MHC class I polypeptide-related sequence B shedding modulates pancreatic tumor immunity via the activation of NKG2DLow T cells.

Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I polypeptide-related sequence A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2DLow T cell activation, and inhibited NKG2DHigh T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2DLow T cells was maintained. In vivo xenograft model revealed that NKG2DHigh T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2DLow T cells within the tumor microenvironment.

Trends in the Implementation of Workplace COVID-19 Measures in Japanese Companies: A One-Year Prospective Cohort Study.

This study evaluated trends in the implementation of workplace measures against COVID-19 by Japanese companies. We conducted a prospective cohort study, using data from December 2020 and December 2021, with 13,419 respondents participating in the follow-up survey. We evaluated nine workplace measures against COVID-19 (e.g., encouraging mask-wearing at work) and used the McNemar test and the Chi-square test for trend in the analysis. Small-sized companies (1-9 employees) exhibited a significant increase in the implementation of all the measures, with a rate of increase ranging from 8.4% to 16.1% (P-value: <0.001). Medium-sized companies (10-49 employees) also showed significant improvements in nearly all the measures (rate of increase: 3.5% to 10.5%, P-values: <0.001 to 0.004), except for one specific measure. Larger companies (more than 50 employees) displayed a mixed pattern, with some measures increasing and others decreasing. A persistent gap was observed between smaller (fewer than 50 employees) and larger companies in the implementation rates of these measures. The findings revealed a positive shift in workplace measures against COVID-19 among smaller companies in Japan over 1 year, although gaps between them and larger companies persisted.

Infants' early recovery from sleep disturbance is associated with a lower risk of developmental delay in the Japan Environment and Children's Study.

To examine whether patterns, such as the timings of onset or recovery from sleep disturbance, are associated with later developmental problems, including autism spectrum disorder (ASD). Mothers participating in the Japan Environment and Children's Study with a child aged 3 years were included in the analyses. Children were assessed for short sleep and frequent awakenings at 1 month, 6 months, and 1 year of age. Developmental problems were evaluated at 3 years of age based on ASD diagnosis and developmental delay, using the Japanese translation of the Ages and Stages Questionnaire (ASQ) 3rd edition. Sleep disturbance patterns were classified by onset age, and developmental problem risks were examined based on onset/recovery ages. Among 63,418 mother-infant dyads, 0.4% of infants were later diagnosed with ASD, and 14.4% had abnormal scores on any ASQ domains. The later the onset of short sleep, the lower the risk of abnormal ASQ scores (RR of short sleep onset at 1 year: 1.41; 6 months: 1.52; 1 month: 1.57). The earlier the infants recovered from short sleep persistence, the lower the risk of developmental delay (RR of remittance of sleep problems identified at 1 month by 6 months: 1.07; 1 year: 1.31; not before 1 year: 1.57). Although not all patterns were significant, later short sleep onset and earlier recovery were associated with lower ASD risk. These findings may have significant implications for future interventions in infant development.

Association between Physical Work Environment during Work from Home and Sleep during the COVID-19 Pandemic: A Prospective Cohort Study in Japan.

OBJECTIVE: The work environment during work from home (WFH) may have a negative impact on workers' health. We investigated the effects of the physical work environment during WFH on sleep. METHODS: We conducted a one-year cohort study of 2,099 Japanese WFH workers. We used eight questions about the physical work environment during WFH as independent variables and the Athens Insomnia Scale as the dependent variable. We performed multilevel logistic regression with residence as a random effect. RESULTS: With the exception of one item, non-conformity with recommendations for the physical work environment during WFH was significantly associated with sleep problems. Further, the number of non-conformities and sleep problems showed a graded relationship. CONCLUSION: An inappropriate physical work environment during WFH may be associated with sleep problems.

Association Between Telecommuting Preference-frequency mismatch and Insomnia among Japanese Workers in the COVID-19 Pandemic: A Prospective Cohort study.

