Effect of a variant histology on the oncological outcomes of Japanese patients with upper tract urothelial carcinomas after radical nephroureterectomy: a multicenter retrospective study.

Background: An earlier systematic review and meta-analysis found that patients with a certain histological variant of upper tract urothelial carcinoma (UTUC) exhibited more advanced disease and poorer survival than those with pure UTUC. A difference in the clinicopathological UTUC characteristics of Caucasian and Japanese patients has been reported, but few studies have investigated the clinical impact of the variant histology in Japanese UTUC patients. Methods: We retrospectively enrolled 824 Japanese patients with pTa-4N0-1M0 UTUCs who underwent radical nephroureterectomy without neoadjuvant chemotherapy. Subsequently, we explored the effects of the variant histology on disease aggressiveness and the oncological outcomes. We used Cox's proportional hazards models to identify significant predictors of oncological outcomes, specifically intravesical recurrence-free survival (IVRFS), recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: Of the 824 UTUC patients, 32 (3.9%) exhibited a variant histology that correlated significantly with a higher pathological T stage and lymphovascular invasion (LVI). Univariate analysis revealed that the variant histology was an independent risk factor for suboptimal RFS, CSS, and OS. However, significance was lost on multivariate analyses. Conclusions: The variant histology does not add to the prognostic information imparted by the pathological findings after radical nephroureterectomy, particularly in Japanese UTUC patients.

Clinical Significance of Intraductal Carcinoma of the Prostate After High-Dose Brachytherapy With External Beam Radiation Therapy: A Single Institution Series and an Updated Meta-Analysis.

BACKGROUND: We compared oncological outcomes between prostate cancer (PCa) patients with and without intraductal carcinoma of the prostate (IDC-P) after high-dose-rate brachytherapy (HDR-BT) with external beam radiation therapy (EBRT). METHODS: We performed a retrospective analysis of 138 patients with clinically high-risk, very high-risk, or locally advanced PCa who received HDR-BT with EBRT. Of these, 70 (50.7 %) patients were diagnosed with IDC-P; 68 (49.3 %) patients with acinar adenocarcinoma of prostate. The oncological outcomes, including biochemical recurrence-free survival (BCRFS) and clinical progression-free survival (CPFS), were assessed using Kaplan-Meier curves. Additionally, Cox proportional hazards models were used to identify significant prognostic indicators or biochemical recurrence (BCR). Meta-analysis of existing literatures was performed to evaluate the risk of BCR in patients with IDC-P after radiation therapy, compared to those without IDC-P. RESULTS: Kaplan-Meier curves demonstrated significantly inferior BCRFS and CPFS in patients with IDC-P. Multivariate analysis revealed that IDC-P and Grade Group 5 status were associated with increased BCR risk. in our meta-analysis, IDC-P was associated with BCR (HR = 2.13, P = .003). CONCLUSION: Amongst the patients who received HDR-BT, patients with IDC-P displayed significantly more rapid disease progression, compared with patients who did not have IDC-P.

Sedation Therapy in Intensive Care Units: Harnessing the Power of Antioxidants to Combat Oxidative Stress.

In critically ill patients requiring intensive care, increased oxidative stress plays an important role in pathogenesis. Sedatives are widely used for sedation in many of these patients. Some sedatives are known antioxidants. However, no studies have evaluated the direct scavenging activity of various sedative agents on different free radicals. This study aimed to determine whether common sedatives (propofol, thiopental, and dexmedetomidine (DEX)) have direct free radical scavenging activity against various free radicals using in vitro electron spin resonance. Superoxide, hydroxyl radical, singlet oxygen, and nitric oxide (NO) direct scavenging activities were measured. All sedatives scavenged different types of free radicals. DEX, a new sedative, also scavenged hydroxyl radicals. Thiopental scavenged all types of free radicals, including NO, whereas propofol did not scavenge superoxide radicals. In this retrospective analysis, we observed changes in oxidative antioxidant markers following the administration of thiopental in patients with severe head trauma. We identified the direct radical-scavenging activity of various sedatives used in clinical settings. Furthermore, we reported a representative case of traumatic brain injury wherein thiopental administration dramatically affected oxidative-stress-related biomarkers. This study suggests that, in the future, sedatives containing thiopental may be redeveloped as an antioxidant therapy through further clinical research.

