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Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, has demonstrated safety and efficacy in patients with graft-versus-host disease (GvHD). This phase 3 randomized trial (REACH3) evaluated the efficacy and the safety of ruxolitinib 10 mg twice daily compared with investigator-selected best available therapy (BAT) in a subgroup of Japanese patients (n = 37) with steroid-refractory or dependent (SR/D) chronic GvHD. At data cut-off, treatment was ongoing in 17 patients and discontinued in 20. The overall response rate (complete or partial) at week 24 was greater with ruxolitinib than BAT (50% vs. 20%; odds ratio, 4.13 [95% CI, 0.90-18.9]). The best overall response rate (complete or partial response at any time point up to week 24) was higher with ruxolitinib than BAT (68.2% vs. 46.7%; odds ratio, 2.69 [95% CI, 0.66-10.9]). Ruxolitinib led to longer median failure-free survival than BAT (18.6 months vs. 3.7 months; hazard ratio, 0.34; [95% CI, 0.14-0.85]). The most common grade ≥ 3 adverse events up to week 24 were anemia (ruxolitinib: 22.7%; BAT: 6.7%) and pneumonia (22.7% and 20.0%, respectively). Ruxolitinib showed a higher response rate and improvement in failure-free survival in Japanese patients with SR/D chronic GvHD, with a safety profile consistent with the overall study population., Competing Interests: Declarations. Conflict of interest: SS, ND, MO, TK, TIshikawa and TIkeda have nothing to disclose. KF and MT received honoraria from Janssen. YO received honoraria from Novartis, Pfizer, Janssen, AsahiKasei, Abbvie, Astellas, Amgen, Chugai, Bristol-Myers Squibb, Symbio, MSD, Meiji Seika, Sumitomo Dainippon, Daiichi Sankyo, Nippon Shinyaku, IQVIA, KISSEI and Kyowa Kirin; research funding from Novartis, Pfizer, Janssen, Meiji Seika, Incyte, and Takara Bio. TG received honoraria from Novartis and Mallinckrodt. HN received honoraria from Novartis, Janssen, Chugai, Astellas, Bristol-Myers Squibb and Takeda; research funding from Novartis, Astellas, Bristol-Myers Squibb and Takeda. YM received research funding from from Asahi Kasei, Eisai, Otsuka, Kyowa Kirin, Taiho, Takeda, Chugai, Japan blood products, Nippon Kayaku, Nippon Shinyaku, Mallinckrodt, and Regimmune; and honoraria from Asahi Kasei, AstraZeneca, Astellas, Amgen, AbbVie, Viatris, Eisai, MSD, Otsuka, ONO, Gilead, Kyorin, Kyowa, Kissei, Konica, Sanofi, Celgene, Bristol-Myers Squibb, Bayer, CSL Behring, Daiichi Sankyo, Sumitomo Dainippon, Takeda, Terumo, Chugai, Nippon Shinyaku, Novartis, Pfizer, Mundipharma, Human Life CORD, Meiji Seika, Janssen and Yakult Honsha. KK received consulting fees from AbbVie, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Janssen, and Novartis; honoraria from Bristol-Myers Squibb, Chugai, Sumitomo Pharma Co., Ltd., Janssen, Kyowa Kirin, MSD, Novartis and ONO; and research funding from AbbVie, MSD, Bristol-Myers Squibb, Janssen, Novartis, Chugai, Daiichi Sankyo, Eisai, Kyowa Kirin, and ONO. NU received honoraria from Novartis and Otsuka. AM, FS and TT are employees of Novartis Pharma K.K., Tokyo, Japan. TS is an employee of Novartis Pharma AG, Basel, Switzerland. TTeshima received honoraria from Novartis, Abbvie, Astellas, NIPPON SHINYAKU, Kyowa Kirin, Bristol-Myers Squibb, Sumitomo Pharma, Merck Sharp & Dohme, Celgene, Chugai, and Janssen; research funding from Astellas, Chugai, Fuji Pharma, Kyowa Kirin, Nippon Shinyaku, Asahi Kasei Pharma, Eisai, Sumitomo Pharma, ONO, Shionogi, Priothera SA, LUCA science and Otsuka; advisory board fees from Meiji Seika Pharma, Daiichi Sankyo, Asahi Kasei Pharma, Astellas, AstraZeneca, Takeda, Janssen, Toche Diagnostics, Sumitomo Pharma, Celgene, and Sanofi., (© 2024. The Author(s).)

Assessing the risk of postoperative cardiovascular events before performing non-cardiac surgery is clinically important. The current risk score systems for preoperative evaluation may not adequately represent a small subset of high-risk populations. Accordingly, this study aimed at applying iterative random forest to analyze combinations of factors that could potentially be clinically valuable in identifying these high-risk populations. To this end, we used the Japan Medical Data Center database, which includes claims data from Japan between January 2005 and April 2021, and employed iterative random forests to extract factor combinations that influence outcomes. The analysis demonstrated that a combination of a prior history of stroke and extremely low LDL-C levels was associated with a high non-cardiac postoperative risk. The incidence of major adverse cardiovascular events in the population characterized by the incidence of previous stroke and extremely low LDL-C levels was 15.43 events per 100 person-30 days [95% confidence interval, 6.66-30.41] in the test data. At this stage, the results only show correlation rather than causation; however, these findings may offer valuable insights for preoperative risk assessment in non-cardiac surgery., (© 2024. The Author(s).)

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5%-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (-0.3% and -0.4%, P = 0.309) or the FPG level (-9.0 and -15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

Standardized suicide mortality rates per 100,000 (SMRs) in Japan consistently decreased from 2009 to 2019 but increased from 2020. The causes of these temporal SMR fluctuations remain to be clarified. Therefore, this study was conducted to identify the causalities underlying the recently transformed fluctuations of suicide mortality in Japan. Monthly suicide numbers disaggregated by sex and social standing, and political uncertainty indices, such as economic policy uncertainty (EPU) and government management instability (AENROP), were obtained from Japanese government databases. Interrupted time-series analysis was performed to analyze temporal fluctuations of SMRs disaggregated by sex/social standing associated with the three General Principles of Suicide Prevention Policy (GPSPP) periods and the COVID-19 pandemic. Panel data and vector autoregressive analyses were conducted to investigate causalities from political uncertainties to SMRs. During the first and second GPSPPs (2009-2017), all SMRs disaggregated by sex and social standing decreased, whereas those of unemployed females did not change. During the third GPSPP (2017-2022), decreasing trends in all SMRs were attenuated compared to previous periods. All female SMRs, except unemployed females, showed sharp increases synchronized with the pandemic outbreak. No male SMRs showed sharply increasing at the pandemic outbreak. SMRs of unemployed males/females drastically increased in the later periods of the pandemic, while SMRs of employed and multiple-person/single-person household males did not increase during the pandemic. SMR of unemployed males was positively related to AENROP but not EPU. Other male SMRs were positively related to EPU/AENROP. On the contrary, not all female SMRs were related to EPU/AENROP. Increasing AENROP generally contributed to increasing male SMRs throughout the observation period; however, susceptibility to AENROP and/or political information might have unexpectedly contributed to suppressing the sharply increasing male SMRs induced by large-scale social shocks (the COVID-19 pandemic outbreak) in Japan.

Objective: The optimal region of lymph node dissection (LND) during segmentectomy in patients with small peripheral non-small cell lung cancer requires clarification. Through a supplemental analysis of the Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L, we investigated the associated factors, distribution, and recurrence pattern of lymph node metastases (LNMs) and proposed the optimal LND region., Methods: Of the 1106 patients included in the JCOG0802/WJOG4607L, 1056 patients with LNDs were included in this supplemental analysis. We investigated the distribution and recurrence pattern of LNMs along with the radiologic findings (with ground-glass opacity, part-solid tumor; without ground-grass opacity component, pure-solid tumor)., Results: The radiologic findings were the only significant factor for LNMs. Of 533 patients with part-solid tumors, 8 (1.5%) had LNMs. Further, only 3 (0.5%) patients had pN2 disease, and no patients had interlobar LNMs from nonadjacent segments. Of the 523 patients with pure-solid tumors, 55 (10.5%) had LNMs, and 28 (5.4%) had pN2 disease. Five patients had metastases to nonadjacent interlobar lymph nodes (LNs). Two (2.0%) patients with S6 tumors had upper mediastinal LNMs. In addition, the incidence of mediastinal LN recurrence in patients with S6 lung cancer was greater in those who underwent selective LND than those who underwent systematic LND (P = .0455)., Conclusions: Nonadjacent interlobar and mediastinal LND have little impact on pathologic nodal staging in patients with part-solid tumors. In contrast, selective LND is recommended at least for patients with pure-solid tumors., Competing Interests: Conflict of Interest Statement H.Y. reported honoraria from Eli Lilly, Chugai, Boehringer Ingelheim, Nippon Kayaku, Astra Zeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Ono, Merck Biopharma, Taiho, Otsuka, Takeda, Novartis, Amgen, Nipro Pharma, Kyowa Kirin, and Pfizer (payments were made to the author) and consulting fees from Delta Fly Pharma (payments were made to the author). M.T. reported participation on a Data Safety Monitoring Board or Advisory Board, Chugai Pharmaceutical Co, Ltd. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients., Methods: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO 3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis., Results: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%)., Conclusions: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases., (© 2024. The Author(s).)

