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Abstract Background In 2019, the shortage of cefazolin led to the demand for cefotiam and cefmetazole exceeding the supply. The Department of Nephro-urology at Nagoya City University Hospital used fosfomycin as a substitute for perioperative prophylaxis. This retrospective preliminary study evaluated the efficacy of fosfomycin and cefotiam for preventing infections following ureterorenoscopy. Methods The study included 182 patients who underwent ureterorenoscopy between January 2018 and March 2021). Perioperative antibacterial treatment with fosfomycin (n = 108) or cefotiam (n = 74) was administered. We performed propensity score matching in both groups for age, sex, preoperative urinary catheter use, and preoperative antibiotic treatment. Results The fosfomycin and cefotiam groups (n = 69 per group) exhibited no significant differences in terms of patients’ median age, operative duration, preoperative urine white blood cell count, preoperative urine bacterial count, and the rate of preoperative antibiotic treatment. In the fosfomycin and cefotiam groups, the median duration of postoperative hospital stay was 3 and 4 days, respectively; the median maximum postoperative temperature was 37.3 °C and 37.2 °C, respectively. The fosfomycin group had lower postoperative C-reactive protein levels and white blood cell count than the cefotiam group. However, the frequency of fever > 38 °C requiring additional antibiotic administration was similar. Conclusions During cefotiam shortage, fosfomycin administration enabled surgeons to continue performing ureterorenoscopies without increasing the complication rate.

Abstract Background Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum‐based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death‐ligand 1 (PD‐L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD‐L1 expression who received MONO or COMB as a first‐line treatment. Here, we report updated data and evaluate the long‐term outcomes. Methods We performed a retrospective multicenter study of 298 patients with NSCLC and high PD‐L1 expression who received MONO or COMB as first‐line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff. Results In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0–1). At the prolonged data cutoff, the median follow‐up was 20.2 (range: 0.1–41.4) months. The median progression‐free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow‐up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO. Conclusions COMB may be effective as a first‐line treatment for NSCLC with high PD‐L1 expression in a selected subset of patients.

Introduction and Objectives: The mechanisms of hepatic fat loss in late-stage metabolic dysfunction-associated fatty liver disease (MASLD) are enigmatic and the prognostic significance of low hepatic fat content (LHF) in chronic liver disease (CLD) is unknown. Proton density fat fraction (PDFF), measured by magnetic resonance imaging (MRI), is considered the most accurate noninvasive method for quantifying hepatic fat content. This study aimed to address these issues by evaluating PDFF. Patients and Methods: This is a single-center, retrospective study involving 762 patients with CLD, measuring liver stiffness (LS) using MR elastography and PDFF using MRI. LHF was defined as a PDFF ≤ 2.7 % and hepatic reserve function was assessed using the albumin-bilirubin (ALBI) score. Multivariate analysis explored associations between variables. Results: LHF was 27 % in the entire cohort, and PDFF was significantly decreased with LS ≥ 5.5 kPa (p < 0.05). On the multivariate analysis, low body mass index and ALBI score were independently associated with LHF (p < 0.05). In advanced CLD (n = 288), ALBI score and PDFF showed a significant negative correlation regardless of etiology (MASLD/non-MASLD: r= -0.613/-0.233), and the prevalence of LHF increased with progression of ALBI grade (p < 0.01 each). In addition, lower PDFF was associated with increased liver-related and all-cause mortality (p < 0.01), and Cox proportional hazards models extracted LHF as an independent prognostic factor, along with ALBI score and hepatocellular carcinoma (p < 0.05 each). Conclusions: In ACLD, hepatic reserve dysfunction contributed to hepatic fat loss independent of nutritional status, suggesting that LHF may be a poor prognostic factor in all etiologies.

Abstract Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC). Although the primary endpoint of disease‐free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer‐related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co‐mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co‐mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co‐mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07–28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co‐mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR‐mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

One of the threats to industrial unmanned aerial vehicles (UAVs), which require a high level of safety, is the degradation of control wireless communication performance due to electromagnetic interference. Self-jamming caused by unintentional electromagnetic (EM) noises from the multiple electronic devices installed in a UAV, such as the power supply and camera, is a fundamental issue independent of the surrounding environment. UAVs are susceptible to self-jamming since electronic devices as noise sources are densely mounted inside their chassis. Therefore, evaluating the self-jamming problem and taking countermeasures to achieve high safety in wireless communication performance are important. In this paper, we focus on mobile communications used for UAV operation and evaluate the impact of EM noise generated by a commercial industrial UAV on the receiver sensitivity of an onboard mobile communication device. It was found that EM noise generated by the UAV degrades the sensitivity in the three communication bands, 800 MHz, 1800 MHz, and 2100 MHz, used over the air. In particular, receiver sensitivity was degraded by up to 29 dB in the 800 MHz band. These results indicate that the self-jamming problem is not negligible for the safe operation of industrial UAVs. In addition, countermeasures for self-jamming were taken at the mechanical design level to suppress EM noise to a level that does not degrade mobile communication performance. This paper clarified that countermeasures for self-jamming are an important element for safe UAV operation.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo–not reached; n = 39) and 23.7 months (95% CI: 14.5–43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29–0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Abstract Background and Aim In this retrospective study, we evaluated the effects of pemafibrate treatment in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) and hypertriglyceridemia using non‐invasive stiffness‐based models, including magnetic resonance elastography (MRE) combined with the fibrosis‐4 (FIB‐4) (MEFIB) index and the magnetic resonance imaging (MRI)‐aspartate aminotransferase (AST) (MAST) score. Methods In total, 179 patients with MASLD treated with pemafibrate were enrolled. We evaluated the effects of 48‐week pemafibrate treatment using the MEFIB index, which classifies patients based on the combination of liver stiffness measurement (LSM) on MRE and FIB‐4 and the MAST score, which is calculated based on LSM on MRE, MRI‐proton density fat fraction (MRI‐PDFF), and AST levels. Results Pemafibrate treatment led to significant reduction in AST, alanine aminotransferase (ALT), and gamma‐glutamyl transferase (GGT) (P = 0.011,