A Study on Pharmacokinetics of Acetylsalicylic Acid Mini-Tablets in Healthy Adult Males-Comparison with the Powder Formulation.

Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was developed. In order to use the mini-tablets safely and effectively, dissolution tests alone are not sufficient. Therefore, an open-label crossover study on six healthy participants was conducted to evaluate comparative pharmacokinetic parameters. The pharmacokinetic parameters of salicylic acid were Cmax: 4.80 ± 0.79 mg/L (powder; P), 5.03 ± 0.97 mg/L (mini-tablet; MT), AUC0-12: 18.0 ± 3.03 mg-h/L (P), 18.9 ± 4.59 mg-h/L (MT), those of acetylsalicylic acid Cmax: 0.50 ± 0.20 mg/L (P), 0.41 ± 0.24 mg/L (MT), AUC0-12: 0.71 ± 0.27 mg-h/L (P), 0.61 ± 0.36 mg-h/L (MT), with no significant differences between the mini-tablet and powder formulations. Although pharmacokinetic results obtained from adults cannot be directly applied to children, the results of this study are important for predicting pharmacokinetics. Furthermore, a formulation that can improve medication adherence in children who have difficulty taking acetylsalicylic acid powder, thus contributing to pediatric drug therapy.

Ability of older male caregivers to seek help when caring for a wife or mother with dementia living at home.

Objective: We aimed to clarify factors associated with the ability to seek help among older male caregivers who care for women with dementia in their families. Patients and Methods: This information will inform strategies to support their continued provision of long-term care. Participants were 364 male caregivers recruited from three places: The study period was 2017-2018. We obtained ethical approval for this study from the relevant ethics committee. Results: The ability to seek help for care problems among male caregivers was normally distributed. We found that more than 90% of older male caregivers did not actively seek help to resolve care problems, suggesting that older male caregivers had problems with long-term care. In the high score group, health status and the number of emotional support persons in the household were significantly and somewhat strongly positively correlated. The low score group showed a significant and rather weak positive correlation between economic status and health status, and the number of emotional supporters inside and outside the household. Positive correlations for the high score group were self-esteem and depressive symptoms, and self-esteem and resources. Positive correlations for the low score group were self-esteem and depressive symptoms, self-esteem and resources, and resources and depressive symptoms. Conclusion: Male caregivers are more likely to seek help if they are employed or play a role in their community. Nurses also need to support male caregivers with positive words and praise to help them use available support and resources and continue to provide long-term care. It is important for healthcare professionals to observe whether a caregiver presents with depressive symptoms or has long-term care problems because older male caregivers do not seek help. Collaboration between caregivers and medical, long-term care, and welfare professionals is necessary. Direct and timely intervention is needed.

Urinary profiles of methoxyphenamine and its metabolite after inhalation of methoxyphenamine smoke in humans: aiming to distinguish between active and passive exposure.

PURPOSE: Methamphetamine (METH) is commonly abused through smoking. However, the lack of evidence regarding differences in urinary METH excretion after its active and passive inhalation has resulted in complications where the accused claims passive exposure. This study aimed to determine the differences in urinary excretion after active and passive inhalation of the drug, using methoxyphenamine (MPA) as a model for METH. METHODS: Body temperature and locomotor activity were measured in mice as indicators of central nervous system toxicity. Six healthy adult male subjects were exposed to passive or active inhalation of MPA smoke in a small room, and urine samples were taken. MPA concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: There were no signs of toxicity in mice exposed to MPA smoke, ensuring the safety of the clinical study. Urinary MPA concentrations were significantly lower with passive inhalation compared with those of active inhalation. The maximum urinary MPA concentration in passive inhalation was 13.4 ng/mL, which was 1/60 of active inhalation with 800 ng/mL. The urinary excretion in passive inhalation until 24 h was 8.21 µg, which was 1/76 of active inhalation with 625 µg. CONCLUSIONS: Since METH and MPA are expected to be excreted similarly, urinary METH concentrations in passively exposed persons are expected to be lower than the cutoff value of the screening kit. If the urine screening test is positive, the suspect should be considered a METH user. TRIAL REGISTRATION NUMBER: jRCTs031210604, registration date: Feb. 9, 2022.