Introduction: Despite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically relevant association with SU change., Method: We conducted retrospective analyses using systematically collected annual medical examination data from October 2012 to October 2022 in a Japanese preventive medicine centre. The exposure was changes in alcohol intake between two consecutive visits. The association of SU changes with alcohol intake changes was estimated by mixed-effect linear regression with adjustment for relevant covariates., Results: We analysed 63 486 participants (median age, 47.0 years; 55% women; 58.6% regular alcohol drinkers with a median of 1.4 drinks/day) with 370 572 visits. The median SU level was 5.3 mg/dL, and 506 (0.8%) participants had diagnoses of gout or hyperuricemia without medication use during the study period. Decreasing one daily alcohol intake had a clinically small association with SU changes (-0.019 (95% CI: -0.021 to -0.017) mg/dL). Beer had the largest association with SU (-0.036 (95% CI: -0.039 to -0.032) mg/dL for one beer decrease). Complete discontinuation of any alcohol from a mean of 0.8 drinks/day was associated with -0.056 mg/dL (95% CI: -0.068 to -0.043) decrease in SU; the association became larger in hyperuricemic participants (-0.110 mg/dL (95% CI: -0.154 to -0.066) for alcohol discontinuation from a mean of 1.0 drinks/day)., Conclusions: This study revealed changes in alcohol intake had small associations with SU change at the general Japanese population level. Complete discontinuation of alcohol in hyperuricemic participants had only modest improvement in SU., Competing Interests: Competing interests: HT reports personal fees from Chugai Pharmaceutical, AbbVie, Ono Pharmaceutical, Kyowa-Kirin, Takeda Pharmaceutical, Astellas Pharma, Tanabe-Mitsubishi, GSK, Pfizer, Dai-ichi-Sankyo, Eisai, Illy-lily and Ayumi, outside the submitted work. MK reports consulting fees and honoraria from AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Celgene, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, Teijin Pharma, and UCB Pharma, outside the submitted work. SKT reports consulting fees from Novartis.DS reports research grants from CorEvitas, Janssen, Moderna, and Novartis, and royalties from UpToDate. All other authors have no conflict of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: Evaluate the long-term safety and tolerability of anifrolumab 300 mg, alongside standard therapy, in patients from Japan with systemic lupus erythematosus (SLE) in the TULIP-LTE trial (NCT02794285)., Methods: TULIP-LTE was a 3-year, randomized, double-blind, placebo-controlled long-term extension (LTE) of the TULIP trials. The primary safety outcome included serious adverse events (SAEs) and AEs of special interest (AESIs) during the LTE period. Exploratory efficacy outcomes included SLE Disease Activity Index 2000 (SLEDAI-2 K) scores and glucocorticoid use. We performed a post hoc subgroup analysis of patients who enrolled in Japan., Results: Exposure-adjusted incidence rates of SAEs during the LTE and follow-up for patients receiving anifrolumab 300 mg (n = 21) were 8.7 per 100 patient-years; AESIs included influenza (6.9) and herpes zoster (3.5). One of three patients receiving placebo had an SAE (13.9). One patient per group discontinued due to an AE. There were no deaths. During the TULIP + LTE period, patients receiving anifrolumab 300 mg (n = 24) had sustained reduction from baseline in mean SLEDAI-2 K scores and cumulative glucocorticoid dosage., Conclusions: Anifrolumab 300 mg showed a favourable benefit-risk profile for the long-term treatment of adult patients with moderate to severe SLE from Japan, with safety, tolerability, and efficacy profiles consistent with the overall population., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results., (© 2024. The Author(s).)

Standardized suicide mortality rates per 100,000 population (SMRs) in Japan consistently decreased from 2009-2019, but these decreasing trends were reversed to increase in 2020. To clarify the mechanisms of recent increasing suicide in Japan, temporal fluctuations of SMRs disaggregated by sex and employment status (employed and unemployed individuals) and labor indices such as working hours, wages, and regular employment opportunity index (REO) from January 2012 to June 2023 were analyzed using interrupted time-series analysis. Additionally, temporal causalities from labor indices to SMRs were analyzed using vector autoregressive and non-linear auto-regressive distributed lag analyses. Decreasing trends among employed SMRs of both sexes were attenuated after the enactment of the "Work Style Reform Program" in 2018, but male SMRs were unaffected by the COVID-19 pandemic. However, female employed SMRs sharply increased, synchronized with the "Work Style Reform Act" and the COVID-19 pandemic outbreak (the COVID-19 impact was greater than the "Work Style Reform Act"). Additionally, unemployed SMRs of both sexes sharply increased with the revision and scale-down of countermeasures against economic deterioration caused by COVID-19 ("revision of economic supportive countermeasures against economic deterioration caused by COVID-19"). Unexpectedly, after enacting the "Work Style Reform Act", wages decreased due to possibly decreasing working hours. Increasing REO, which consistently increased, was a protective factor for male suicides, but unemployed SMRs were not affected by any labor indices. It has been established that controlling a heavy workload plays an important role in suppressing the deterioration of physical and mental conditions, including suicide; however, this study suggested that, at least within appropriate ranges of working hours, decreasing working hours due to excessive management probably contributes to increasing suicides of some vulnerable individuals via de-creasing their wages. Although governmental welfare and economic support measures had to be revised according to rapidly changing situations during the COVID-19 pandemic, this study also suggested that temporal gaps among a part of revisions of several welfare and economic support measures were unexpectedly involved in drastically/sharply increasing suicides of unemployed individuals in 2022.

Background: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results., Methods: Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200 mg every 3 weeks or investigator's choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients., Results: The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6 months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5 months with tislelizumab (n = 10) versus 2.9 months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7 months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6 months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy., Conclusions: As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population., Clinical Trial Registry: ClinicalTrials.gov: NCT03430843., (© 2024. The Author(s).)