OBJECTIVE: We hypothesized that telecommuting's impact on sleep varied based on preference-frequency mismatch. Here, we evaluated this relationship in a large cohort of Japanese workers. METHODS: We collected data from 33,302 Japanese workers through an online survey, and analyzed participant preferences and frequency of telecommuting in 9,425 individuals who responded to a follow-up survey. We evaluated sleep using the Athens Insomnia Scale, and estimated odds ratios of insomnia using multilevel logistic regression. RESULTS: Workers preferring telecommuting had a higher risk of insomnia as telecommuting frequency decreased. OR for insomnia was 1.87 (p < 0.001) in those who telecommuted less than once per week. CONCLUSION: Telecommuting's impact on workers' sleep depends on preference mismatch, with a higher risk of insomnia among those who prefer telecommuting but are unable to utilize it.

Enhancement of keratinocyte survival and migration elicited by interleukin 24 upregulation in dermal microvascular endothelium upon welding-fume exposure.

Occupational exposure to welding fumes constitutes a serious health concern. Although the effects of fumes on the respiratory tract have been investigated, few apparent reports were published on their effects on the skin. The purpose of this study was to investigate the effects of exposure to welding fumes on skin cells, focusing on interleukin-24 (IL-24), a cytokine involved in the pathophysiology of skin conditions, such as atopic dermatitis and psoriasis. Treatment with welding fumes increased IL-24 expression and production levels in human dermal microvascular endothelial cells (HDMEC) which were higher than that in normal human epidermal keratinocytes. IL-24 levels in Trolox and deferoxamine markedly suppressed welding fume-induced IL-24 expression in HDMEC, indicating that oxidative stress may be involved in this cytokine expression. IL-24 released from HDMEC protected keratinocytes from welding fume-induced damage and enhanced keratinocyte migration. Serum IL-24 was higher in welding workers than in general subjects and was positively correlated with elevated serum levels of 8-hydroxy-2'-deoxyguanosine, an oxidative stress marker. In summary, welding fumes enhanced IL-24 expression in HDMEC, stimulating keratinocyte survival and migration. IL-24 expression in endothelial cells may act as an adaptive response to welding-fume exposure in the skin.

Comparison of Protective Effects of Antidepressants Mediated by Serotonin Receptor in Aß-Oligomer-Induced Neurotoxicity.

Amyloid ß-peptide (Aß) synthesis and deposition are the primary factors underlying the pathophysiology of Alzheimer's disease (AD). Aß oligomer (Aßo) exerts its neurotoxic effects by inducing oxidative stress and lesions by adhering to cellular membranes. Though several antidepressants have been investigated as neuroprotective agents in AD, a detailed comparison of their neuroprotection against Aßo-induced neurotoxicity is lacking. Here, we aimed to elucidate the neuroprotective effects of clinically prescribed selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants at the cellular level and establish the underlying mechanisms for their potential clinical applications. Therefore, we compared the neuroprotective effects of three antidepressants, fluoxetine (Flx), duloxetine (Dlx), and mirtazapine (Mir), by their ability to prevent oxidative stress-induced cell damage, using SH-SY5Y cells, by evaluating cell viability, generation of reactive oxygen species (ROS) and mitochondrial ROS, and peroxidation of cell membrane phospholipids. These antidepressants exhibited potent antioxidant activity (Dlx > Mir > Flx) and improved cell viability. Furthermore, pretreatment with a 5-hydroxytryptamine 1A (5-HT1A) antagonist suppressed their effects, suggesting that the 5-HT1A receptor is involved in the antioxidant mechanism of the antidepressants' neuroprotection. These findings suggest the beneficial effects of antidepressant treatment in AD through the prevention of Aß-induced oxidative stress.

Effects of Passiflora incarnata and Valeriana officinalis in the control of anxiety due to tooth extraction: a randomized controlled clinical trial.

