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Background: This study aimed to assess the clinical relevance of three-dimensional occupational stress (job stressor score [A score], psychological and physical stress response score [B score], and social support for workers score [C score]) of the Brief Job Stress Questionnaire (BJSQ) in the national stress check program in Japan to irregular menstruation.Methods: The present retrospective cohort study included 2,078 female employees aged 19–45 years who had both annual health checkups and the BJSQ between April 2019 and March 2022 in a national university in Japan. The outcome was self-reported irregular menstruation measured at annual health checkups until March 2023. A dose-dependent association between BJSQ scores and incidence of irregular menstruation was examined using Cox proportional hazards models to calculate multivariable-adjusted hazard ratios (HRs) of four quantile (0–49% [Q0–49], 50–74% [Q50–74], 75–89% [Q75–89], and 90–100% [Q90–100]) of the BJSQ scores.Results: During 2.0 years of the median observational period, 257 (12.4%) women reported irregular menstruation. B score, not A or C scores, was identified as a significant predictor of irregular menstruation (adjusted HR of A, B, and C scores per 1 standard deviation: 1.06 [95% confidence interval CI, 0.89–1.27], 1.35 [95% CI, 1.15–1.57], and 0.93 [95% CI, 0.80–1.08], respectively). Women with higher B score had a significantly higher risk of irregular menstruation in a dose-dependent manner (adjusted HR of Q0–49, Q50–74, Q75–89, and Q90–100: 1.00 [reference], 1.38 [95% CI, 1.00–1.90], 1.48 [95% CI, 1.00–2.18], and 2.18 [95% CI, 1.38–3.43], respectively).Conclusion: Psychological and physical stress response predicted irregular menstruation.

Smoking causes various health problems. Limited studies have reported a clinical effect of skipping breakfast on smoking initiation among adolescents. This retrospective cohort study aimed to assess the dose-dependent association between skipping breakfast and smoking initiation in university students. This study included 17,493 male and 8880 female students aged 18−22 years at a national university in Japan. The association between breakfast frequency (eating every day and skipping occasionally, often, and usually) and smoking initiation was evaluated using Cox proportional hazards models adjusted for clinically relevant factors. Smoking initiation was observed in 2027 (11.6%) male and 197 (2.2%) female students over the median observational period of 3.0 and 3.1 years. Skipping breakfast was significantly associated with smoking initiation in a dose-dependent fashion in male students (the adjusted hazard ratios [95% confidence interval] of eating breakfast every day and skipping occasionally, often, and usually: 1.00 [reference], 1.30 [1.15, 1.46], 1.47 [1.21, 1.79], and 1.77 [1.40, 2.25], respectively). Female students skipping breakfast occasionally and often were more vulnerable to smoking initiation than those who ate breakfast every day (1.00 [reference], 1.86 [1.24, 2.78], 2.97 [1.66, 5.32], and 1.76 [0.55, 5.64], respectively). Breakfast frequency may be useful to identify university students at risk of smoking initiation who need improvement in their health literacy.

Frequency of alcohol drinking is a potential predictor of binge drinking of alcohol, a serious social problem for university students. Although previous studies have identified skipping breakfast as a predictor of various health-compromising behaviors and cardiometabolic diseases, few studies have assessed the association between skipping breakfast and the incidence of frequent alcohol drinking. This retrospective cohort study included 17,380 male and 8799 female university students aged 18–22 years admitted to Osaka universities between 2004 and 2015. The association between breakfast frequency (eating every day, skipping occasionally, and skipping often/usually) and the incidence of frequent alcohol drinking, defined as drinking ≥4 days/week, was assessed using multivariable-adjusted Cox proportional hazards models. During the median observational period of 3.0 years, 878 (5.1%) men and 190 (2.2%) women engaged in frequent alcohol drinking. Skipping breakfast was significantly associated with the incidence of frequent alcohol drinking (adjusted hazard ratios [95% confidence interval] of eating every day, skipping occasionally, and skipping often/usually: 1.00 [reference], 1.02 [0.84–1.25], and 1.48 [1.17–1.88] in men; 1.00 [reference], 1.60 [1.03–2.49], and 3.14 [1.88–5.24] in women, respectively). University students who skipped breakfast were at a higher risk of frequent alcohol drinking than those who ate breakfast every day.