Abstract Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.

Abstract Background There is no well‐established late‐line treatment for advanced nonsquamous non‐small cell lung cancer (NSCLC). Therefore, we retrospectively determined the efficacy and safety of platinum rechallenge with paclitaxel‐carboplatin and bevacizumab in patients with nonsquamous NSCLC as a late‐line therapy in a clinical setting. Methods Thirty patients with nonsquamous NSCLC who received paclitaxel‐carboplatin with bevacizumab therapy as a late‐line treatment at Sendai Kousei Hospital (Miyagi, Japan) between December 2011 and December 2021 were enrolled into the study. The efficacy and safety of this treatment were evaluated. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were estimated. Results The median progression‐free survival (PFS) was 6.3 (range, 4.9–6.8) months, and the median overall survival (OS) was 11.8 (range, 7.2–17.2) months. There were no significant differences in PFS and OS between patients with and those without epidermal growth factor receptor mutations. In the univariate analyses of this study, responders were younger than nonresponders (p = 0.012). No fatal adverse events were reported. Conclusions With the increase in the number of treatment options in recent years, the sequence of treatments and overall therapeutic strategy are becoming increasingly important. Thus, platinum rechallenge with paclitaxel‐carboplatin and bevacizumab, a late‐line treatment for patients with nonsquamous NSCLC, may be an effective therapeutic option.

Abstract Background The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L). Methods B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing. Discussion The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC. Trial registration jRCT identifier: jRCTs041210103.

We compute the canonical partition functions and the Lee–Yang zeros in Nf=2 lattice QCD at temperature T=1.20Tc lying above the Roberge–Weiss phase transition temperature TRW. The phase transition is characterized by the discontinuities in the baryon number density at specific values of imaginary baryon chemical potential. We further develop our method to compute the canonical partition functions using the asymptotic expression for respective integral. Then, we compute the Lee–Yang zeros and study their behavior in the limit of high baryon density.

Introduction: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. Methods: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. Results: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%–90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%–99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo–not reached). The overall response rate was 64.0% (95% CI: 45.2%–82.8%), median PFS was 11.5 months (95% CI: 6.9 mo–not reached), and median survival time was 23.7 months (95% CI: 16.5 mo–not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). Conclusions: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. Trial registration: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.

Introduction: Perioperative treatment in NSCLC has gained marked attention with the introduction of immune checkpoint inhibitors. Such a paradigm shift has given us additional opportunities to evaluate potential biomarkers in patients with these curable disease stages. Methods: This study (WJOG12319LTR) was designed as a biomarker study to evaluate whether soluble immune markers were prognostic or predictive on relapse-free survival in patients with stage II to IIIA NSCLC who underwent complete resection and adjuvant chemotherapy with cisplatin plus S-1, which is an oral fluoropyrimidine formulation that consists of tegafur, gimeracil, and oteracil, or S-1 alone in the previous WJOG4107 study. Archived plasma samples were assayed for soluble (s) forms of programmed cell death protein 1 (sPD-1), programmed death-ligand 1(sPD-L1), and CTLA-4 (sCTLA-4) with the highly sensitive HISCL system. Using time-dependent receiver operating characteristic curve analysis, the area under the curves were derived and optimal cutoff values were determined. Using the cutoff values, whether the marker was prognostic or predictive was assessed by survival analysis. Results: A total of 150 patients were included in the study. The time-dependent receiver operating characteristics analysis revealed that the area under the curves for sPD-1, sPD-L1, and sCTLA-4 were 0.54, 0.51, and 0.58, respectively. The survival analysis did not reject that hazard ratios were 1 in terms of the soluble immune marker and the treatment-marker interaction for all three markers. Conclusions: There was no proof that circulating concentrations of sPD-1, sPD-L1, and sCTLA-4 were prognostic or predictive factors of the outcome for adjuvant chemotherapy after complete resection in patients with NSCLC.