OBJECTIVE: This study evaluated the efficacy of Valeriana officinalis L. and Passiflora incarnata L. to control anxiety, surgical discomfort, and changes in vital signs of patients undergoing extraction of two unilateral third molars. MATERIALS AND METHODS: This study is a randomized, triple-blinded clinical trial. Fifty-four patients were allocated into three groups (Valeriana officinalis L., Passiflora incarnata L., and placebo). Anxiety levels were assessed using the State-Trace Anxiety Inventory (STAI) index, surgical discomfort using the QCirDental, and through the measurement of vital signs. The surgical times evaluated were before (T0), during (T1), and after surgery (T2). RESULTS: There was evidence that both Valeriana officinalis L. and Passiflora incarnata L., reduced STAY-S scores between T0 and T2 (p < .05), unlike placebo (p = .129). There was no change in surgical discomfort in all groups over time, and vital signs presented variable results. CONCLUSION: Phytotherapy drugs showed a reduction in anxiety state compared to the placebo group during third molar extraction procedure.  CLINICAL TRIAL REGISTRATION: klRBR-6kcxvrc, March 10, 2022.

Association of placental weight at birth with maternal whole blood concentration of heavy metals (cadmium, lead, mercury, selenium, and manganese): The Japan Environment and Children's Study (JECS).

BACKGROUND: Lifelong health is dependent on prenatal growth and development, influenced by the placental intrauterine environment. Charged with dual functions--exchange of oxygen and nutrients as well as a barrier against toxins--the placenta itself is susceptible to environmental exposure to heavy metals. OBJECTIVE: To examine the use of placenta weight as a biomarker for heavy metal exposure using a large Japanese cohort of pregnant women. METHODS: The placenta weight, as a biomarker of exposure to heavy metals (cadmium, lead, and mercury), was investigated using data from the Japan Environment and Children's Study (2011-2014). Selenium and manganese were included as factors directly affecting fetal growth or heavy metal toxicity. Maternal blood samples collected in the second or third trimester were used to measure heavy metal concentrations. The association between maternal blood metal concentrations and placenta weight was explored by applying Z scores and multivariable logistic regression analysis and classifying participants into quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. RESULTS: This study included a total of 73,005 singleton pregnant women who delivered via live births and met the inclusion criteria. The median heavy metal concentrations in the maternal whole blood were 0.662 ng/g cadmium, 5.85 ng/g lead, 3.61 ng/g mercury, 168 ng/g selenium, and 15.3 ng/g manganese. Regression analysis revealed a significant correlation between placenta weight Z scores and maternal blood metal concentrations: cadmium, 0.0660 (standard error = 0.0074, p < 0.001); selenium, -0.3137 (standard error = 0.0276, p < 0.001); and manganese, 0.1483 (standard error = 0.0110, p < 0.001). CONCLUSION: This study provides a robust examination of the association between heavy metal exposure and placenta weight. Cadmium and manganese showed a positive correlation with significant differences, whereas selenium showed a negative correlation. Essential elements notably affect placenta weight differently. No significant association was noted between lead or mercury and placenta weight.

Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

The effect of parental age on child development at 36 months: Insights from the Japan environment and children's study.

BACKGROUND: The impact of parent-childbearing age on child development at 36 months of age is controversial. AIMS: We used data from a large cohort study with multiple imputation and mediation analyses of variables. METHODS AND PROCEDURES: A total of 72,606 parent-child pairs from the Japan Environment and Children's Study were included in the study. Parents' ages were categorized into five groups. We used five domains of the Japanese translation of the Ages and Stages Questionnaire, Third Edition (J-ASQ-3). Scores below the cutoff value at 36 months were defined as developmental delays in each domain. We used three logistic analysis models. In Model 3, we analyzed maternal and paternal age using other variables and covariates. OUTCOMES AND RESULTS: The outcome was a developmental delay in the five domains of J-ASQ-3. In Model 3, ORs for the developmental delay scores regarding parental age were significantly associated with all five domains of J-ASQ-3. The mediation analysis showed a significant mediation interaction effect for mothers but localized for fathers. CONCLUSION: Advanced paternal and maternal ages were associated with developmental delay in children. Awareness of the risks of childbearing at an advanced age is crucial. WHAT'S THE PAPER ADDS: This manuscript used data from a large cohort study with multiple imputation and mediation analyses. With these analyses, we identified the pure effect of advanced parental age on their children's development at 36 months.

