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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Non-classical Monocytes Enhance the Efficacy of Immune Checkpoint Inhibitors on Colon Cancer in a Syngeneic Mouse Model.

BACKGROUND/AIM: The response rate to immune checkpoint inhibitors (ICIs) is approximately 10%-30% and only in a few cancer types. In the present study, we determined whether non-classical monocytes (NCMs) could enhance ICI efficacy in colon cancer using a syngeneic mouse model. MATERIALS AND METHODS: The MC38 C57BL/6 mouse colon cancer model was used. Cells collected from the bone marrow of C57BL/6 mice were cultured, and NCMs were fractionated by cell sorting and administered via the tail veins to the mice implanted with MC38 cells. The anti-mouse PD-L1 antibody was administered three times, and tumor volume and overall survival were observed. RESULTS: More tumors were eradicated and more complete response occurred, after cotreatment with ICIs and NCMs than after treatment with ICIs alone. Moreover, no efficacy was observed when NCMs were administered alone. CONCLUSION: NCMs enhance ICI efficacy. The underlying mechanisms and clinical applications will be studied in the future.

The quantity and quality of scientific evidence about the health of working women in occupational health of Japan: A scoping review.

OBJECTIVE: We aim to investigate the quantity and quality of scientific evidence dealing with comprehensive health issues of working women in occupational health. METHODS: This scoping review of original articles that investigated comprehensive health issues of working women aged 19-64 years in Japan was published in PubMed (1967-2022) and Igaku Chuo Zasshi (or Ichu-shi, 1982-2022). Using identical broad search terms, we first identified 17 122 English and 6154 Japanese articles. We excluded those with clinically relevant topics, or ethnicity other than Japanese and included 853 English and 855 Japanese articles for review and classified them into nine research areas considered to be critical factors for women in the workforce and five study design groups to investigate the quality of the evidence accumulated. RESULTS: Among 853 English-language articles in PubMed, "Mental health" was the most frequent area studied, followed by "Work-related disease" and "Lifestyle-related disease." Among 855 Japanese-language articles from Ichu-shi, "Mental health" was the most frequently studied area followed by "Work and balance," and "Work-related disease." "Infertility, pregnancy, and childbirth" and "Menstruation, menopause, and genital disease" were well studied in Ichu-shi but scarcely published in PubMed. "Harassment and discrimination" were sparsely reported in both databases. As for research designs, many articles in both PubMed and Ichu-shi employed descriptive or cross-sectional study designs. However, a few studies employed cohort/longitudinal or interventional studies. CONCLUSION: The results underscored the need for higher-quality study designs with more scientific evidence on working women's health in the field of occupational health.

Novel quantitative immunohistochemical analysis for evaluating PD-L1 expression with phosphor-integrated dots for predicting the efficacy of patients with cancer treated with immune checkpoint inhibitors.

Introduction: Programmed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method. Methods: In total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression. Results: PD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group. Conclusion: Quantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.

Maternal DHA intake in mice increased DHA metabolites in the pup brain and ameliorated MeHg-induced behavioral disorder.

Although pregnant women's fish consumption is beneficial for the brain development of the fetus due to the DHA in fish, seafood also contains methylmercury (MeHg), which adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women's sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier study revealed that DHA and its metabolite 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) produced by cytochrome P450s (P450s) and soluble epoxide hydrolase (sEH) can suppress MeHg-induced cytotoxicity in mouse primary neuronal cells. In the present study, DHA supplementation to pregnant mice suppressed MeHg-induced impairments of pups' body weight, grip strength, motor function, and short-term memory. DHA supplementation also suppressed MeHg-induced oxidative stress and the decrease in the number of subplate neurons in the cerebral cortex of the pups. DHA supplementation to dams significantly increased the DHA metabolites 19,20-epoxydocosapentaenoic acid (19,20-EDP) and 19,20-DHDP as well as DHA itself in the fetal and infant brains, although the expression levels of P450s and sEH were low in the fetal brain and liver. DHA metabolites were detected in the mouse breast milk and in human umbilical cord blood, indicating the active transfer of DHA metabolites from dams to pups. These results demonstrate that DHA supplementation increased DHA and its metabolites in the mouse pup brain and alleviated the effects of MeHg on fetal brain development. Pregnant women's intake of fish containing high levels of DHA (or DHA supplementation) may help prevent MeHg-induced neurotoxicity in the fetus.

Extracellular high molecular weight α-synuclein oligomers induce cell death by disrupting the plasma membrane.

α-Synuclein (αS), the causative protein of Parkinson's disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer (HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular αS aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-αSo or LMW-αS. Extracellular HMW-αSo was more cytotoxic than LMW-αS and was a crucial factor for inducing plasma membrane damage and cell death. HMW-αSo induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-αSo also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-αSo causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for α-synucleinopathies.

Monocyte subsets associated with the efficacy of anti­PD­1 antibody monotherapy.

Immune checkpoint inhibitors (ICIs) are among the most notable advances in cancer immunotherapy; however, reliable biomarkers for the efficacy of ICIs are yet to be reported. Programmed death (PD)-ligand 1 (L1)-expressing CD14+ monocytes are associated with shorter overall survival (OS) time in patients with cancer treated with anti-PD-1 antibodies. The present study focused on the classification of monocytes into three subsets: Classical, intermediate and non-classical. A total of 44 patients with different types of cancer treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) were enrolled in the present study. The percentage of each monocyte subset was investigated, and the percentage of cells expressing PD-L1 or PD-1 within each of the three subsets was further analyzed. Higher pretreatment classical monocyte percentages were correlated with shorter OS (r=-0.32; P=0.032), whereas higher non-classical monocyte percentages were correlated with a favorable OS (r=0.39; P=0.0083). PD-L1-expressing classical monocytes accounted for a higher percentage of the total monocytes than non-classical monocytes with PD-L1 expression. In patients with non-small cell lung cancer (NSCLC), a higher percentage of PD-L1-expressing classical monocytes was correlated with shorter OS (r=-0.60; P=0.012), which is similar to the observation for the whole patient cohort. Comparatively, higher percentages of non-classical monocytes expressing PD-L1 were significantly associated with better OS, especially in patients with NSCLC (r=0.60; P=0.010). Moreover, a higher percentage of non-classical monocytes contributed to prolonged progression-free survival in patients with NSCLC (r=0.50; P=0.042), with similar results for PD-L1-expressing non-classical monocytes. The results suggested that the percentage of monocyte subsets in patients with cancer before anti-PD-1 monotherapy may predict the treatment efficacy and prognosis. Furthermore, more classical monocytes and fewer non-classical monocytes, especially those expressing PD-L1, are involved in shortening OS time, which may indicate the poor efficiency of anti-PD-1 treatment approaches.