Introduction: Docetaxel plus ramucirumab could be a promising treatment for chemo-naive elderly patients with NSCLC, but high incidence of febrile neutropenia (FN) is a critical concern. We thus adopted a routine primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) to reduce FN and maximize the efficacy of docetaxel plus ramucirumab in elderly patients. Methods: This is a single arm phase 2 trial for chemo-naive elderly patients (aged ≥75 y) with advanced NSCLC. Docetaxel (60 mg/m2, d 1) plus ramucirumab (10 mg/kg, d 1) with PEG-G-CSF (3.6 mg, d 2) was administered every 3 weeks until progression. The primary end point was overall response rate (ORR) (expected ORR: 35%). Results: Between February 2018 and January 2021, 54 patients were enrolled. Median age was 78 (range: 75–86). A total of 21 (38.9%) partial response, 22 (40.7%) stable disease, nine (16.7%) progressive disease, and two (3.7%) not assessable were confirmed, resulting in ORR of 38.9% (90% confidence interval [CI]: 27.7%–51.0%) and disease control rate of 79.6%. Median progression-free survival and overall survival were 5.2 (95% CI: 4.2–6.9) and 12.7 (95% CI: 10.2–18.9) months, respectively. There were one (1.9%) FN, two (3.7%) bleeding grade greater than or equal to 3, and one (1.9%) treatment-related death (pneumonitis). Pneumonitis occurred in five patients (9.3%). Main adverse events grade greater than or equal to 3 were observed: four (7%) thrombocytopenia; three (5.6%) neutropenia; six (11.1%) hyposodium; five (9.3%) infection; five (9.3%) hypertension; four (7.4%) anorexia; and three (5.6%) oral mucositis. Conclusions: Docetaxel plus ramucirumab with PEG-G-CSF revealed efficacy and safety for chemo-naive elderly patients with NSCLC. Primary prophylactic PEG-G-CSF highly prevented FN.

Abstract Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p

Abstract We develop a disposable and cost-effective non-enzymatic glucose sensor consisting of an extended gate field effect transistor (EG-FET) to obtain effortless operation. The sensor is fabricated by printing, gold (Au) precursor ink and copper oxide nanoparticles (CuO NPs) inks using a commercial inkjet printer on a flexible Polyimide (PI) substrate. First, sensing properties are tested electrochemically. The sensor shows a sensitivity of 728.5 μA cm−2 mM−1 and a detection limit of 0.01 mM with a correlation coefficient (R) of 0.998. The observed linear dynamic range is from 0.5 to 7 mM. After that, the sensing electrode is adapted to the EG-FET. Two linear response ranges extend from 0.1 to 4 mM of a low concentration range of glucose with a sensitivity of 1295 μA cm−2 mM−1, and from 5 to 30 mM of a high concentration range of glucose with a sensitivity of 164 μA cm−2 mM−1 are observed. The EG-FET approach can enhance the detection sensitivities using amplification for a low concentration glucose range and extending a detection range for high concentration glucose. The presented work demonstrates that simply printed CuO NPs sensors can be used at low cost for disposable wide-range glucose detection devices. Article Highlights A non-enzymatic printed glucose sensor using an inkjet printer has been successfully developed. CuO nanoparticles ink is printed on thin gold electrodes on Polyimide film. We evaluate the glucose detection of extended-gate field-effect transistor (EG-FET) sensors. The sensitivity is estimated to be 1295 μA cm−2 mM−1. The EG-FET structure has the merit of a simple operation and cost-effective personal health care devices.

Abstract Management of cancer-associated venous thromboembolism (VTE) is essential in treatment selection and cancer prognosis. However, to date, there is no method to assess the risk of VTE specifically associated with advanced lung cancer. Our aim was to create a new risk assessment scoring system that can predict the concomitant or incidence of VTE in advanced lung cancer. We used the dataset of 1008 patients with lung cancer in the Rising-VTE/NEJ037 study, of which 100 (9.9%) developed VTE. The items extracted in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2, and diastolic blood pressure. This model had a maximum score of 8 points, with ≥ 5 points indicating a high risk of VTE. This simple risk-assessment model for VTE complications with advanced lung cancer could help identify cases that required monitoring for VTE.

Background: Osimertinib was first approved for the treatment of non-small cell lung cancer (NSCLC) in patients who have developed the epidermal growth factor receptor (EGFR) T790M mutation after treatment with EGFR tyrosine kinase inhibitors (TKIs). We routinely evaluated the plasma of NSCLC patients with the T790M mutation to more rapidly detect an increase in disease activity and resistance to treatment. Methods: Eligible patients received osimertinib after resistance to the first- or second-generation of EGFR-TKIs in NSCLC harboring T790M mutation detectable in tumor tissue or plasma. Plasma samples were collected every 8 weeks during osimertinib treatment. The plasma analysis was performed using an improved PNA-LNA PCR clamp method. We tested samples for a resistance mechanism, including EGFR-activating, T790M, and C797S mutations, and assessed the association between the mutations and osimertinib treatment. Results: Of the 60 patients enrolled in the study, 58 were eligible for this analysis. In plasma collected before osimertinib treatment, activating mutations were detected in 47 of 58 patients (81.0%) and T790M was detected in 44 patients (75.9%). Activating mutations were cleared in 60.9% (28/46) and T790M was cleared in 93.0% (40/43). Of these, 71.4% (20/28) of activating mutations and 87.5% (35/40) of T790M mutation were cleared within 8 weeks of treatment. The total response rate (RR) was 53.4% (31/58). The median duration of treatment was 259 days, with a trend toward longer treatment duration in patients who experienced the clearance of activating mutations with osimertinib. At the time of disease progression during osimertinib treatment, C797S was detected in 3 of 37 patients (8.1%). Conclusion: Plasma EGFR mutation analysis was effective in predicting the effect of osimertinib treatment.