Incidence of coronary heart disease among remote workers: a nationwide web-based cohort study.

Coronary heart disease (CHD) risk is influenced by socioeconomic status-related parameters, particularly occupation. We investigated occupational gaps in CHD risk and how the introduction of remote work moderated the observed occupational differences in CHD risk during the coronavirus disease 2019 pandemic in Japan. Data from a web-based, nationwide cohort study, comprising 17,640 workers (aged 20-65 years) with baseline data from December 2020, were analyzed. Participants were grouped by occupation as upper-level nonmanual workers (managers/professionals) and others (reference group). The primary outcome was CHD (angina pectoris/myocardial infarction) onset retrospectively confirmed at the 1-year follow-up survey. Upper-level nonmanual workers exhibited a higher CHD incidence than others (2.3% vs. 1.7%). This association was pronounced in the younger (20-49 years) population, with a significant CHD risk (adjusted risk ratio = 1.88). Upper-level nonmanual workers exhibited nearly 15% higher remote work prevalence, with a significant remote work-related CHD risk (adjusted risk ratio = 1.92). The mediating effects of remote work explained an overall disparity of 32% among the younger population. Occupational gaps in CHD incidence in Japan differ from those in Western countries, where upper-level nonmanual workers have lower cardiovascular risk. In Japan, remote work can mediate CHD risk in the younger population of upper-level nonmanual workers.

A prospective cohort study of presenteeism and increased risk of unemployment among Japanese workers during the COVID-19 pandemic.

OBJECTIVES: Presenteeism adversely affects workers' quality of life, leading to further deterioration of their health and affecting their ability to continue working. Unemployment is one of the most serious consequences for workers experiencing presenteeism. A worker's ability to work depends on the degree of mismatch between their health status and job demands and work factors. The COVID-19 pandemic has affected workers' experiences of presenteeism as well as their employment status. We examined the association between presenteeism and risk of job resignations and unemployment among Japanese workers during the COVID-19 pandemic. METHODS: A prospective study of 27 036 internet monitors was conducted, starting in December 2020, with 18 560 (68.7%) participating in the follow-up by December 2021. The Work Functioning Impairment Scale (WFun) was used to measure the degree of work function impairment. RESULTS: The group with the highest WFun scores had higher odds ratios (ORs) for both retirement and unemployment for health reasons than the group with the lowest WFun scores. ORs were 2.99 (95% CI, 2.48-3.62; P < .001) and 1.82 (95% CI, 1.65-2.00; P < .001), respectively. CONCLUSIONS: Workers with work functioning impairment are at increased risk of resignation or unemployment. Management strategies for workers with work functioning impairment are needed to reduce their disadvantages in employment.

Measurement of Bisphenol A Diglycidyl Ether (BADGE), BADGE derivatives, and Bisphenol F Diglycidyl Ether (BFDGE) in Japanese infants with NICU hospitalization history.