In the open-label, phase III CheckMate 816 study (NCT02998528), neoadjuvant nivolumab plus chemotherapy demonstrated statistically significant improvements in event-free survival (EFS) and pathological complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC). Here we report efficacy and safety outcomes in the Japanese subpopulation. Patients with stage IB-IIIA, resectable NSCLC were randomized 1:1 to nivolumab plus chemotherapy or chemotherapy alone for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. The primary end-points (EFS and pCR) and safety were assessed in patients enrolled at 16 centers in Japan. Of the Japanese patients randomized, 93.9% (31/33) in the nivolumab plus chemotherapy arm and 82.9% (29/35) in the chemotherapy arm underwent surgery. At 21.5 months' minimum follow-up, median EFS was 30.6 months (95% confidence interval [CI], 16.8-not reached [NR]) with nivolumab plus chemotherapy versus 19.6 months (95% CI, 8.5-NR) with chemotherapy; hazard ratio, 0.60 (95% CI, 0.30-1.24). The pCR rate was 30.3% (95% CI, 15.6-48.7) versus 5.7% (95% CI, 0.7-19.2), respectively; odds ratio, 7.17 (95% CI, 1.44-35.85). Grade 3/4 treatment-related adverse events were reported in 59.4% versus 42.9% of patients, respectively, with no new safety signals identified. Neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate versus chemotherapy alone in Japanese patients, consistent with findings in the global population. These data support nivolumab plus chemotherapy as a neoadjuvant treatment option in Japanese patients with resectable NSCLC., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although segmentectomy was better than lobectomy in terms of overall survival for patients with non-small-cell lung cancer (NSCLC) with a pure-solid tumour appearance on thin-section CT in the open-label, multicentre, randomised, controlled, phase 3 JCOG0802/WJOG4607L trial, the reasons why segmentectomy was associated with better overall survival were unclear. We aimed to compare the survival, cause of death, and recurrence patterns after segmentectomy versus lobectomy in trial participants with NSCLC with a pure-solid appearance METHODS: We conducted a post-hoc supplemental analysis of the JCO0802/WJOG4607L randomised, controlled, non-inferiority trial for the patients (aged 20-85 years) with small-sized NSCLC with radiologically pure-solid appearance on thin-section CT (≤2 cm, consolidation tumour ratio 1·0). The primary aim was to compare the overall and relapse-free survival, cause of death, and recurrence patterns associated with segmentectomy and lobectomy for patients with radiologically pure-solid NSCLC to determine why the overall survival of segmentectomy was superior to that of lobectomy, even for oncologically invasive lung cancers. JCO0802/WJOG4607L is registered with the UMIN Clinical Trials Registry, UMIN000002317, and is complete., Findings: Between Aug 10, 2009, and Oct 21, 2014, 1106 patients were randomly assigned to undergo either lobectomy or segmentectomy. Of these participants, 553 (50%) had radiologically pure-solid NSCLC and were eligible for this post-hoc supplemental analysis. Of these 553 participants, 274 (50%) patients underwent lobectomy and 279 (50%) underwent segmentectomy. Median patient age was 67 years (IQR 61-73), 347 (63%) of 553 patients were male and 206 (37%) were female, and data on race and ethnicity were not collected. As of data cutoff (June 13, 2020), after a median follow-up of 7·3 years (IQR 6·0-8·5), the 5-year overall survival rate was significantly higher after segmentectomy than after lobectomy (86·1% [95% CI 81·4-89·7] in the lobectomy group, with 55 deaths vs 92·4% [88·6-95·0] in the segmentectomy group, with 38 deaths; hazard ratio (HR) 0·64 [95% CI 0·41-0·97]; log-rank test p=0·033), whereas the 5-year relapse-free survival was similar between the groups (81·7% [95% CI 76·5-85·8], with 34 events vs 82·0% [76·9-86·0], with 52 events; HR 1·01 [95% CI 0·72-1·42]; p=0·94). Deaths after a median follow-up of 7·3 years due to lung cancer occurred in 20 (7%) of 274 patients after lobectomy and 19 (7%) of 279 after segmentectomy, and deaths due to other causes occurred in 35 (13%) patients after lobectomy compared with 19 (7%) after segmentectomy (lung cancer death vs other cause of death, p=0·19). The locoregional recurrence was higher after segmentectomy (21 [8%] vs 45 [16%]; p=0·0021). In subgroup analyses, better 5-year overall survival after segmentectomy than after lobectomy was observed in the subgroup of patients aged 70 years or older (77·1% [95% CI 68·2-83·8] with lobectomy vs 85·6% [77·5-90·9] with segmentectomy; p=0·013) and in male patients (80·5% [73·7-85·7] vs 92·1% [87·0-95·2]; p=0·0085). By contrast, better 5-year relapse-free survival after lobectomy than after segmentectomy was observed in the subgroup younger than 70 years (87·4% [95% CI 81·2-91·7] with lobectomy vs 84·4% [77·9-89·1] with segmentectomy; p=0·049) and in female patients (94·2% [87·6-97·4] vs 82·2% [73·2-88·4]; p=0·047)., Interpretation: This post-hoc analysis showed improved overall survival after segmentectomy in patients with pure-solid NSCLC compared with lobectomy. However, survival outcomes of segmentectomy depend on the patient's age and sex. Given the results of this exploratory analysis, further research is necessary to determine clinically relevant indications for segmentectomy in radiologically pure-solid NSCLC., Funding: Japanese National Cancer Center Research and Development Fund and Practical Research for Innovative Cancer Control Fund, and a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan., Competing Interests: Declaration of interests AH, KS, KT, YT, RN, KA, HS, MT, MO, HA, and SW report research funding from the National Cancer Center Research and Development Fund by the National Cancer Center, Practical Research for Innovative Cancer Control Fund by Japan Agency for Medical Research and Development and a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan. MW reports honoraria from Nihon Medi-Physics. HS reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from MSD, Boehringer Ingelheim, Ethicon, Covidien, Chugai Pharmaceutical, Astellas Pharma, Fujifilm Medical, and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study classifies the nursing informatics competency requirements for nurses and healthcare leaders in the United States according to each of the four levels listed in the "Management Ladder for Hospital Nurse Managers (JNA version)" published by the Japanese Nursing Association. Computer skills were included in Level I. Fifteen informatics knowledge items and four informatic competency items that could not be classified for the levels of the management ladder for nurse managers in Japan. This list of nursing informatics competencies, categorized according to the management levels of hospital nurse managers, can be used to provide nursing informatics training to them.

Background: Patients with Gaucher disease (GD), a rare lysosomal storage disorder, have reduced health-related quality of life (HRQOL). A patient-reported outcome measure (PROM) for HRQOL developed for type 1 GD (GD1) is not appropriate for patients with neuronopathic GD (nGD) types 2 (GD2) and 3 (GD3). In this study, we developed a new PROM for use in all GD types. We previously reported the qualitative analysis of interviews with Japanese patients with nGD, which was used to create nGD-specific PROM items. Here we evaluated the full PROM combining the type 1 questionnaire with the new nGD-specific items., Methods: Patients with confirmed GD were recruited (Association of Gaucher Disease Patients in Japan or leading doctors) for pre-testing (May 2021) or the main survey (October-December 2021). The PROM had three parts: Parts 1 and 2 were translated into Japanese from the pre-existing GD1 PROM, whereas Part 3 was newly developed. Patients (or their caregivers, where necessary) completed the PROM questionnaire on paper and returned it by mail. Mean scores were determined overall and by GD type. Inter-item correlations, content consistency (Cronbach's alpha), and test-retest reliability (Cohen's kappa; main survey only, taken 2 weeks apart) were calculated., Results: Sixteen patients (three with GD1; six with GD2; seven with GD3) and 33 patients (nine with GD1; 13 with GD2; 11 with GD3) participated in the pre-test and main survey, respectively. All GD2 patients and one-third (6/18) of GD3 patients required caregivers to complete the questionnaire. Mean scores indicated that the burden was highest in GD2 and lowest in GD1. In the main survey, internal consistency was high (Cronbach's alpha = 0.898 overall, 0.916 for Part 3), and test-retest reliability was high for Part 3 (kappa > 0.60 for 13/16 items) but low for Part 1 (kappa < 0.60 for 12/15 items)., Conclusions: We have developed a flexible and reliable PROM that can be tailored for use in all types of GD and propose using Parts 1 and 2 for GD1, Parts 2 and 3 for GD2, and Parts 1, 2, and 3 for GD3., (© 2024. The Author(s).)

Background: Tacrolimus is one of the major treatment options for systemic lupus erythematosus (SLE) and is considered to be a pregnancy-compatible medication. Since little is known about tacrolimus safety during pregnancy complicated by SLE, this study was designed., Methods: We included SLE pregnant patients who were followed up at two Japanese tertiary referral centers. We performed multivariate logistic regression analysis to assess each adverse pregnancy outcome (APO) risk. Moreover, we assessed the influence of tacrolimus on the APO ratio in pregnant patients with lupus nephritis, and the impact of combined tacrolimus-aspirin therapy on the APO ratio relative to patients exclusively administered tacrolimus., Results: Of the 124 pregnancies, 29 were exposed to tacrolimus. Multivariate analysis showed no statistical difference in APO ratio. (overall APO: adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.23-2.03; p = 0.50; maternal APO: aOR, 1.17; 95% CI, 0.36-3.83; p = 0.80; neonatal APO: aOR, 1.10; 95% CI, 0.38-3.21; p = 0.86; PROMISSE APO: aOR, 0.50; 95% CI, 0.14-1.74; p = 0.27). Blood pressure and estimated glomerular filtration rate (eGFR) during pregnancy and after delivery did not differ between the two groups. Receiver operating characteristic (ROC) curve showed that tacrolimus concentration > 2.6 ng/ml was related to reduced preterm birth rate. (AUC = 0.85, 95% CI: 0.61-1.00, sensitivity: 93% and specificity: 75%). Regarding effect of tacrolimus on lupus nephritis during pregnancy, tacrolimus showed no increased risk of APO, blood pressure or eGFR during pregnancy and after delivery. (overall APO: OR, 1.00; 95% CI, 0.25-4.08; p = 0.98; maternal APO: OR 1.60, 95% CI, 0.39-6.64; p = 0.51; neonatal APO: OR, 0.71; 95% CI, 0.17-3.03; p = 0.65, PROMISSE APO: OR, 0.50; 95% CI, 0.08-3.22; p = 0.47). Tacrolimus-aspirin combination therapy showed a protective tendency against hypertensive disorders during pregnancy, preeclampsia and low birth weight., Conclusions: Tacrolimus use during pregnancy with SLE and lupus nephritis showed no significant influence on APO, blood pressure, or renal function; therefore tacrolimus may be suitable for controlling lupus activity during pregnancy. In addition, when using tacrolimus during pregnancy, we should aim its trough concentration ≥ 2.6 ng/ml while paying careful attention to possible maternal side effects of tacrolimus., Trial Registration: Retrospectively registered., (© 2024. The Author(s).)

A Filipino woman in her forties had facial erythema that was being self-treated with over-the-counter (OTC) drugs purchased outside of Japan. The drugs included clobetasol propionate, antibiotic, and antifungal components. Her facial erythema symptoms were worse during summertime. KOH direct examination of annular erythema was positive for fungal hyphae and negative for Demodex folliculorum. Fungal culture revealed Trichophyton indotineae based on internal transcribed spacer sequence analysis. Minimal inhibitory concentration for terbinafine was 0.06 µg/mL. We made a diagnosis of tinea faciei with steroid rosacea. We treated the patient with oral itraconazole. Physicians should be aware of increasing T. indotineae infections and increasing self-medication using topical OTC steroids combined with antifungals and antibiotics not only in India but also among foreign people living in other countries such as Japan.