Abstract Background NJLCG1402 was a phase I/II trial investigating biweekly nanoparticle albumin‐bound paclitaxel (nab‐PTX) in patients with advanced non‐small cell lung cancer (NSCLC). Methods The study included patients aged ≥20 years with previously treated NSCLC. Nab‐PTX (100–150 mg/m2) was administered biweekly in a 28‐day cycle. The phase I portion was performed to determine the recommended phase II dose of nab‐PTX. In the phase II portion, the primary endpoint was the objective response rate. Secondary endpoints were disease control rate, progression‐free survival, overall survival, and safety. Results A total of 15 patients received biweekly nab‐PTX (100–150 mg/m2) and 12 patients in phase II were treated with 150 mg/m2. In the phase I portion, 150 mg/m2 was determined as the recommended dose. Among those treated with 150 mg/m2, the objective response rate was 22%, and the median progression‐free and overall survival was 3.6 and 11.2 months, respectively. Adverse events grade ≥3 were observed in 39% of patients. Conclusions Biweekly nab‐PTX monotherapy was well tolerated and exhibited favorable antitumor activity in patients with previously treated NSCLC.

Abstract Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1–73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9–23.9) months. The median overall survival was not reached (95% confidence interval 24.6–not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

Abstract is missing (Short communication)

Abstract Background A cisplatin plus irinotecan (CPT‐11) regimen is used for patients with extensive disease small cell lung cancer (ED‐SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open‐label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED‐SCLC who responded to induction therapy. Methods Patients with histologically‐ or cytologically‐confirmed ED‐SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m2 on day 1) plus CPT‐11 (60 mg/m2 on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT‐11 (60 mg/m2 on days 1 and 8) every three weeks, or AMR (35 mg/m2 on days 1–3) every three weeks. Results A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT‐11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6–11.8), and the median overall survival was 20.1 months (95% CI: 13.7–not reached). No statistically significant difference in progression‐free survival (PFS) were noted between patients treated with CPT‐11 and those treated with AMR. There were no treatment‐related deaths in this study. Conclusions Maintenance therapy with CPT‐11 or AMR after induction therapy might be effective in some patients.

Abstract Background The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti‐programmed cell death‐1 antibody in patients with advanced non‐small cell lung cancer (NSCLC). Methods Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time‐to‐treatment failure (TTF), progression‐free survival (PFS), and overall survival (OS). Results CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months–not reached] vs. 3.9 months [95% CI: 3.4–5.1 months, p

Background: Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors. Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation. Results: Data were available for 1008 patients. The median age was 70 years (range: 30–94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group. Conclusions: VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate. Trial registration: jRCTs061180025.

Abstract Polytetrafluoroethylene (PTFE) fine powder with 93% crystallinity was irradiated by an electron beam (EB) at various temperatures under a nitrogen atmosphere. Trapped free radicals in PTFE were studied using electron spin resonance (ESR) spectroscopy. The observed spectra of the samples exposed to air after irradiation at various temperatures showed asymmetrical signals, which are middle-chain type peroxide macroradicals derived from fluoroalkyl radicals. The radical yields at each irradiation temperature increased with increasing absorbed dose, and eventually saturated. The higher irradiation temperature resulted in higher radical yields when compared at the same exposed dose. Furthermore, the G-value of the radicals (G(R·)) increases with increasing irradiation temperatures corresponding to each relaxation and transition temperature. It is concluded that the chain reaction by the fluorine extraction from the main chain due to the end-chain radical generated via β-scission after dissociative electron attachment (DEA) is enhanced by the synergistic effect of heat and radiation.

Cats urgently visit emergency hospitals due to respiratory distress, and the chief cause is cardiogenic pulmonary edema (CPE). Although cats with CPE were frequently encountered in clinics, the prognostic factors were poorly reported. The objective of this retrospective study was to investigate the association of physical examination and venous blood gas parameters with the survival of cats with CPE in an emergency hospital. Thirty-six cats with CPE were ultimately included in the present study, and eight of them died within 12 h after their presentation to our hospital. Statistical analyses of clinical parameters between cats that died within 12 h and those that survived for 12 h were conducted using Mann–Whitney U test with Bonferroni correction. Cats that died within 12 h had significantly lower rectal temperatures and higher PvCO2 than those that did not die within 12 h. Moreover, hypotension and vasoconstrictor use were related to death within 12 h of presentation and higher PvCO2. These findings indicated the prognostic utility of body temperature and PvCO2, and the association between hypercapnia and the severity of CPE or hypotension. A large number of prospective studies should be performed to validate these results.