The chloroplast genome of Pyrus was found to be 159,922 bp in length which included a pair of inverted repeats (IRs) of 26,392 bp, separated by a small single-copy region of 19,237 bp and a large single-copy region (LSC) of 87,901 bp. A total of 130 predicted genes (113 unique genes and 17 genes, which were duplicated in the IR) including 79 protein-coding genes, four ribosomal RNA genes and 30 tRNA genes were identified based on similarity to homologs from the chloroplast genome of Nicotiana tabacum. Genome organization was very similar to the inferred ancestral angiosperm chloroplast genome. Comparisons between Pyrus, Malus, and Prunus in Rosaceae revealed 220 indels (≥10 bp). Excluding ycf1 and ycf2, which contained deletions in the coding region, all of these were detected in the spacer or intron regions. Three insertions and 13 deletions were detected in Pyrus compared to the same loci in Malus and Prunus. After comparing 89 noncoding chloroplast DNA regions in Pyrus and Malus, highly variable regions such as ndhC-trnV and trnR-atpA were identified. In Pyrus and Malus, the IR/LSC borders were 62 bp shorter than those of Prunus. In addition, there were length mutations at the IRa/LSC junction and in trnH. A total of 67 simple sequence repeats (more than 10 repeated motifs) were identified in the Pyrus chloroplast genome. The indels and simple sequence repeats will be useful evolutionary tools at both intra- and interspecific levels. Phylogenetic analysis demonstrated a close relationship between Pyrus and Prunus in the Rosaceae.

PurposeThe aim of this study was to clarify an association between short sleep duration and smoking initiation.MethodsParticipants eligible for this retrospective cohort study were university students who were admitted to a single national university in Japan between 2007 and 2015. Baseline sleep duration and smoking status were measured using general questionnaires at health checkups at admission. During a 6-year observation period, smoking initiation was assessed using general questionnaires at annual health checkups. Cox proportional hazards models adjusted for clinically relevant factors were used to assess the association between sleep duration and smoking initiation.ResultsOf 17,493 men, including 540, 5,568, 8,458, 2,507, and 420 men with sleep duration of < 5, 5–6, 6–7, 7–8, and ≥ 8 h, respectively, smoking initiation was observed in 16.1%, 12.5%, 11.2%, 10.0%, and 11.7%, respectively, during a median observation period of 3.0 years. Men with shorter sleep duration were at a higher risk of smoking initiation (adjusted hazard ratio 1.49 [95% confidence interval 1.19–1.85], 1.11 [1.01–1.22], 1.00 [reference], 0.92 [0.80–1.06], and 1.00 [0.75–1.34], respectively). Of 8,880 women, including 267, 3,163, 4,220, and 1,230 women with sleep duration of < 5, 5–6, 6–7, and ≥ 7 h, respectively, smoking initiation was observed in 4.9%, 2.3%, 2.0%, and 2.2%, respectively, during a median observation period of 3.0 years. A similar dose dependent association was ascertained in women (2.50 [1.39–4.49], 1.18 [0.86–1.62], 1.00 [reference], and 1.22 [0.79–1.89], respectively).ConclusionThis study clarified that university students with short sleep duration were vulnerable to smoking initiation.

BackgroundProgrammed cell death 1 (PD-1)-based treatments are approved for several cancers. CheckMate 648, a global, phase 3 trial, showed that first-line nivolumab (anti-PD-1 antibody) plus ipilimumab (NIVO + IPI) or nivolumab plus chemotherapy (NIVO + Chemo) significantly increased survival in advanced esophageal squamous cell carcinoma (ESCC) without new safety signals versus chemotherapy alone (Chemo).MethodsWe evaluated the Japanese subpopulation of CheckMate 648 (n = 394/970), randomized to receive first-line NIVO + IPI, NIVO + Chemo, or Chemo. Efficacy endpoints included overall survival (OS) and progression-free survival assessed by blinded independent central review in Japanese patients with tumor-cell programmed death-ligand 1 (PD-L1) expression ≥ 1% and in all randomized Japanese patients.ResultsIn the Japanese population, 131, 126, and 137 patients were treated with NIVO + IPI, NIVO + Chemo, and Chemo, and 66, 62, and 65 patients had tumor-cell PD-L1 ≥ 1%, respectively. In patients with tumor-cell PD-L1 ≥ 1%, median OS was numerically longer with NIVO + IPI (20.2 months; hazard ratio [95% CI], 0.46 [0.30–0.71]) and NIVO + Chemo (17.3 months; 0.53 [0.35–0.82]) versus Chemo (9.0 months). In all randomized patients, median OS was numerically longer with NIVO + IPI (17.6 months; 0.68 [0.51–0.92]) and NIVO + Chemo (15.5 months; 0.73 [0.54–0.99]) versus Chemo (11.0 months). Grade 3–4 treatment-related adverse events were reported in 37%, 49%, and 36% of all patients in the NIVO + IPI, NIVO + Chemo, and Chemo arms, respectively.ConclusionSurvival benefits with acceptable tolerability observed for NIVO + IPI and NIVO + Chemo treatments strongly support their use as a new standard first-line treatment in Japanese patients with advanced ESCC.ClinicalTrials.gov IDNCT03143153.