Using the Japanese version of the Impact of Migraine on Partners and Adolescent Children (IMPAC) and Family Question prepared based on IMPAC, we investigated the impact of migraine on family members from the perspectives of both patients and their family members. Our results showed that migraine had an impact on the family members living with the patients in Japan as well, and the perception of migraine differed partially between patients and their family members. We also found that the Japanese version of the IMPAC showed a correlation with existing instruments to evaluate impact of migraine, indicating its validity. The application of this study's findings in clinical practice could help alleviate the disease burden of migraine on patients and their family members.

The older adult population in Japan is expected to increase. Therefore, long-term care and frailty prevention are important. However, the relationship between masticatory performance, nutritional intake, and frailty remains unclear. This cross-sectional study aimed to examine energy, protein, and vitamin D intake and its association with frailty and masticatory performance in older adults. Patients between January 2022 and January 2023 were recruited and divided into robust and frail groups. Masticatory performance, nutrition, frailty, and other data, such as age and sex, were evaluated through onsite measurements and a questionnaire. Logistic regression analysis was conducted with frailty as a dependent variable and masticatory performance as an independent variable, adjusting for age, sex, skeletal muscle mass, living alone, energy intake, protein-energy ratio, and vitamin D intake. No significant differences were observed between the groups regarding age or sex. The robust group showed significantly better results for protein-energy ratio, vitamin D intake, and subjective and objective masticatory performance than the frail group. Logistic regression analysis revealed a significant correlation between skeletal muscle mass, protein-energy ratio, and objective masticatory performance with frailty. Masticatory performance was associated with frailty, independent of the intake of nutrients such as energy, protein, and vitamin D.

A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions. We identified FIC anticancer drugs using pharmacological classes for the Japanese drug pricing system. Most FIC anticancer drugs were first approved in the US. The median approval time for anticancer drugs in new pharmacological classes during the last two decades in Japan (5072 d) was significantly different (p = 0.043) from that in the US (4253 d), though it was not significantly different from that in the EU (4655 d). Submission and approval lags between the US and Japan were more than 2.1 years, and those between the EU and Japan were more than 1.2 years. However, those between the US and the EU were less than 0.8 years. The development rate of FIC anticancer drugs in Japan is slower than in other regions. Even among developed countries, FIC anticancer drug lags exist. Considering the high impact of FIC anticancer drugs on society worldwide, we should work together to reduce drug lag among regions using an improved international cooperative framework.

Objective: Tacrolimus is one of the drugs that can be used in pregnancies complicated with systemic lupus erythematosus (SLE), but there are still few reports on its pregnancy outcomes. Although tacrolimus has been reported to cause adverse events, such as increased blood pressure, abnormal glucose metabolism, and susceptibility to infection, there have been no studies on the impact of tacrolimus in SLE pregnancies at these points. We performed a retrospective observational study of pregnancies complicated by SLE at St Luke's International Hospital in Tokyo from April 2003 to August 2021., Methods: Basic clinical information on SLE, pregnancy outcomes, disease activity before and after pregnancy, laboratory results, blood pressure, blood glucose levels, treatment regimens, and presence of infection was extracted from electronic medical records. We defined overall adverse pregnancy outcomes (APOs) as follows: (1) fetal death after 10 gestational weeks, (2) preterm delivery, (3) delivery due to hypertensive disorders of pregnancy, preeclampsia, or placental insufficiency, or (4) the diagnosis of small for gestational age infants. We also examined whether there was a statistical difference in APO incidence between patients treated with and without tacrolimus., Results: Pregnancy outcomes were obtained for 48 patients with a total of 60 pregnancies complicated by SLE. In 20 (33.3%) of these pregnancies, the patients took tacrolimus, and 28 (46.7%) of the pregnancies had APOs. APO incidence did not statistically differ between the tacrolimus and non-tacrolimus groups in the multivariate analysis ( p = 1.00, adjusted OR 1, 95% CI: 0.23-4.39). Multiple regression analyses indicated that tacrolimus use did not significantly affect systolic blood pressure in the third trimester (B = -2.23, p = .74) or blood glucose levels in the first trimester (B = 10.2, p = .056). Incidence of infections did not significantly differ between patients treated with and without tacrolimus in the univariate analysis (10.8% vs. 21.1%, p = .42)., Conclusion: Tacrolimus did not significantly affect pregnancy outcomes, blood pressure, or glucose levels. Further research is required to confirm its effects in a larger population.

Importance: There have been few studies on the heterogeneous interconnection of COVID-19 outbreaks occurring in different social settings using robust, surveillance epidemiological data., Objectives: To describe the characteristics of COVID-19 transmission within different social settings and to evaluate settings associated with onward transmission to other settings., Design, Setting, and Participants: This is a case series study of laboratory-confirmed COVID-19 cases in Tokyo between January 23 and December 5, 2020, when vaccination was not yet implemented. Using epidemiological investigation data collected by public health centers, epidemiological links were identified and classified into 7 transmission settings: imported, nightlife, dining, workplace, household, health care, and other., Main Outcomes and Measures: The number of cases per setting and the likelihood of generating onward transmissions were compared between different transmission settings., Results: Of the 44 054 confirmed COVID-19 cases in this study, 25 241 (57.3%) were among male patients, and the median (IQR) age of patients was 36 (26-52) years. Transmission settings were identified in 13 122 cases, including 6768 household, 2733 health care, and 1174 nightlife cases. More than 6600 transmission settings were detected, and nightlife (72 of 380 [18.9%]; P < .001) and health care (119 [36.2%]; P < .001) settings were more likely to involve 5 or more cases than dining, workplace, household, and other settings. Nightlife cases appeared in the earlier phase of the epidemic, while household and health care cases appeared later. After adjustment for transmission setting, sex, age group, presence of symptoms, and wave, household and health care cases were less likely to generate onward transmission compared with nightlife cases (household: adjusted odds ratio, 0.03; 95% CI, 0.02-0.05; health care: adjusted odds ratio, 0.57; 95% CI, 0.41-0.79). Household settings were associated with intergenerational transmission, while nonhousehold settings mainly comprised transmission between the same age group. Among 30 932 cases without identified transmission settings, cases with a history of visiting nightlife establishments were more likely to generate onward transmission to nonhousehold settings (adjusted odds ratio, 5.30 [95% CI, 4.64-6.05]; P < .001) than those without such history., Conclusions and Relevance: In this case series study, COVID-19 cases identified in nightlife settings were associated with a higher likelihood of spreading COVID-19 than household and health care cases. Surveillance and interventions targeting nightlife settings should be prioritized to disrupt COVID-19 transmission, especially in the early stage of an epidemic.

Background: Previous cardiovascular risk prediction models in Japan have utilized prospective cohort studies with concise data. As the health information including health check-up records and administrative claims becomes digitalized and publicly available, application of large datasets based on such real-world data can achieve prediction accuracy and support social implementation of cardiovascular disease risk prediction models in preventive and clinical practice. In this study, classical regression and machine learning methods were explored to develop ischemic heart disease (IHD) and stroke prognostic models using real-world data., Methods: IQVIA Japan Claims Database was searched to include 691,160 individuals (predominantly corporate employees and their families working in secondary and tertiary industries) with at least one annual health check-up record during the identification period (April 2013-December 2018). The primary outcome of the study was the first recorded IHD or stroke event. Predictors were annual health check-up records at the index year-month, comprising demographic characteristics, laboratory tests, and questionnaire features. Four prediction models (Cox, Elnet-Cox, XGBoost, and Ensemble) were assessed in the present study to develop a cardiovascular disease risk prediction model for Japan., Results: The analysis cohort consisted of 572,971 invididuals. All prediction models showed similarly good performance. The Harrell's C-index was close to 0.9 for all IHD models, and above 0.7 for stroke models. In IHD models, age, sex, high-density lipoprotein, low-density lipoprotein, cholesterol, and systolic blood pressure had higher importance, while in stroke models systolic blood pressure and age had higher importance., Conclusion: Our study analyzed classical regression and machine learning algorithms to develop cardiovascular disease risk prediction models for IHD and stroke in Japan that can be applied to practical use in a large population with predictive accuracy.

Similar to other countries, the Japanese government quickly undertook preventative measures against increasing suicides during the pandemic, but could not suppress the increase. Suicide mortality among both sexes under 20 and females aged 20-39 significantly increased during the pandemic, but unexpectedly had already slowed decreasing trends before the pandemic onset. Furthermore, before the pandemic, a higher complete unemployment rate contributed to increasing suicide mortality of both sexes, whereas during the pandemic, the positive relationship between females suicide mortalities and complete unemployment rates was not observed., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest relevant to the contents of the manuscript., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies., Methods: A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed., Results: During a median of 10 (1-103) cycles with a median follow-up after several ICI initiations of 384 (21-1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P < 0.0001) and baseline eosinophil count ≥130/μL (HR, 3.01 for < 130; P = 0.012) as independent risk factors for the incidence of immune-related liver injury with grade ≥ 2. Patients who developed irAEs had a higher disease control rate (P < 0.0001) and an increased overall survival rate compared to those without irAEs (P < 0.0001)., Conclusion: Combination therapy with anti-PD-1 and anti-CTL-4 antibodies resulted in higher a frequency of irAEs. Baseline absolute eosinophil count was found to be a predictive factor for immune-related liver injury. Occurrence of irAEs may be associated with higher efficacy of ICI treatment and longer survival among patients who receive ICI therapy., (© 2022. The Author(s).)