In July 2017, the Japanese Association for Infectious Diseases issued guidance for the administration of the PPSV23 revaccination. Despite increasing recognition of its protective benefits, levels of PPSV23 revaccination coverage rate in Japanese elderly population are unclear at present. Here, we report the results of a survey to know PPSV23 revaccination rates among elderly patients aged 65 and older. We asked an array of questions related to PPSV23 revaccination to Elderly adults and doctors across Japan via Web-based surveys in June 2018. The sampled population consisted of 5,085 men and women aged 65 and older. The PPSV23 revaccination coverage rate was estimated by survey questions regarded vaccination counts, intervals, and vaccine type. In addition, 400 internal medicine physicians were surveyed and asked about their reasons for recommending PPSV23 revaccination to elderly patients. In total, 1,648 elderly adults had received at least one PPSV23 dose; of these, 58 had received it at least twice (revaccination coverage rate: 3.5%). The most commonly cited justification for revaccination with PPSV23 among the surveyed physicians was that the benefits of revaccination exceed the risks of revaccination. In addition, multivariate analysis showed revaccinated status was most strongly associated with recommendations from peers (e.g. spouse, family, friends) among elderly subjects. This study reports PPSV23 revaccination coverage rate among Japanese adults aged 65 and older for the first time and concludes that the coverage rate is very low.

The 23-valent capsular polysaccharide pneumococcal vaccine (PPSV23) was introduced in Japan’s routine immunization schedule October 2014. It was recommended for adults aged 65 years (including those ≥65 during the transition period), and for adults 60–64 with cardiac, renal, or respiratory dysfunction equivalent to Level 1 physical disability. Several studies have shown that patients aged 50+ with chronic medical conditions (CMC) are at elevated risk of pneumococcal infection. Nonetheless, PPSV23 vaccination rates among this population remains low. In our study, we report the results of a survey investigation into PPSV23 vaccination rates among Japanese patients aged 50+ with CMC. Patients aged 50+ comprised the patient population (n = 5,078) and internal medicine physicians comprised the doctor population (n = 400) located all over Japan were asked an array of questions relevant to PPSV23 immunization in June 2018 via Web-based surveys. PPSV23 coverages among chronic patients aged 50–59, 60–64, and 65+ years were respectively 1.3%, 2.9%, and 37.8%. The high disease-specific PPSV23 rates seen in the 65+ group was 50.0% and 49.4%, for chronic liver disease and chronic lung disease, respectively. Doctors most frequently cited a lack of municipal subsidies as justification for recommending the vaccine to patients with CMC aged 50–64 years, and deference to patients’ wishes as justification for patients with CMC aged 65+. In conclusion, PPSV23 has poor coverage among Japanese adults aged 50–64 with CMC. Doctors and local authorities need to raise public awareness to improve the vaccination rate, given the high risk of pneumococcal infectious disease among patients with CMC.

The spot size at which the electric field distribution for higher-order modes in few-mode fibers (FMFs) is approximated by a higher-order Gaussian profile is a promising parameter for estimating various transmission characteristics. To establish a technique for measuring the mode field diameter (MFD) corresponding to higher-order Gaussian spot size for any-order mode in FMFs, we investigate the relation between the higher-order Gaussian spot size and the values yielded by conventional MFD definitions. We then present formulas that output the MFD values corresponding to higher-order Gaussian spot size. Some examples of the MFD values for typical few-mode fibers determined experimentally and numerically are also shown.

Marine phytoplankton are major primary producers, and their growth is primarily limited by nitrogen in the oligotrophic ocean environment. The haptophyte Braarudosphaera bigelowii possesses a cyanobacterial endosymbiont (UCYN-A), which plays a major role in nitrogen fixation in the ocean. However, host-symbiont interactions are poorly understood because B. bigelowii was unculturable. In this study, we sequenced the complete genome of the B. bigelowii endosymbiont and showed that it was highly reductive and closely related to UCYN-A2 (an ecotype of UCYN-A). We succeeded in establishing B. bigelowii strains and performed microscopic observations. The detailed observations showed that the cyanobacterial endosymbiont was surrounded by a single host derived membrane and divided synchronously with the host cell division. The transcriptome of B. bigelowii revealed that B. bigelowii lacked the expression of many essential genes associated with the uptake of most nitrogen compounds, except ammonia. During cultivation, some of the strains completely lost the endosymbiont. Moreover, we did not find any evidence of endosymbiotic gene transfer from the endosymbiont to the host. These findings illustrate an unstable morphological, metabolic, and genetic relationship between B. bigelowii and its endosymbiont.

We calculate for the first time the scattering cross section between lightest glueballs in SU(2) pure Yang-Mills theory, which are good candidates of dark matter. In the first step, we evaluate the interglueball potential on lattice using the HAL QCD method, with several lattice spacings (β=2.1,2.2,2.3,2.4, and 2.5). The systematics associated with nonzero angular momentum effect is removed by subtracting the centrifugal force. The statistical accuracy is improved by employing the cluster-decomposition error reduction technique and by using all space-time symmetries. We then determine the low energy glueball effective Lagrangian and the scattering cross section at low energy, which is compared with the observational constraint on the dark matter self-scattering. We derive the lower bound on the scale parameter of the SU(2) Yang-Mills theory, as Λ>60 MeV.

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

BackgroundStudies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone.MethodsWe conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors.ResultsA total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology, EGFR or ALK genetic alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively.ConclusionsAfter accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.