Effect of vitamin D receptor activators on cardiovascular events in patients on hemodialysis-A post hoc analysis of the LANDMARK study.

INTRODUCTION: The clinical benefit of vitamin D receptor activators (VDRA) in patients with well-controlled secondary hyperparathyroidism undergoing dialysis remains unclear. METHODS: This post hoc analysis of the LANDMARK study investigates if VDRA use is associated with cardiovascular benefits. Data of 2135 patients undergoing hemodialysis who were at risk for vascular calcification were analyzed using a Cox proportional hazards model with propensity-score matching. RESULTS: The hazard ratio (HR) for VDRA use was 0.99 (95% confidence interval [CI]: 0.67-1.46; p = 0.945) for cardiovascular events and 0.89 (95% CI: 0.62-1.28; p = 0.541) for all-cause mortality at baseline. Among patients who always used VDRA, the HR was 1.12 (95% CI: 0.67-1.89; p = 0.666) for cardiovascular events and 1.11 (95% CI: 0.67-1.85; p = 0.688) for all-cause mortality compared to those who never used VDRA. CONCLUSION: The use of VDRA does not reduce the risks of cardiovascular events or all-cause mortality in patients on dialysis with well-controlled secondary hyperparathyroidism.

Adolescent Persistent Atrial Fibrillation Concomitant with Pectus Excavatum.

A 19-year-old man with pectus excavatum developed symptomatic persistent atrial fibrillation (AF). He had no remarkable medical history or comorbidities and had not exercised intensely during childhood. Electrical cardioversion and pre-treatment with amiodarone for two months failed to maintain sinus rhythm. Computed tomography before ablation revealed compression of the right and left atria between the sternal bone and vertebral bodies. Voltage mapping revealed that the right and left atrial voltages were preserved within the normal limit. However, radiofrequency catheter ablation successfully eliminated recurrent persistent AF. No recurrence was observed during eight months of follow-up.

Target phosphate and calcium levels in patients undergoing hemodialysis: a post-hoc analysis of the LANDMARK study.

BACKGROUND: It is necessary to re-examine the optimal phosphate (P) and calcium (Ca) target values in the contemporary management of chronic kidney disease-mineral and bone disorder to reduce the risks of cardiovascular events in patients receiving hemodialysis. METHODS: We performed a post-hoc analysis of the LANDMARK study. The outcomes were defined as cardiovascular events and all-cause death. Data from 2135 patients receiving hemodialysis at risk of vascular calcification were analyzed using a time-dependent Cox proportional hazard model adjusted for background factors. RESULTS: On the hazard ratio (HR) curve, the ranges where the lower 95% confidence interval (CI) were below the minimum of HR (= 1.00) were as follows: P = 3.5-5.5 mg/dL; albumin-adjusted Ca < 9.1 mg/dL for cardiovascular events; and P = 3.6-5.3 mg/dL; albumin-adjusted Ca < 9.1 mg/dL for all-cause mortality. In stratified analysis, the HRs for cardiovascular events in P < 3.5 mg/dL and P ≥ 5.5 mg/dL were similar to that of P = 3.5-5.5 mg/dL (P ≥ 0.05), and albumin-adjusted Ca ≥ 9.1 mg/dL had higher HR than values < 9.1 mg/dL [1.30 (95% CI 1.00-1.68; P = 0.046)]. For all-cause mortality, the HR in P < 3.6 mg/dL was higher than that in P = 3.6-5.3 mg/dL [1.76 (95% CI 1.25-2.48; P = 0.001)], while the HRs between P ≥ 5.3 mg/dL and P = 3.6-5.3 mg/dL as well as those between albumin-adjusted Ca ≥ 9.1 and < 9.1 mg/dL were not significantly different (P ≥ 0.05). CONCLUSIONS: Managing albumin-adjusted Ca < 9.1 mg/dL may reduce the cardiovascular risk among patients undergoing hemodialysis. Hypophosphatemia < 3.6 mg/dL may be associated with mortality.