Introduction: This study will compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl esters on fasting apolipoprotein B-48 (apoB-48), a surrogate marker reflecting postprandial hypertriglyceridaemia, which is a residual risk for atherosclerotic cardiovascular disease with statin treatment., Methods and Analysis: This is a prospective, multicentre, open-label, randomised, parallel group, comparative trial. Adult Japanese patients with dyslipidaemia receiving statin treatment for more than 4 weeks with a fasting triglyceride level ≥177 mg/dL will be randomly assigned in a 1:1 ratio to receive pemafibrate (0.4 mg orally per day) or omega-3 fatty acid ethyl esters (4 g orally per day) for 16 weeks. The primary endpoint is the percentage change in fasting apoB-48 from baseline to 16 weeks. The key secondary endpoints include the change in fasting apoB-48 from baseline to 16 weeks, the percentage changes in clinical variables from baseline to 16 weeks and the incidence of adverse events. A total sample size of 128 was set by considering the increased drop-out rate due to the COVID-19 pandemic, in addition to estimation based on a two-sided alpha of 0.05 and a power of 0.8 for apoB-48., Ethics and Dissemination: The study protocol has been approved by the Certified Review Board of the University of the Ryukyus for Clinical Research Ethics (No. CRB7200001) and will be performed in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants. The results of the study will be disseminated through publications and conference presentations to participants, healthcare professionals and the public., Trial Registration Number: jRCTs071200011., Competing Interests: Competing interests: YT, MO and MS have no potential competing interests to disclose. IS received an honorarium for a lecture from GlaxoSmithKline and research funding from Kowa. SH has received honoraria for lectures from Bayer Yakuhin, Daiichi Sankyo, Kowa, Mitsubishi Tanabe Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical and Takeda Pharmaceutical. SU has received honoraria for lectures from Daiichi Sankyo, Kowa and Taiho Pharmaceutical and grants from Bayer Yakuhin, Bristol-Myers Squibb and Kowa., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To clarify Japanese real-world clinical data on the use of desmopressin 25 and 50 μg orally disintegrating tablets (ODT) for male patients with nocturia and evaluate the predictive factors to improve nighttime frequency., Methods: We retrospectively accumulated real-world clinical data from 27 institutions in Japan. Male patients with two or more episodes of nocturia who received desmopressin ODT for nocturnal polyuria (NP) from 2019 through 2021 were included. The primary endpoint was the change of nighttime frequency until 3 months after desmopressin administration. The secondary endpoints were to clarify the persistence rate, adverse events, and predictive factors of decreasing nighttime frequency., Results: A total of 118 patients were eligible to participate in this study. The persistence rate of desmopressin on the Kaplan-Meier curve at week 12 was 51.3. The reason for discontinuation was mainly the occurrence of adverse events in 67 patients (56.8%), particularly hyponatremia in 7 patients (5.9%). Nighttime frequencies at baseline, - 1 month and 1 - 3 months after desmopressin administration were 4.1 ± 1.3, 2.9 ± 1.4 (P < .01), and 2.6 ± 1.3 (P < .01), respectively. The mean nighttime urine volume voided at baseline was significantly larger in patients whose nighttime frequency decreased by two or more times than in those with a decrease of less than two times., Conclusions: Desmopressin 25 and 50 μg ODT treatments are feasible for male patients with NP in Japanese real-world clinical practice. Patients with higher voided volumes, particularly in the nighttime, may have great benefit from desmopressin., (© 2022 John Wiley & Sons Australia, Ltd.)

During the early stages of the ongoing COVID-19 pandemic, suicides did not increase in most countries/regions. Japan, however, was an exception to this, reporting increased numbers of female suicides with no changes in male suicide. To explore the trends of increasing suicides, the fluctuations of personal consumption (as an indicator of lifestyle) and standardized suicide death rate (SDR) disaggregated by age, sex, and prefecture, were determined using a linear mixed-effect model. Additionally, fixed effects of personal consumption on SDR during the pandemic were also analyzed using hierarchical linear regression models with robust standard errors. During the first wave of the pandemic, SDR for both sexes decreased slightly but increased during the second half of 2020. SDR of females younger than 70 years old and males younger than 40 years old continued to increase throughout 2021, whereas SDR for other ages of both sexes did not increase. Personal consumption expenditures on out-of-home recreations (travel agencies, pubs, and hotels) and internet/mobile communication expenses decreased, but expenditures on home-based recreations (contents distribution) increased during the pandemic. Increased expenditures on internet/mobile communication were related to increasing SDR of both sexes. Increasing expenditures on content distributions were related to increasing females' SDR without affecting that of males. Decreasing expenditures on pubs were related to increasing SDR of both sexes in the non-metropolitan region. These findings suggest that transformed individual lifestyles, extended time at home with a decreased outing for contact with others, contributed to the progression of isolation as a risk of suicide. Unexpectedly, increasing compensatory contact with others using internet/mobile communication enhanced isolation resulting in increased suicide risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Matsumoto, Kawano, Motomura, Shiroyama and Okada.)

Background: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer., Methods: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given., Results: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies., Conclusion: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347)., (Published by Oxford University Press 2022.)

Objective: Epidemiological evidence on the relationship between hearing loss (HL) and depressive symptoms, especially in the middle aged, is limited. The present cross-sectional study investigated this issue in middle-aged and older Japanese individuals separately., Methods: Study subjects were 1018 Japanese adults aged 36-84 years. We used the audiometric definition of HL, which identifies the speech-frequency pure tone average (PTA) hearing thresholds at 0.5, 1, 2, and 4 kHz as an average of four frequencies. HL was defined as present when PTA was > 25 dB HL in the better-hearing ear. Presence of depressive symptoms was defined as a Center for Epidemiological Studies Depression Scale score ≥ 16. Adjustment was made for age, sex, smoking status, alcohol consumption, leisure time physical activity, hypertension, dyslipidemia, diabetes mellitus, body mass index, waist circumference, employment, education, and household income., Results: The prevalence values of HL and depressive symptoms were 11.5% and 15.0%, respectively, among the 575 subjects aged < 65 years and 42.2% and 10.4%, respectively, among the 443 subjects aged ≥ 65 years. Among the 1018 participants, HL was independently related to a higher prevalence of depressive symptoms: the multivariate-adjusted OR was 1.92 (95% CI: 1.19-3.08). This positive association was stronger among middle-aged participants, with a multivariate-adjusted OR of 2.70 (95% CI: 1.34-5.27), but was not significant in the elderly, with a multivariate-adjusted OR of 1.71 (95% CI: 0.83-3.54)., Conclusion: HL may be positively associated with depressive symptoms in middle-aged, but not older, individuals., (Copyright © 2022. Published by Elsevier B.V.)

A combination of pharmaceutical and non-pharmaceutical interventions as well as social restrictions has been recommended to prevent the spread of coronavirus disease 2019 (COVID-19). Therefore, social contact surveys play an essential role as the basis for more effective measures. This study attempts to explore the fundamental basis of the expansion of COVID-19. Temporal bidirectional causalities between the numbers of newly confirmed COVID-19 cases (NCCC) and individual mobilisations with consumption motives across prefecture borders in three metropolitan regions in Japan were analysed using vector autoregression models. Mobilisation with consumption in pubs from Kanto to Tokai contributed to the spread of COVID-19 in both regions. Meanwhile, causal mobilisation with consumption motives in Kansai also contributed to the expansion of COVID-19; however, the pattern was dependent on the industrial characteristics of each prefecture in Kansai. Furthermore, the number of pub visitors in Kanto immediately decreased when NCCC increased in Kanto. In contrast, the causal mobilisations for the expansion of COVID-19 in the Tokai and Kansai regions were unaffected by the increasing NCCC. These findings partially proved the validity of the conventional governmental measures to suppress pub visitors across prefectural borders. Nevertheless, the individual causal mobilisations with consumption motives that contributed to the increasing COVID-19 cases are not identical nationwide, and thus, regional characteristics should be considered when devising preventive strategies.