The amount of hydrogen released after high-pressure hydrogen loading in carbonate was evaluated. Calcium carbonate (CaCO3) and Mg-substituted CaCO3 were selected as adsorbents. Their crystal structures, specific surface areas (SBET), hydrogen content at high pressure, and the amount of hydrogen released in water were investigated. Calcitic CaCO3 and (Ca0.94,Mg0.06)CO3 structures were identified for the respective samples, and their adsorption forms were found to be of type II as per IUPAC classification. The SBET values were 2.9–6.8 m2/g. The hydrogen content in (Ca0.94,Mg0.06)CO3 was found to be higher than that of calcite CaCO3 at high pressures. Furthermore, the amount of hydrogen released by the (Ca0.94,Mg0.06)CO3 sample was ~20-times higher than that from calcitic CaCO3, measured by gas chromatography. Keywords: Carbonate, Hydrogen absorption/release, Loading hydrogen at high pressure, Gas chromatography (GC)

Background/Purpose: Blood cultures for patients suspected of having bacteremia are standard practice, although several studies demonstrate that blood cultures have limited utility because of a low true-positive rate and infrequent resultant changes in antibiotic treatment. However, most reports exclude immunocompromised patients such as transplant recipients. We assessed the utility of blood cultures in transplant recipients hospitalized for community-acquired infections and evaluated clinical characteristics to predict bacteremia. Methods: This retrospective study included 136 febrile cases in 97 kidney transplant recipients admitted to our hospital for whom blood cultures were performed between February 2001 and March 2013. Results: Among the 136 cases, blood cultures were positive, contaminated, and negative in seven (5.1%) cases, 12 (8.8%) cases, and 117 cases (86.1%), respectively. All bacteria detected in the seven cases were sensitive to the initial empirical antibiotics. Antibiotic treatment was changed based on the blood culture results only in one case for which the coverage was narrowed. The white blood cell count and C-reactive protein level were significantly higher in the patients with bacteremia. The predictive model based on these two factors successfully identified the high-risk group with a sensitivity and specificity of 86% and 91%, respectively. Conclusion: Among the outpatient kidney transplant recipients, positive blood cultures were uncommon and scarcely affected antibiotic therapy, especially in patients with upper respiratory tract or urinary tract infections. Therefore, it may be reasonable to perform blood cultures only for patients with marked leukocytosis and high C-reactive protein level, even among transplant recipients.

Background: Cough-variant asthma (CVA) and cough-predominant asthma (CPA) are the major causes of persistent cough in Japan. The utility of fractional exhaled nitric oxide (FeNO) measurement in the differential diagnosis of persistent cough has been reported, but the influence of atopic status, which is associated with higher FeNO levels, on the diagnostic utility of FeNO has been unknown. Methods: We retrospectively analyzed 105 non-smoking patients with prolonged and chronic cough that were not treated with corticosteroids and anti-leukotrienes. Results: CPA was diagnosed in 37 patients, CVA in 40, and non-asthmatic cough (NAC) in 28. FeNO levels were significantly higher in the CPA [35.8 (7.0–317.9) ppb] and CVA [24.9 (3.1–156.0) ppb] groups than in the NAC group [18.2 (6.9–49.0) ppb] (p

We investigated the mechanisms underlying the suppression of the rewarding effects of opioids using the femur bone cancer (FBC) mouse model. The rewarding and antinociceptive effects of subcutaneously administered morphine and oxycodone in the FBC model mice were assessed using the conditioned place preference test and the von-Frey test. In FBC mice, antinociceptive doses of morphine (30 mg/kg) and oxycodone (5 mg/kg) did not produce the rewarding effects but excessive doses of morphine (300 mg/kg) and oxycodone (100 mg/kg) did. Western blot analyses revealed a transient and significant increase in phosphorylated-extracellular regulated kinase (p-ERK) levels in ventral tegmental area (VTA) 5 min after the administration of morphine in sham-group. Interestingly, in FBC group, a regular dose of morphine did not increase p-ERK levels but a high dose of morphine caused an increase in p-ERK level 5 min after administration. The rewarding effects of a regular dose of and a high dose of morphine in the sham-operation and FBC model, respectively, were significantly inhibited by the MEK inhibitor. The suppression of p-ERK might result in resistance to these rewarding effects under the conditions of bone cancer.

This paper presents the concept, design, and characterization of a new type of integrated device with a hybrid structure. The proposed device is hybridized with an electrothermal actuator and a bending sensor with temperature-compensating ability, which can serve as a self-sensing system. The sensor displays a parallel change in the electrical resistance upon the temperature alteration, resulting enables a cancellation of cross talk. The actuator exhibits a visible maximum strain of 1.2% at an electric power intensity of around 1.05 mW/mm3, and the bending sensor can display the curvature without the need for an external monitoring system such as a laser displacement meter. The traceability of the motion is represented well while power is supplied, but a slight delay occurs when the power is switched off, this being due to the difference in thermal conductivity between the composite of the actuator and the sensor. This proposed hybrid device realizes a simple self-sensing operation using a simple power supply and monitoring reading lines. It offers ease of fabrication and promising practical applications in remote sensing/operating devices.