BACKGROUND: Bisphenol A diglycidyl ether (BADGE) and Bisphenol F diglycidyl ether (BFDGE) are used in medical devices, such as intravenous sets, syringes, and catheters. Several studies have reported that these compounds are endocrine disruptors, cytotoxic, and genotoxic, raising concerns about their adverse effects on infants, in a stage of remarkable growth and development. The present study aimed to measure the serum concentrations of BADGE, derivatives of BADGE, and BFDGE in infants and examine the factors that influence them. METHODS: Ten infants admitted to the neonatal intensive care unit (NICU) were enrolled in the present study. Blood samples from each infant and questionnaires from their mothers were collected twice, at 1-2 months and 7 months of age. BADGE, BADGE·H2O, BADGE·2H2O, and BFDGE were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Serum BADGE·2H2O was identified in all infants, at both 1-2 months (2.30-157.58 ng/ml) and 7 months of age (0.86-122.85 ng/ml). One of the two infants who received invasive ventilation showed a substantially increased BADGE·2H2O concentration. There was no significant difference in BADGE·2H2O concentrations at 7 months of age between the group that ate commercial baby food at least ≥ 1 time per week and the group that did not. CONCLUSIONS: BADGE·2H2O was detected in the serum of all infants with a history of NICU hospitalization. Future studies are needed to determine the source of BADGE exposure and investigate its effects on infant development.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Nivolumab receptor occupancy on effector regulatory T cells predicts clinical benefit.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

Relationship Between Infection or Close Contact With COVID-19 and Workplace Mistreatment Among Japanese Workers: A Cross-sectional Study.

OBJECTIVE: Discriminatory treatment against those with emerging infection is a long-standing problem. The present study investigates whether workers infected or in close contact with COVID-19 were susceptible to workplace mistreatment during the pandemic in Japan. METHODS: This Internet-based cross-sectional study analyzed a total of 18,170 workers aged 20 to 60 years in Japan in December 2020. Odds ratios (ORs) for workplace mistreatment were estimated. RESULTS: For workers with close contact or infection, ORs for workplace mistreatment in a model adjusted for socioeconomic factors were 7.64 (95% CI: 5.52-10.6, P < 0.001) and 10.7 (95% CI: 8.44-13.6, P < 0.001), respectively. CONCLUSIONS: Workers with infection or close contact were significantly more likely to experience workplace mistreatment. Actions against workplace mistreatment for workers with emerging infection are still required.

Effects of the Need for Support From the Workplace and Resilience on Psychological Distress in Japanese Employees: A 1-Year Prospective Study.

PURPOSE: This study examines workplace support and resilience's influence on psychological distress in Japanese employees. METHOD: A 1-year prospective online cohort study was conducted. Logistic regression analyzed prevalence odds ratios and 95% confidence intervals for psychological distress. Participants were grouped based on their support and resilience levels. RESULTS: Prevalence odds ratios for psychological distress followed this pattern for low and high resilience groups: "necessary but not received" (prevalence odds ratio and 95% confidence interval for low/high resilience: 9.71, 6.88-13.69 and 4.72, 2.97-7.52, respectively), "received" (6.65, 4.29-10.29 and 2.27, 1.21-4.25), and "not necessary" (4.43, 3.30-5.95 and reference). Workplace support had a stronger impact on psychological distress in low-resilience employees. CONCLUSIONS: We provided evidence that the combination of the need for support from the workplace and resilience affects psychological distress in employees.

A Cross-sectional Study on the Impact of Unfair Treatment Associated With COVID-19 Infection and Psychological Distress in Japanese Workers.

OBJECTIVE: Psychological distress is commonly reported sequela in COVID-19-infected people. We investigated the association between experiencing COVID-19 infection and psychological distress in Japan. METHOD: A total of 14,901 persons who participated in a follow-up survey in December 2022 were included in the analysis. Odds ratios and regression coefficients were estimated by statistical analysis, with history of COVID-19 infection as the independent variable and presence of psychological distress as the dependent variable. RESULT: Experiencing COVID-19 infection was associated with psychological distress. In a model adjusted for "feeling treated unfairly," the association between infection experience and a high K6 score was significantly attenuated. CONCLUSIONS: The results showed that the experience of COVID-19 infection is associated with psychological distress. Moreover, most cases of psychological distress among those who experienced COVID-19 infection can be at least partly explained by a perception of unfair treatment.