Alopecia areata (AA) is a non-scarring hair loss disorder affecting approximately 2% of the global population. AA is reported to have a significant negative impact on the emotional and psychological well-being of the patients. This study aimed to evaluate the health-related quality of life (HRQoL) of Japanese patients with AA in comparison to the Japanese population norms (national standard values for Japanese) using Short Form Health Survey 36 Item Version 2.0 (SF-36v2). The study also aimed to access the negative effect of AA on patients' daily lives and the proportion of patients having anxiety and/or depression. This cross-sectional, non-interventional web-based survey study included 400 participants aged 17-84 years currently suffering from medically diagnosed AA. The assessment tools integrated in the online questionnaire included SF-36v2, the Dermatology Life Quality Index (DLQI), and the Hospital Anxiety and Depression Scale (HADS). All outcome measures from the tools were evaluated across the study population. SF-36v2 subscale scores for patients with AA revealed lower scores specifically for mental health (45.7 ± 10.1 points), social functioning (45.8 ± 10.9 points), vitality (46.2 ± 9.8 points), and role emotional (46.9 ± 11.6 points) as compared to the Japanese population norms of 50 ± 10 points each. The DLQI questionnaire-based analysis indicated that 32.1% of respondents showed a moderate to extremely large effect on their lives; and HADS-A (anxiety) and HADS-D (depression) scores categorized 46.0% and 41.8% respondents as doubtful-to-definite cases, respectively. Multivariate linear regression revealed that hair loss range, age, comorbidities, and depression significantly worsened DLQI scores. In conclusion, the results of this survey demonstrated that a significant decrease in the HRQoL scores was observed in Japanese patients with AA in comparison with the national norms. Hence, emphasis on mental health is crucial for AA management., (© 2022 Pfizer Japan Inc. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: Few reports about surgical outcomes in malignant pleural mesothelioma (MPM) have been based on reliable nationwide databases. Here, we analyzed the incidence, surgical outcome, and operative risk factors using Japanese nationwide database., Methods: Characteristics and perioperative data from 622 patients who underwent curative-intent surgery for MPM between January 2014 and December 2017 were recorded from National Clinical Database of Japan. We analyzed the incidence, surgical outcomes, and risk factors for surgical complications after 2 surgical procedures (extrapleural pneumonectomy [EPP] and pleurectomy/decortication [P/D])., Results: During 4 years, EPP was performed in 279 patients and P/D in 343. EPP was more frequently performed in institutions less experienced in MPM, while P/D was more frequently performed in institutions well experienced in MPM (P < .001), especially in high-volume centers with more than 10 cases during this period. P/D was more frequently performed, especially in high-volume centers. The morbidity rates were 45.2% in EPP and 35.9% in P/D. Heart failure and pneumonia were most frequent in EPP, while prolonged air leakage was most frequent in P/D. Thirty-day and in-hospital mortality rates were 1.1% and 3.2% (EPP) and 1.2% and 3.2% (P/D), respectively. Regression analyses revealed that higher age (>65 years) was associated with operative complications in EPP (odds ratio, 3.56 [95% confidence interval, 1.26-8.56]), whereas no risk factor was observed in P/D., Conclusions: In Japanese nationwide annual database, P/D was more frequently performed, especially in high-volume centers. Morbidity was higher in EPP than P/D; however, the mortality rates were quite low in Japan regardless surgical procedures., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation., Patients and Methods: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m 2 on day 1) plus vinorelbine (25 mg/m 2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS)., Results: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively., Conclusion: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial., Competing Interests: Hirohito TadaHonoraria: Chugai Pharma Tetsuya MitsudomiHonoraria: AstraZeneca, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharma, Taiho Pharmaceutical, Lilly, Novartis, MSD K.K., Kyowa Hakko Kirin, Amgen, Daiichi-Sankyo, Guardant Health, Ethicon, Thermofisher Scientific Biomarkers, Merck KGaA, Janssen Oncology, TakedaConsulting or Advisory Role: AstraZeneca, Pfizer, Boehringer Ingelheim, Chugai Pharma, Ono Pharmaceutical, MSD Oncology, Lilly, Novartis, Amgen, Daiichi Sankyo, Thermo Fisher ScientificResearch Funding: Boehringer Ingelheim (Inst), AstraZeneca (Inst), Pfizer (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Sanofi/Aventis (Inst), Daiichi Sankyo (Inst), MSD K.K. (Inst), Kyowa Hakko Kirin (Inst) Toshihiro MisumiSpeakers' Bureau: Chugai Pharma, AstraZeneca Kenji SugioHonoraria: AstraZeneca, Chugai PharmaResearch Funding: Covidien Japan, Lilly Japan Masahiro TsuboiHonoraria: AstraZeneca Japan, Chugai Pharma, Taiho Pharmaceutical, Teijin Pharma, Johnson & Johnson, Novartis, MSD K.K., Ono Pharmaceutical, Bristol Myers Squibb Japan, MedtronicResearch Funding: Boehringer Ingelheim (Inst), Merck (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai/Roche (Inst) Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Yakult Honsha, Kyowa Kirin Shinji AtagiHonoraria: Chugai Pharma, MSD K.K., Ono Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Lilly Japan, Pfizer, Bristol Myers Squibb Japan, Hisamitsu Pharmaceutical, Kyowa Hakko Kirin, Merck, Novartis, Thermo Fisher ScientificResearch Funding: MSD K.K. (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Lilly Japan (Inst), Pfizer (Inst), Bristol Myers Squibb Japan (Inst), Roche (Inst), Merck (Inst) Toshiaki TakahashiHonoraria: AstraZeneca KK, Chugai Pharma, Lilly Japan, Ono Pharmaceutical, MSD K.K., Pfizer, Boehringer Ingelheim, Roche, Takeda Pharmaceutical Co Ltd, Yakult HonshaResearch Funding: AstraZeneca KK (Inst), Lilly Japan (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), MSD K.K. (Inst), Pfizer (Inst), Amgen (Inst), Boehringer Ingelheim (Inst) Hidetoshi HayashiHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, Lilly, Taiho Pharmaceutical, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, MSD, Novartis, Merck SeronoConsulting or Advisory Role: Lilly, AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Pfizer, Merck Serono, Shanghai HaiHe Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo/UCB JapanResearch Funding: Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca, AbbVie (Inst), AC Medical (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Lilly Japan (Inst), EPS Associates Co, Ltd (Inst), GlaxoSmithKline (Inst), Japan Clinical Research Operations (Inst), Kyowa Hakko Kirin (Inst), Merck Serono (Inst), Novartis (Inst), Otsuka (Inst), Parexel (Inst), Pfizer (Inst), PPD-SNBL (Inst), Quintiles Inc (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Yakult Honsha (Inst)Patents, Royalties, Other Intellectual Property: Sysmex Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (Inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Hiroshige YoshiokaHonoraria: Lilly, Chugai Pharma, Boehringer Ingelheim, Taiho Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Novartis, Kyowa Kirin Co, Ltd, Daiichi Sankyo, Nippon Kayaku, Delta-Fly Pharma, PfizerConsulting or Advisory Role: Delta-Fly Pharma Kazuhisa TakahashiSpeakers' Bureau: AstraZeneca Ichiro YoshinoHonoraria: Johnson & Johnson, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Shionogi, Astra Zeneca, Intuitive Surgical, Daiichi Sankyo, Boehringer Ingelheim, Covidien/MedtronicConsulting or Advisory Role: Astra Zeneca, Intuitive Surgical, Covidien/MedtronicResearch Funding: Chugai Pharma (Inst), Taiho Pharmaceutical (Inst), Pfizer (Inst), Shionogi (Inst) Kazuhiko NakagawaHonoraria: AstraZeneca KK, Ono Pharmaceutical, Chugai Pharma, Nippon Boehringer Ingelheim, Lilly, Pfizer, Bristol Myers Squibb, Novartis, CareNet, Taiho Pharmaceutical, Yodosha, Nikkei Business Publications, Inc, Kyorin, Takeda, Medical Review Co, Ltd, MSD K.K., AbbVie, Merck, Roche Diagnostics, Bayer Yakuhin, Nippon Kayaku, Amgen, Kyowa Kirin Co, Ltd, Medical Mobile Communications Co, Ltd, 3H Clinical Trial, Astellas Pharma, Yomiuri Telecasting Corporation, Medicus Shuppan, publishers Co, Ltd, Thermo Fisher Scientific, Hisamitsu Pharmaceutical Co, Inc, Nichi-iko, Nanzando Co, Ltd, Daiichi Sankyo Co, LtdConsulting or Advisory Role: Pfizer, Kyorin Pharmaceutical Co, Ltd, Lilly Japan, Ono Pharmaceutical, Astellas Pharma, TakedaResearch Funding: Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Pfizer (Inst), Takeda (Inst), Nippon Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Lilly (Inst), Parexel International Corp. (Inst), A2 Healthcare (Inst), Novartis (Inst), IQvia (Inst), SymBio Pharmaceuticals (Inst), AstraZeneca KK (Inst), Kissei Pharmaceutical (Inst), EPS Holdings (Inst), Bayer Yakuhin (Inst), MSD K.K. (Inst), Pfizer (Inst), Otsuka (Inst), Syneos Health (Inst), EPS International (Inst), PRA Health Sciences (Inst), PPD-SNBL (Inst), Covance (Inst), GlaxoSmithKline K.K. (Inst), Sysmex (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Japan Clinical Research Operations (Inst), Sanofi (Inst), Medical Research Support (Inst), ICON (Inst), CMIC (Inst), Kyowa Kirin Co, Ltd (Inst)No other potential conflicts of interest were reported.