Identification of factors associated with the efficacy of atomoxetine in adult attention-deficit/hyperactivity disorder.

AIM: Atomoxetine (ATX) is a non-central stimulant and a standard treatment for adult attention-deficit/hyperactivity disorder (ADHD). The long-term efficacy of Atomoxetine is about 40% at 6 months. The variability in efficacy between individuals is thought to be related to patient-specific factors, but no detailed research has been conducted. In this retrospective cohort study, we aimed to identify the factors associated with Atomoxetine efficacy. METHODS: A total of 147 patients with attention-deficit/hyperactivity disorder aged ≥18 years who were using Atomoxetine for the first time were included in this study. The outcome was treatment success (treatment maintained for at least 6 months and improvement in symptoms). Symptom assessment was based on the overall improvement in symptoms judged by an expert physician. RESULTS: Of the patient sample, 103 (70.1%) achieved the outcome. Logistic regression analysis identified "the maximum dose of ATX" and "gambling habit" as factors associated with efficacy ( P  < 0.05). In the process of Atomoxetine titration, the larger the maximum dose, the higher the efficacy was shown to be. Gambling habits may be indicative of impulsivity, which is among the core symptoms of attention-deficit/hyperactivity disorder. Thus, a gambling habit may be considered a surrogate marker for impulsivity. CONCLUSIONS: Knowledge of these factors will help healthcare professionals to predict the likely efficacy of Atomoxetine in a given patient before subscribing it, facilitating individualized pharmacotherapy for adult attention-deficit/hyperactivity disorder.

A case of bronchial asthma as an immune-related adverse event of pembrolizumab treatment for bladder cancer: A case report.

RATIONALE: Bladder cancer is one of the most common cancers worldwide. The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab, which is an immune checkpoint inhibitor (ICI), has improved survival in bladder cancer. We report a case of bladder cancer that had a high antitumor effect with anti-programmed cell death PD-1 antibody pembrolizumab, an ICI, but asthma occurred an immune-related adverse event (irAE). PATIENT CONCERNS: A 70-year-old female patient was diagnosed as unresectable bladder cancer who was indicated for ICI treatment. DIAGNOSIS: After ICI administration as a treatment for bladder cancer, the patient had a grade 3 asthma attack. Cytotoxic T lymphocyte antigen 4 (CTLA-4) in CD4+ FOX3+ T cells was upregulated in the early phase before the development of asthma attacks. Moreover, T-cell immunoglobulin and mucin domain 3 (TIM-3) was upregulated in all memory T cells among CD4+ T cells. However, no change in the expression of TIM-3 was observed in any CD8+ T-cell subtype. In contrast, the proportion of CD161- T helper 17 cell (Th17) cells increased. INTERVENTIONS: The patient was treated with betamethasone, montelukast, salbutamol nebulization, and a combination of salmeterol (50 µg) and fluticasone (500 µg) (SFC). OUTCOMES: The patient's wheezing resolved, and her peak flow rate reached 100% of the predicted value; therefore, the patient continued treatment with SFC and montelukast and was discharged from the hospital. CONCLUSION: Increases in CTLA-4 and TIM-3 expression in CD4+ T cells (not CD8+), as well as an increase in Th17 cells, may reflect asthma-related inflammation activity. Immune-related adverse events during immune checkpoint inhibitor administration may be predictive markers of antitumor efficacy.

Antibiotic Usage Reduced Overall Survival by over 70% in Non-small Cell Lung Cancer Patients on Anti-PD-1 Immunotherapy.