Muscle atrophy can be caused by unloading stress such as microgravity environments or cast immobilization. Therapies for such disuse muscle atrophy and their underlying mechanisms are incompletely understood. Here, we investigated the therapeutic effects of local vibration stimulation on immobilization-induced skeletal muscle atrophy. A rat model was made by placing the left hindlimb in a cast for 1 week, leading to oxidative myofiber atrophy without myopathic changes in soleus skeletal muscle. Vibration stimulus (90 Hz, 15 min) to the plantar fascia of the atrophic hindlimb was performed once a day using a hand-held vibration massager after removal of a cast at the end of the immobilization period. After 2 weeks, rats were dissected, and quantitative analysis of the cross-sectional areas of soleus myofibers was performed. The results revealed that vibration induced significant recovery from disuse muscle atrophy, compared with untreated immobilized samples. Furthermore, vibration treatment suppressed the fiber transition from slow to fast fiber types compared with vibration-untreated immobilized samples. Western blotting analyses of mechanical stress-induced factors revealed that the expression of mechano-growth factor (MGF), systemic insulin-like growth factor I, and the mechanotransduction protein, Yes-associated protein 1 (YAP1), was decreased in untreated immobilized soleus muscle, whereas vibration stimulation restored their expression. No change in the level of phosphorylation of YAP1Ser127 was observed, leading to no change in p-YAP1/YAP1 ratio in vibration-treated immobilized soleus muscle. The results indicate that vibration stimulus is effective to restore immobilization-induced inactivation of YAP1 pathway. Phosphorylation of ERK 1/2, but not AKT, was enhanced in vibration-treated immobilized soleus muscle. Furthermore, vibration stimuli restored immobilization-induced downregulation of the paired box transcription factor, PAX7, a critical factor for regenerative myogenesis in muscle satellite cells. Our results indicate that cyclic vibration stimuli are effective in activating satellite cells and facilitate recovery from immobilization-induced oxidative myofiber atrophy through upregulation of MGF and YAP1.

The aim of this cross-sectional study was to investigate relationships between individuals’ ratings of satisfaction and performance of activities that they found meaningful and depressive symptoms. Data was obtained from 806 older adults (mean age 74.9 ± 6.3 years, women = 63.0%) who participated in a community-based health check survey (Tarumizu Study 2018). Participants selected meaningful activities from 95 activities using the Aid for Decision-Making in Occupation Choice and evaluated their satisfaction and performance. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15) and defined by a GDS-15 score of ≥5. Non-linear logistic regression analyses were used separately by gender to examine the association between satisfaction and performance of meaningful activities and depressive symptoms. The prevalence of depressive symptoms was 15.8%. We found no significant difference between meaningful activity choice between older adults with depressive symptoms and those without, in both men and women. After adjusting for potential covariates, satisfaction was associated with depressive symptoms in both men (OR 0.52, 95% CI 0.35−0.77) and women (OR 0.67, 95% CI 0.49−0.91), but performance was limited in women (OR 0.87, 95% CI 0.77−0.99). Our findings suggest that depressive symptoms are associated with satisfaction in meaningful activities regardless of activity categories.

We report on the successful synthesis of a p-type, substitutional doping at S-site, MoS2 thin film using Phosphorous (P) as the dopant. MoS2 thin films were directly sulfurized for molybdenum films by chemical vapor deposition technique. Undoped MoS2 film showed n-type behavior and P doped samples showed p-type behavior by Hall-effect measurements in a van der Pauw (vdP) configuration of 10×10 mm2 area samples and showed ohmic behavior between the silver paste contacts. The donor and the acceptor concentration were detected to be ∼2.6×1015 cm-3 and ∼1.0×1019 cm-3, respectively. Hall-effect mobility was 61.7 cm2V-1s-1 for undoped and varied in the range of 15.5 ∼ 0.5 cm2V-1s-1 with P supply rate. However, the performance of field-effect transistors (FETs) declined by double Schottky barrier contacts where the region between Ni electrodes on the source/drain contact and the MoS2 back-gate cannot be depleted and behaves as a 3D material when used in transistor geometry, resulting in poor on/off ratio. Nevertheless, the FETs exhibit hole transport and the field-effect mobility showed values as high as the Hall-effect mobility, 76 cm2V-1s-1 in undoped MoS2 with p-type behavior and 43 cm2V-1s-1 for MoS2:P. Our findings provide important insights into the doping constraints for transition metal dichalcogenides.