In plants, the photosystem I (PSI) core complex stably associates with its light-harvesting chlorophyll a/b complex I (LHCI) to form the PSI-LHCI supercomplex. The vascular plant PSI core complex associates with four distinct LHCI subunits, whereas that of the green alga Chlamydomonas reinhardtii binds nine distinct LHCI subunits (LHCA1–LHCA9). The stoichiometry and configuration of these LHCI subunits in the PSI-LHCI supercomplex of C. reinhardtii remain controversial. Here, we determined the stoichiometry of the nine distinct LHCI subunits relative to PSI subunits through uniform labeling of total proteins using ¹⁴C. We separated the nine LHCI polypeptides by three different sodium dodecyl sulfate-polyacrylamide gel electrophoresis systems. Our data revealed that the PSI-LHCI supercomplex contains two LHCA1 proteins and one of each of the other eight LHCI subunits. Subsequently, we identified their cross-linked products by immunodetection and mass spectrometry to determine the configuration of the 10 LHCI subunits within the PSI-LHCI supercomplex. Furthermore, analyses of PSI-LHCI complexes isolated from ΔLHCA2 and ΔLHCA5 mutants and oligomeric LHCI from a PSI-deficient (ΔpsaA/B) mutant provided supporting evidence for the LHCI subunit configuration. In conclusion, eight LHCI subunits bind to the PSI core at the site of PSAF subunit in two layers: LHCA1-LHCA8-LHCA7-LHCA3 from PSAG to PSAK, in the inner layer, and LHCA1-LHCA4-LHCA6-LHCA5 in the outer layer. The other two LHCI subunits, LHCA2 and LHCA9, bind PSAB between PSAG and PSAH, PSAG-LHCA9-LHCA2-PSAH. Our study provides new insights into the LHCI configuration linked to the PSI core.

Background First‐line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab‐containing regimens in many countries. We report longer‐term follow‐up data. Methods This open‐label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression‐free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD‐L1) expression of ≥1% and then in the overall population. Results A total of 970 patients were randomly assigned. After 29 months of minimum follow‐up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46–0.76]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65–0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48–0.80]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65–0.92]). In patients with tumor cell PD‐L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51–0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79–1.36]). Among all treated patients (n = 936), Grade 3–4 treatment‐related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. Conclusions Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow‐up, further supporting use as first‐line standard treatment options for patients with advanced ESCC.

BackgroundThis study investigated the clinical impact of carcinoma in situ (CIS) in intravesical Bacillus Calmette-Guérin (BCG) therapy for patients with non-muscle-invasive bladder cancer (NMIBC).MethodsThis study retrospectively evaluated 3035 patients who were diagnosed with NMIBC and treated by intravesical BCG therapy between 2000 and 2019 at 31 institutions. Patients were divided into six groups according to the presence of CIS as follows: low-grade Ta without concomitant CIS, high-grade Ta without concomitant CIS, high-grade Ta with concomitant CIS, high-grade T1 without concomitant CIS, high-grade T1 with concomitant CIS, and pure CIS (without any papillary lesion). The endpoints were recurrence- and progression-free survival after the initiation of BCG therapy. We analyzed to identify factors associated with recurrence and progression.ResultsAt a median follow-up of 44.4 months, recurrence and progression were observed in 955 (31.5%) and 316 (10.4%) patients, respectively. Comparison of six groups using univariate and multivariate analysis showed no significant association of CIS. However, CIS in the prostatic urethra was an independent factors associated with progression.ConclusionConcomitant CIS did not show a significant impact in the analysis of Ta and T1 tumors which were treated using intravesical BCG. Concomitant CIS in the prostatic urethra was associated with high risk of progression. Alternative treatment approaches such as radical cystectomy should be considered for patients with NMIBC who have a risk of progression.

Nivolumab, an immune checkpoint inhibitor is the first-line therapy for platinum-resistant recurrent/metastatic head and neck cancer, and highly effective for some patients. However, no factors have been identified that could predict response or prognosis after nivolumab administration. We retrospectively investigated the association between tumor infiltrating lymphocytes (TILs) of initial pathology and prognosis in patients treated with nivolumab. Twenty-eight patients with human papilloma virus and Epstein–Barr virus unrelated head and neck squamous cell carcinoma were enrolled. CD8 + cells, FoxP3 + cells and FoxP3 − CD4 + cells in the tumoral and peritumoral stromal area and PD-L1 were measured. In result, FoxP3 − CD4 + TIL, FoxP3 + TIL, and CD8 + TIL were not correlated with survival in either intratumoral and stromal area. In univariate analysis, objective response was significant prognostic factor both in progression-free survival and overall survival ( p  = 0.01, 0.006, respectively). PD-L1 was also significant prognostic factor both in progression-free survival and overall survival ( p  = 0.01, 0.01, respectively). ECOG Performance status was a significant prognostic factor in overall survival ( p  = 0.0009). In the combined analysis of stromal CD8 + TIL and PD-L1, PD-L1 positive with high stromal CD8 + TIL subgroups had a better prognosis than PD-L1 negative with low stromal CD8 + TIL subgroups in progression-free survival ( p  = 0.006). Although these results require a further investigation, PD-L1 and ECOG Performance status and the combination of stromal CD8 + TIL and PD-L1 positivity have potential as useful prognostic markers in patients of virus unrelated head and neck squamous cell carcinoma treated with nivolumab.