BACKGROUND/AIM: There is an increasing use of immunotherapy for non-small cell lung cancer (NSCLC) patients. The present study analysed the effect of antibiotic use on the outcome of NSCLC patients undergoing treatment with anti-programmed cell death-1 (anti-PD-1) immunotherapy. PATIENTS AND METHODS: This was a retrospective study of 69 NSCLC patients. Eighteen out of 69 patients received antibiotics within 21 days before or within 21 days after start of anti-PD-1 therapy. RESULTS: Patients treated with anti-PD-1 antibodies receiving antibiotics had greatly decreased objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) compared to those who did not use antibiotics. Multivariate analysis showed that antibiotic treatment of patients on anti-PD-1 antibody therapy was an independent negative predictive factor of PFS; however, it was not a significant independent predictive factor of OS. CONCLUSION: Use of antibiotics within 21 days before and after anti-PD-1 treatment initiation in patients with NSCLC strongly reduced OS and PFS, suggesting the two treatments should not be combined.

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death. PATIENTS CONCERNS: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses. DIAGNOSIS: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct. INTERVENTIONS: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered. OUTCOMES: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death. CONCLUSION: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.

Rare Nivolumab-associated Super Hyper Progressive Disease in Patients With Advanced Gastric Cancer.

BACKGROUND/AIM: Rapid tumor growth after administration of immune checkpoint inhibitors is designated hyper progressive disease (HPD). In this study, besides the conventional HPD category, we proposed the "super HPD" category where the disease is naturally rapidly growing. PATIENTS AND METHODS: Patients treated for advanced gastric cancer with irinotecan or nivolumab as a third-line treatment were retrospectively compared. RESULTS: Eighteen and 26 patients were treated with irinotecan or nivolumab, respectively. There were 3 HPD cases (16.7%) in the irinotecan group, 6 cases (23.1%) in the nivolumab group, and the frequency of HPD was not significantly different. Two cases satisfied the super HPD definition only in the nivolumab group. When one of them was analyzed immunologically, the number of regulatory T cells was found to be increased, resulting in a low neutrophil-to-lymphocyte ratio. CONCLUSION: Our proposed super HPD was likely to represent a true HPD, with a frequency of 7.7%.

Stagnant forearc mantle wedge inferred from mapping of shear-wave anisotropy using S-net seafloor seismometers.

Shear-wave anisotropy in Earth's mantle helps constrain the lattice-preferred orientation of anisotropic minerals due to viscous flow. Previous studies at the Japan Trench subduction zone using land-based seismic networks identified strong anisotropy in the mantle wedge, reflecting viscous flow induced by the subducting slab. Here we map anisotropy in the previously uninvestigated offshore region by analyzing shear waves from interplate earthquakes that are recorded by a new seafloor network (the S-net). The newly detected anisotropy is not in the mantle wedge but only in the overlying crust (∼0.1 s time delay and trench-parallel fast direction). The distinct lack of anisotropy indicates that the forearc mantle wedge offshore is decoupled from the slab and does not participate in the viscous flow, in sharp contrast with the rest of the mantle wedge. A stagnant forearc mantle wedge provides a stable and cold tectonic environment that is important for the petrological evolution and earthquake processes of subduction zones.

Bioequivalence of perampanel fine granules and tablets in healthy Japanese subjects.