A previous study reported that low baseline cerebral oxygen saturation (ScO2) (≤50%) measured with near-infrared spectroscopy was predictive of poor clinical outcomes after cardiac surgery. However, such findings have not been reconfirmed by others. We conducted the current study to evaluate whether the previous findings would be reproducible, and to explore mechanisms underlying the ScO2-based outcome prediction.We retrospectively investigated 573 consecutive patients, aged 20 to 91 (mean ± standard deviation, 67.1 ± 12.8) years, who underwent major cardiovascular surgery. Preanesthetic baseline ScO2, lowest intraoperative ScO2, various clinical variables, and hospital mortality were examined.Bivariate regression analyses revealed that baseline ScO2 correlated significantly with plasma brain natriuretic peptide concentration (BNP), hemoglobin concentration (Hgb), estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) (p < 0.0001 for each). Baseline ScO2 correlated with BNP in an exponential manner, and BNP was the most significant factor influencing ScO2. Logistic regression analyses revealed that baseline and lowest intraoperative ScO2 values, but not relative ScO2 decrements, were significantly associated with hospital mortality (p < 0.05), independent of the EuroSCORE (p < 0.01). Receiver operating curve analysis of ScO2 values and hospital mortality revealed an area under the curve (AUC) of 0.715 (p < 0.01) and a cutoff value of ≤50.5% for the baseline and ScO2, and an AUC of 0.718 (p < 0.05) and a cutoff value of ≤35% for the lowest intraoperative ScO2. Low baseline ScO2 (≤50%) was associated with increases in intubation time, intensive care unit stay, hospital stay, and hospital mortality.Baseline ScO2 was reflective of severity of systemic comorbidities and was predictive of clinical outcomes after major cardiovascular surgery. ScO2 correlated most significantly with BNP in an exponential manner, suggesting that BNP plays a major role in the ScO2-based outcome prediction.

Abstract.: Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3 – 0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017 – 0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 μg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [35S]-GTPγS binding assay, activation of μ-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model. Keywords:: opioid, antinociception, oxaliplatin, neuropathy, Gi/o protein

The rewarding effects of μ-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used μ-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of μ-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug–induced neuropathic pain. Nevertheless, no information is available regarding whether μ-receptor agonists produce psychological dependence under chemotherapeutic drug–induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of μ-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of μ-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of μ-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on μ-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain. Keywords:: rewarding effect, oxaliplatin, paclitaxel, neuropathic pain, μ-opioid receptor agonist

Abstract.: Although norepinephrine transporter (NET) inhibition has an additional effect on μ-opioid receptor (MOR)-mediated anti-nociception in inflammatory and neuropathic pain, its effect on cancer pain is not well characterized. We investigated the additional effect of NET inhibition on MOR activation using a mouse femur bone cancer (FBC) pain model by comparing the antinociceptive effect of the dual-acting opioids tramadol and tapentadol and the clinically used MOR-targeted opioids oxycodone and morphine. The anti-nociceptive effects of subcutaneously administered opioids were assessed using the von-Frey filament test. Oxycodone (1 – 10 mg/kg) and morphine (5 – 50 mg/kg) dose-dependently exhibited potent anti-nociceptive effects, whereas tramadol (10 – 56 mg/kg) and tapentadol (10 – 30 mg/kg) exhibited partial effects. Rota-rod analyses of tapentadol at a higher dose (> 30 mg/kg) showed a significant decrease in motor coordination, which was partially recovered by pretreatment with MOR or α1-adrenoceptor antagonists. The partial anti-nociceptive effect of tapentadol (30 mg/kg) was completely suppressed by a MOR antagonist, but not by α1- or α2-adrenoceptor antagonists, suggesting that neither α1-adrenoceptor- nor α2-adrenoceptor-mediated pathways are involved in anti-nociception in the FBC model. We conclude that addition of NET inhibition does not contribute to MOR-mediated anti-nociception in bone cancer pain. Keywords:: femur bone cancer pain, norepinephrine transporter, oxycodone, tapentadol, μ-opioid receptor (MOR)

The drag and lift of footballs have been mainly measured by wind tunnel tests. In the present study, computational fluid dynamics (CFD) and the lattice Boltzmann method were used to visualise the wakes of spinning and non-spinning footballs and analyse the dynamics of the observed vortex structures. The dominant vortex structures in the wakes of the footballs were determined to be large-scale counter-rotating vortex pairs. The fluctuation of the vortex pair for the spinning football was also estimated to be smaller and more stable than that for the non-spinning football. Although the presence of an unstable, large-scale counter-rotating vortex pair in the wake of a non-spinning ball has been previously observed in wind tunnel tests, the present study particularly found that the dominant vortex structure of a spinning ball was a stable, large-scale counter-rotating vortex pair.

Morphine, oxycodone, and fentanyl are clinically prescribed drugs for the management of severe pain. We investigated whether these opioids possess different efficacy profiles on several types of pain in mouse pain models. When the three opioids were tested in the femur bone cancer model, all of them significantly reversed guarding behavior, whereas the effects on limb-use abnormality and allodynia-like behavior differed among the opioids. Particularly, although oxycodone (5 – 20 mg/kg) and fentanyl (0.2 mg/kg) significantly reversed limb-use abnormality, not even a high dose of morphine (50 mg/kg) could reverse it. When the effects of these opioids were examined in a sciatic nerve ligation (SNL) model of neuropathic pain, oxycodone was the most effective, producing an antinociceptive effect without affecting the withdrawal threshold of sham-treated animals. When the effects of these opioids were examined with the tail-flick test using naive animals, oxycodone, morphine, and fentanyl exhibited antinociceptive effects on thermal nociception. These results show that the three opioids exhibit different efficacy outcomes in multiple pain models and that the efficacy profile of oxycodone does not overlap those of morphine and fentanyl. Keywords:: oxycodone, morphine, fentanyl, neuropathic pain-like state, bone cancer pain