Purpose: We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone., Patients and Methods: Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate)., Results: Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( P < .001) and 0.3% versus 3.6% ( P < .001), respectively., Conclusion: FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting., Competing Interests: Akito HataConsulting or Advisory Role: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, MSDSpeakers' Bureau: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, Taiho PharmaceuticalResearch Funding: Boehringer Ingelheim (Inst), MSD (Inst), Lilly (Inst), AstraZeneca (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai and Roche (Inst) Naoki InuiSpeakers' Bureau: Chugai Pharma, AstraZeneca and Daiichi Sankyo, Lilly, Nippon Boehringer Ingelheim, Novartis, Ono Yakuhin, Taiho PharmaceuticalResearch Funding: Chugai Pharma, Daiichi Sankyo and UCB Japan, Lilly, Nippon Boehringer Ingelheim, MSD K K, Taiho Pharmaceutical Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co, Ltd (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Masahiro MoriseSpeakers' Bureau: Chugai and Roche, AstraZeneca, Ono Pharmaceutical, LillyResearch Funding: Boehringer Ingelheim (Inst), Novartis (Inst), AstraZeneca (Inst), Lilly (Inst), Taiho Pharmaceutical (Inst), Chugai and Roche (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), Merck Serono (Inst), Kissei Pharmaceutical (Inst) Masayuki TakedaHonoraria: AstraZeneca Japan, Chugai Pharma, Bristol Myers Squibb Company, Novartis, Ono Pharmaceutical, Boehringer Ingelheim Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K K, Yakult Honsha, Kyowa Kirin Naofumi ShinagawaResearch Funding: Olympus Kaoru KubotaHonoraria: Bristol Myers Squibb Japan, Daiichi Sankyo, Boehringer Ingelheim, Taiho Pharmaceutical, Lilly Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Nihonkayaku, Takeda, PfizerResearch Funding: Daiichi Sankyo (Inst), Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Ono Pharmaceutical (Inst) Toshiaki SaekiResearch Funding: Taiho Pharmaceutical (Inst), Eisai (Inst) Tomohide TamuraHonoraria: Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, MSD, CMIC, Lilly, NihonkayakuNo other potential conflicts of interest were reported.

Aims: Treating patients with acute heart failure is difficult at the local hospitals in medically depopulated areas where cardiologists are generally absent. These patients require long-distance and time-consuming transportation to the intensive care units. It is well known that tolvaptan is effective for the treatment of congestive heart failure, but the effect of prehospital tolvaptan use in patients is not well evaluated. The aim of this study was to evaluate the efficacy and safety of prehospital tolvaptan use in patients with acute congestive heart failure who require long-distance and time-consuming transportation., Methods: This retrospective study included 30 patients who were newly diagnosed with acute heart failure at Wakkanai City Hospital and transported to Nayoro City General Hospital between January 2013 and May 2020. The patients were classified into those who received tolvaptan (tolvaptan group, n = 18) and did not receive tolvaptan (control group, n = 12)., Results: The percentage of patient survival at discharge did not show a statistically significant difference between the groups (100% [tolvaptan] vs. 91% [control], p = 0.414). During transportation, the percentage of patients in the tolvaptan group who required increased oxygen doses was statistically significantly lower than that in the control group (0% vs. 36%, p = 0.0181). Patients in the tolvaptan group had statistically significantly shorter intensive care unit stays (median: 2 days vs. 6 days, p = 0.0376), less days to discontinuation of oxygen (median: 2.8 days vs. 6.9 days, p < 0.00125), and less days to ambulation (median: 1.5 days vs. 7.5 days, p = 0.0362) compared with the control group. In the tolvaptan group, blood pressure was not different; however, heart rate was statistically significantly reduced (99 ± 21 vs. 88 ± 21 beats per minute, p = 0.016) during transportation., Conclusion: The use of tolvaptan in patients with acute heart failure requiring long-distance transport is safe and may show better clinical course compared with conventional therapies., Competing Interests: Declaration of competing interest Shuko Iwata – No conflicts of interest. Masaru Yamaki – No conflicts of interest. Takeshi Nishiura – No conflicts of interest. Keita Nakagawa – No conflicts of interest. Shota Tokuno – No conflicts of interest. Hirotsuka Sakai – No conflicts of interest. Motoi Okada – No conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Bacterial and fungal infections are serious, life-threatening conditions after kidney transplantation. The development of oral/oesophageal candidiasis after kidney transplantation is not a reported risk factor for subsequent severe infection. This study was performed to investigate the relationship between oral/oesophageal candidiasis after kidney transplantation and the development of subsequent infection requiring hospitalization., Methods: This retrospective study included 522 consecutive patients who underwent kidney transplantation at Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital from 1 January 2010 to 1 February 2019. Ninety-five percentage of patients were living donor transplant recipients. Visual examination was performed to detect oral candidiasis, beginning immediately after kidney transplantation; upper gastrointestinal endoscopy was performed 8-10 months after kidney transplantation. Twenty-five patients developed candidiasis (Candida-onset group) and 497 did not (non-Candida-onset group). The follow-up periods were 67 (37-86) months in the Candida-onset group and 55 (34-89) months in the non-Candida-onset group. Severe infection was defined as bacterial or fungal infection requiring hospitalization; viral infections were excluded., Results: Severe infection developed in 9/25 (36%) patients in the Candida-onset group and in 77/497 (15%) patients in the non-Candida-onset group (p = .006). Binomial logistic analysis revealed that Candida infection (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.06-6.06; p = .037) and use of rituximab (OR 1.81, 95% CI 1.12-2.93; p = .016) were significant predictors of subsequent severe infection., Conclusion: Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation and suggests an over-immunosuppressive state, which should prompt evaluation of immunosuppression., (© 2021 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Purpose: The objective of our study was to develop a clinical prediction model for prolonged air leak (PAL) after lobectomy for lung cancer using preoperative variables in a large patient dataset from the National Clinical Database (NCD) in Japan., Methods: The preoperative characteristics of 57,532 and 30,967 patients who had undergone standard lobectomy for lung cancer were derived from the 2014 to 2015 and 2016 NCD datasets, respectively. PAL was defined as air leak persisting ≥ 7 days postoperatively or requiring postoperative interventional treatment, such as pleurodesis or reoperation. Risk models were developed from the 2014 to 2015 dataset and validated using the 2016 dataset. When performing model derivation, the least absolute shrinkage and selection operator (LASSO) method were applied for parameter selection., Results: The rate of PAL was 4.5% in 2014-2015 and 5.3% in 2016. The age, sex, body mass index, comorbid interstitial pneumonia, smoking habits, forced expiratory volume in 1 s, tumor histology, multiple lung cancer, and tumor location were selected as important variables for PAL. Our risk model for predicting PAL was fair with a concordance index of 0.6895., Conclusion: The LASSO-based risk model for PAL after lobectomy provided important preoperative variables for PAL and risk weighting for each variable., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life., Methods: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed., Findings: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47)., Interpretation: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression., Funding: Chugai Pharmaceutical., Competing Interests: Declaration of interests TF reports personal fees from Chugai Pharmaceutical, during the conduct of the study, and personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work. HS reports grants from Chugai Pharmaceutical, AstraZeneca, and MSD, outside the submitted work, and personal fees from Ono Pharmaceutical, Nippon Boehringer Ingelheim, and Novartis Pharma, outside the submitted work. NF reports personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, Novartis, Taiho, Kyowa Kirin, MSD, and Pfizer, outside the submitted work. SS reports personal fees from Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Hakko Kirin, and Yakult Honsha, outside the submitted work. SI reports grants from Ono Pharmaceutical, and personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, MSD, Bristol-Myers Squibb, Eli Lilly Japan, Taiho Pharmaceutical, and Daiichi Sankyo, outside the submitted work. OY reports personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, and Eli Lilly Japan, outside the submitted work. MO reports grants from Chugai Pharmaceutical, during the conduct of the study. MS reports grants and personal fees from Chugai Pharmaceutical, during the conduct of the study. KA reports personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, Astra Zeneca, MSD Oncology, and Bristol-Myers Squibb, outside the submitted work. YTsub reports personal fees from Chugai Pharmaceuticals, AstraZeneca, and Daiichi Sankyo, outside the submitted work. YF reports personal fees from Eli Lilly, Chugai Pharmaceutical, AstraZeneca, and Bristol-Myers Squibb, outside the submitted work. SW reports grants from AstraZeneca and Boehringer Ingelheim, and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis, and Daiichi Sankyo, outside the submitted work. KH reports grants from Taiho Pharmaceutical, Ono Pharma, and MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharma, Boehringer Ingelheim, Novartis, Kyorin Pharmaceutical, and Bristol-Myers Squibb, outside the submitted work, and has a patent EGFR mutation test licensed to LSI Medience. SM reports personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Pfizer Japan, Taiho Pharmaceutical, and Ono Pharmaceutical, outside the submitted work. KK reports personal fees from AstraZeneca, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Boehringer Ingelheim, and Taiho Pharmaceutical, outside the submitted work. MMa reports grants and personal fees from Chugai Pharmaceutical during the conduct of the study, and personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, and Eli Lilly, outside the submitted work. All other authors declare no competing interests, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Smoking is a known risk factor for postoperative mortality and morbidity. However, the significance of cumulative smoking dose in preoperative risk assessment has not been established. We examined the influence of preoperative cumulative smoking dose on surgical outcomes after lobectomy for primary lung cancer., Methods: A total of 80,989 patients with primary lung cancer undergoing lobectomy from 2014 to 2016 were enrolled. Preoperative cumulative smoking dose was categorized by pack-years (PY): nonsmokers, PY = 0; light smokers, 0 < PY < 10; moderate smokers, 10 ≤ PY < 30; and heavy smokers, 30 ≤ PY. The risk of short-term outcomes was assessed according to PY by multivariable analysis adjusted for other covariates., Results: Postoperative 30-day mortality, as well as pulmonary, cardiovascular, and infectious complications, increased with preoperative PY. Multivariable analysis revealed that the odds ratios (ORs) for postoperative mortality compared with nonsmokers were 1.76 for light smokers (P = .044), 1.60 for moderate smokers (P = .026), and 1.73 for heavy smokers (P = .003). The ORs for pulmonary complications compared with nonsmokers were 1.20 for light smokers (P = .022), 1.40 for moderate smokers (P < .001), and 1.72 for heavy smokers (P < .001). Heavy smokers had a significantly increased risk of postoperative cardiovascular (OR, 1.26; P = .002) and infectious (OR, 1.39; P = .007) complications compared with nonsmokers., Conclusions: The risk of mortality and morbidity after lung resection could be predicted according to preoperative cumulative smoking dose. These findings contribute to the development of strategies in perioperative management of lung resection patients., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Suicide mortality in Japan reduced in the period of 2009-2018. A number of studies identified the impact of financial governmental support for social welfare systems on suicide mortality; however, the detailed effects of specific regional policies, designed according to regional cultural, economic, education and welfare situations, on suicide mortality remain to be clarified. Therefore, the present study analyses the associations between the regional governmental expenditure of six major divisions, "public health", "public works", "police", "ambulance/fire services", "welfare" and "education", and suicide mortalities caused by six major suicidal motives, related to "family", "health", "economy", "employment", "romance" and "school", across the 47 prefectures in Japan during the period of 2009-2018, using fixed-effect analysis of hierarchal linear regression with robust standard error. The expenditure of "public works" displayed a positive relationship with suicide mortality of females caused by family-related motives but was not related to other suicide mortalities, whereas the expenditures in "public health", "police", "ambulance/fire services", "welfare" and "education" contributed to a reduction in suicide mortality, at least in some statistical indicators. The expenditures of both "ambulance/fire" and "education" were predominantly effective among the six major divisions of regional governmental expenditure in reducing suicide mortalities. In the education subdivisions, the expenditure of "kindergarten" was related to a reduction in suicide mortalities caused by a wide spectrum of motives. The amount of expenditure of welfare indicated the limited possibility of facilitating a reduction in suicide mortalities caused by only motives associated with economy or employment. However, in the welfare subdivisions, the expenditure of "child welfare" and "social welfare" was effective in reducing suicide mortalities, but the expenditure of "elderly welfare" was unexpectedly related to an increase in suicide mortalities. These results suggest that most Japanese people are struggling to bring up children even in the situation of an increasing elderly population with a decreasing birth rate. Therefore, it is important to enhance the investment welfare policy for the future to improve the childcare environment. Although the issue of an increasing elderly population and a decreasing birth rate in Japan has not yet improved, the obtained results suggest that evidence-based welfare expenditure redistributions of prefectures and municipalities could improve Japanese society and welfare systems.