OBJECTIVE: Perampanel is an approved anti-seizure drug. A new formulation of perampanel fine granules (FG; 1% perampanel) has been developed for patients who are unable to take tablets. Bioequivalence between the 4-mg FG and tablet perampanel formulations, as well as their safety and tolerability, were assessed. MATERIALS AND METHODS: In this phase I, single-center, open-label, 2-period, 2-sequence, crossover, bioequivalence study (NCT03399734), healthy Japanese subjects were randomized to receive single doses of the 4-mg FG perampanel and 4-mg perampanel tablet (separated by a ≥ 6-week washout period). Plasma samples for perampanel concentration analysis were collected pre-dose and at intervals up to 168 hours post-dose. The maximum observed concentration (Cmax) and area under the concentration-time curve from time zero to 168 hours (AUC(0-168h)) were used to assess the bioequivalence of the two formulations. RESULTS: The 90% confidence intervals (CIs) for the geometric mean ratio of test/reference for Cmax and AUC(0-168h) were within the bioequivalence criteria of 80 - 125% (Cmax 90% CI 90.8%, 110%; AUC(0-168h) 90% CI 98.2%, 112%; N = 21). 10/24 (41.7%) subjects with FG experienced ≥ 1 treatment-emergent adverse event (TEAE). The events were mild in severity and resolved within 4 hours of onset. There were no deaths, severe TEAEs, serious AEs, or TEAEs leading to study-drug withdrawal. CONCLUSION: Bioequivalence of 4-mg FG and 4-mg tablet of perampanel was demonstrated. Both perampanel formulations were generally safe and well tolerated. These data suggest that perampanel FG may be a suitable alternative formulation for patients with epilepsy who have difficulties taking perampanel tablets.

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment.

Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open-label, single-dose, parallel-group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration-time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.

Enhanced Operational Durability of Thermally Activated Delayed Fluorescence-Based Organic Light-Emitting Diodes with a Triazine Electron Transporter.

In organic light-emitting diodes (OLEDs) based on materials that show thermally activated delayed fluorescence (TADF), the internal quantum efficiency of 100 % can be obtained without using phosphorescence-based organometallics that contain rare metals. Therefore, with TADF-based emitters, it is possible to fabricate high-performing OLEDs at a lower cost. However, compared with fluorescence- and phosphorescence-based OLEDs, an understanding of degradation mechanisms in TADF-based OLEDs is still insufficient for future commercialization. In particular, it is widely recognized that the development of electron transport materials is crucial for improving OLED characteristics, especially driving voltages and operational durability. In this study, it was demonstrated that the operational durability of TADF-based OLEDs was greatly improved by introducing a triazine-based material of 2,4,6-tris(1,1'-biphenyl-4-yl)-[1,3,5]triazine (pT2T) as a hole-blocking layer (HBL) compared with a conventional HBL material of 2,4,6-tris(biphenyl-3-yl)-[1,3,5]triazine (T2T). Several experiments were carried out to make the reasons of the improved durability clearer, and attributed the improved durability to the shift of a carrier recombination zone from the emitting layer/HBL interface and the suppressed formation of excited-state quenchers in the pT2T HBL, because of the higher electron mobility of pT2T and the better stability of its radical anion state.

A Phase 1, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Subcutaneous Tezepelumab in Healthy Japanese Men.

Tezepelumab, a human immunoglobulin G2 monoclonal antibody against thymic stromal lymphopoietin, is currently under clinical development for the treatment of severe, uncontrolled asthma. This phase 1, randomized, placebo-controlled, single-ascending-dose study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Participants were assigned to 1 of 3 tezepelumab dose cohorts (35, 105, or 280 mg; n = 8 per cohort) and randomized (6:2) to receive a single subcutaneous dose of tezepelumab or placebo, with a follow-up period of 84 to 112 days. The overall incidences and severities of treatment-emergent adverse events were similar across tezepelumab doses and between the tezepelumab and placebo groups. Tezepelumab was absorbed slowly, reaching a maximum serum concentration (mean, 5.2-39.7 µg/mL) after 7 to 10 days. Area under the concentration-time curve (mean, 207.2-1612.0 µg · day /mL) increased in an approximate dose-proportional manner. Tezepelumab had a long terminal serum half-life (mean, 23.9-26.3 days) and a small apparent distribution volume, suggesting limited distribution into peripheral tissues. No participants developed anti-tezepelumab antibodies. Single-dose, subcutaneous administration of tezepelumab 35 to 280 mg resulted in an acceptable safety profile with linear pharmacokinetics in healthy Japanese men. No clear differences in tezepelumab safety and pharmacokinetics between Japanese and non-Japanese populations were identified.