U in the case of the BC15 system. The recovery ratios of V and U were more than 80%. On the other hand, entirely overlapping chromatograms were obtained in the case of the BC18 system, and accordingly, the recovery ratios of V and U were much lower. In short, the separation efficiency of V with BC15 is more pre-eminent than that with BC18. Judging from these results, the durability of BC15 was finally assessed for industrial applications, that is, the aforementioned chromatography experiment was repeatedly carried out to check whether V, U, and Li were stably and mutually separated from seawater or not. The evidence that the recovery performances of V, U, and Li from seawater do not decrease at all after at least five cycle tests was provided. This indicates that this information will be valuable for the development of a practical chromatographic technology to simultaneously recover V, U, and Li from seawater.

First-line pembrolizumab for patients with early relapsing urothelial carcinoma after perioperative chemotherapy: a retrospective analysis of bladder cancer and upper urinary tract cancer.

BACKGROUND: First-line pembrolizumab is available for recurrent disease within 12 months after the receipt of platinum-based perioperative chemotherapy. However, the benefit of first-line pembrolizumab is unclear. This study evaluated the oncological outcome of patients treated with pembrolizumab compared with chemotherapy as first-line therapy for early relapsing disease after the receipt of platinum-based perioperative chemotherapy. METHODS: Data from a multicenter study included 454 patients diagnosed with unresectable or metastatic UC from November 2006 to July 2021. We identified patients with early and non-early relapsing disease. Oncological outcomes were evaluated using progression-free survival, overall survival, and survival with disease control. RESULTS: Fifty-three patients with early relapsing disease and 15 patients with non-early relapsing disease were identified. Of 53 patients with early relapsing disease, 26 (49.1%) were treated with pembrolizumab and 27 (50.9%) were treated with chemotherapy as first-line therapy. Fifteen patients with non-early relapsing disease were treated with chemotherapy. Early relapsing disease was associated with shorter progression-free survival and overall survival than non-early relapsing disease. Pembrolizumab was associated with longer progression-free survival and survival with disease control than chemotherapy in patients with early relapsing disease. There was no significant difference in overall survival between pembrolizumab and chemotherapy, but overall survival plateau with a long tail was observed in pembrolizumab. CONCLUSIONS: First-line pembrolizumab in earlier clinical settings for highly malignant tumors might improve the prognosis of patients with early relapsing disease after the receipt of platinum-based perioperative chemotherapy.

Age- and sex-based changes in spike protein antibody status after SARS-CoV-2 vaccination and effect of past-infection in healthcare workers in Osaka.

OBJECTIVE: We aimed to compare the changes in SARS-CoV-2 spike protein antibody titres based on age group and sex using paired blood sampling after vaccination in association with the presence of nucleocapsid protein antibody. METHODS: All participants were healthcare workers at Yao Municipal Hospital in Osaka who voluntarily provided peripheral blood samples (n = 636, men/women 151/485, mean age 45 years). We investigated the serial changes in SARS-CoV-2 spike protein antibody titres at 1 and 7 months after the second vaccination regarding their relationship with sex and age group. At 7 months, we also examined anti-nucleocapsid assays. Antibody titres were shown as logarithmic values and the differences were assessed using a paired or unpaired student's t-test as appropriate. RESULTS: Among participants younger than 30 years, the antibody titres of spike protein were significantly higher in women one (p = 0.005) and seven (p = 0.038) months after vaccination. However, among those aged 30-49 years, the antibody titres were not different between the sexes at either follow-up time point. In contrast, among those aged 50-59 years, between-sex differences in antibody titres were observed only at 7 months, which was associated with a significant reduction in men. A significant negative correlation was observed between the antibody titres for spike protein at both time points in participants with positive nucleocapsid protein antibody at 7 months (r = - 0.467, p = 0.043), although a significant positive correlation was observed in those with negative results (r = 0.645, p < 0.001), CONCLUSIONS: Between-sex differences in SARS-CoV-2 spike protein antibody titres by paired blood sampling at different time points after vaccination depended on age group. The presence of nucleocapsid protein antibody was associated with changes in spike protein antibody titres after vaccination.

Preferential Expression of Ca2+-Stimulable Adenylyl Cyclase III in the Supraventricular Area, including Arrhythmogenic Pulmonary Vein of the Rat Heart.

Ectopic excitability in pulmonary veins (PVs) is the major cause of atrial fibrillation. We previously reported that the inositol trisphosphate receptor in rat PV cardiomyocytes cooperates with the Na+-Ca2+ exchanger to provoke ectopic automaticity in response to norepinephrine. Here, we focused on adenylyl cyclase (AC) as another effector of norepinephrine stimulation. RT-PCR, immunohistochemistry, and Western blotting revealed that the abundant expression of Ca2+-stimulable AC3 was restricted to the supraventricular area, including the PVs. All the other AC isotypes hardly displayed any region-specific expressions. Immunostaining of isolated cardiomyocytes showed an enriched expression of AC3 along the t-tubules in PV myocytes. The cAMP-dependent response of L-type Ca2+ currents in the PV and LA cells is strengthened by the 0.1 mM intracellular Ca2+ condition, unlike in the ventricular cells. The norepinephrine-induced automaticity of PV cardiomyocytes was reversibly suppressed by 100 µM SQ22536, an adenine-like AC inhibitor. These findings suggest that the specific expression of AC3 along t-tubules may contribute to arrhythmogenic automaticity in rat PV cardiomyocytes.

Organ-Specific and Mixed Responses to Pembrolizumab in Patients with Unresectable or Metastatic Urothelial Carcinoma: A Multicenter Retrospective Study.

To investigate the organ-specific response and clinical outcomes of mixed responses (MRs) to immune checkpoint inhibitors (ICIs) for unresectable or metastatic urothelial carcinoma (ur/mUC), we retrospectively analyzed 136 patients who received pembrolizumab. The total objective response rate (ORR) and organ-specific ORR were determined for each lesion according to the Response Evaluation Criteria in Solid Tumors version 1.1 as follows: (i) complete response (CR), (ii) partial response (PR), (iii) stable disease (SD), and (iv) progressive disease (PD). Most of the organ-specific ORR was 30−40%, but bone metastasis was only 5%. There was a significant difference in overall survival (OS) between responders and non-responders with locally advanced lesions and lymph node, lung, or liver metastases (HR 9.02 (3.63−22.4) p < 0.0001; HR 3.63 (1.97−6.69), p < 0.0001; HR 2.75 (1.35−5.59), p = 0.0053; and HR 3.17 (1.00−10.0), p = 0.049, respectively). MR was defined as occurring when PD happened in one lesion plus either CR or PR occurred in another lesion simultaneously, and 12 cases were applicable. MR was significantly associated with a poorer prognosis than that of the responder group (CR or PR; HR 0.09 (0.02−0.35), p = 0.004). Patients with bone metastases benefitted less. Care may be needed to treat patients with MR as well as patients with pure PD. Further studies should be conducted in the future.