Background: Lysophosphatidic acid (LPA) is involved in numerous biological processes, including neurodevelopment, chronic inflammation, and immunologic response in the central nervous system. Autotaxin (ATX) is a secreted enzyme that produces LPA from lysophosphatidylcholine (LPC). Previous studies have demonstrated decreased protein levels of ATX in cerebrospinal fluid (CSF) of patients with major depressive disorder (MDD). Based on those studies, the current study investigated the levels of lysophospholipids species including LPA and related metabolic enzymes, in CSF of patients with MDD and schizophrenia (SCZ)., Methods: The levels of lysophospholipids species and related metabolic enzymes were measured with either liquid chromatography-tandem mass spectrometry or enzyme-linked immunosorbent assay. Japanese patients were diagnosed with DSM-IV-TR. CSF was obtained from age- and sex-matched healthy controls (n = 27) and patients with MDD (n = 26) and SCZ (n = 27)., Results: Of all lysophospholipids species, the levels of LPA 22:6 (LPA - docosahexaenoic acid) were significantly lower in patients with MDD and SCZ than in healthy controls. These levels were negatively correlated with several clinical symptomatic scores of MDD, but not those of SCZ. In addition, the levels of LPA 22:6 were significantly correlated with the levels of LPC 22:6 among all 3 groups. On the other hand, the levels of LPA 22:6 were not correlated with ATX activity in patients with MDD and SCZ., Conclusion: The lower levels of LPA 22:6 in patients with MDD and SCZ suggest an abnormality of LPA 22:6 metabolism. In addition, several depressive symptoms in patients with MDD were significantly associated with the lower levels of LPA 22:6, suggesting an involvement of LPA 22:6 in the pathophysiology of MDD., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Purpose: To determine whether the correlations between the axial length and the aging-dependent and birth year-dependent age are significant., Design: Retrospective cross-sectional study., Methods: This study included Japanese patients ≥50 years who had undergone cataract surgery at numerous clinics from 2002 to 2020. Only 1 eye/patient was analyzed. The axial length was measured with the IOL Master. The age-dependent changes were determined by the significance of the correlation between the axial length and age by the birth year. The birth year-dependent changes were determined by the significance of the correlation between the axial length and birth year in the different age groups. The age refers to the age at the time of the cataract surgery. Spearman correlations were calculated. The turning points were identified by the LOESS, NLIN, and HPMIXED procedures., Results: A total of 62,362 eyes (35,508 women, 26,854 men) were studied. The mean age was 72.9 ± 8.4 (standard deviation) years (range, 50-101 years), and the mean axial length was 23.90 ± 1.66 mm (standard deviation) (range, 19.20-37.07 mm). The birth year ranged from 1908 to 1970. Analyses of the birth year-dependent changes showed significant positive correlations in 48 of 81 (59.3%) groups for women and men. The increase in the axial length was birth year-dependent, and the turning point was 1939.4 for women and 1936.7 for men., Conclusions: The negative and significant correlation between the axial length and age is due to birth year-dependent changes. A birth year-dependent increase in axial length might have continued for several decades from the birth year of the late 1930s., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background & Aims: Surgery is the standard of care for T1bN0M0 esophageal squamous cell carcinoma (ESCC), whereas chemoradiotherapy (CRT) is a treatment option. This trial aimed to investigate the noninferiority of CRT relative to surgery for T1bN0M0 ESCC., Methods: Clinical T1bN0M0 ESCC patients were eligible for enrollment in this prospective nonrandomized controlled study of surgery versus CRT. The primary endpoint was overall survival, which was determined using inverse probability weighting with propensity scoring. Surgery consisted of an esophagectomy with 2- or 3-field lymph node dissection. CRT consisted of 2 courses of 5-fluorouracil (700 mg/m 2 ) on days 1-4 and cisplatin (70 mg/m 2 ) on day 1 every 4 weeks with concurrent radiation (60 Gy)., Results: From December 20, 2006 to February 5, 2013, a total of 368 patients were enrolled in the nonrandomized portion of the study. The patient characteristics in surgery arm and CRT arm, respectively, were as follows: median age, 62 and 65 years; proportion of males, 82.8% and 88.1%; and proportion of performance status 0, 99.5% and 98.1%. Comparisons were made using the nonrandomized groups. The 5-year overall survival rate was 86.5% in the surgery arm and 85.5% in the CRT arm (adjusted hazard ratio, 1.05; 95% confidence interval, 0.67-1.64 [<1.78]). The complete response rate in the CRT arm was 87.3% (95% confidence interval, 81.1-92.1). The 5-year progression-free survival rate was 81.7% in the surgery arm and 71.6% in the CRT arm. Treatment-related deaths occurred in 2 patients in the surgery arm and none in the CRT arm., Conclusions: CRT is noninferior to surgery and should be considered for the treatment of T1bN0M0 ESCC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)