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.

Subacute exposure to bisphenol F diglycidyl-ether induces chronic dermatitis characterized by psoriasis-like skin inflammation in mice.

Bisphenol F diglycidyl ether (BFDGE) is widely used in the synthesis process of plastic products. While exposure to bisphenol A diglycidyl ether (BADGE), which has a similar structure to BFDGE and which is used for the same purpose, has been reported to cause health risks, there is still little information on BFDGE. Because it is estimated that the industrial workers are exposed to large amounts of BFDGE, the health risks associated with BFDGE exposure need to be clarified. We investigated the toxicity of cutaneous exposure to BFDGE using an in vitro evaluation system and a mouse exposure model. The tumorigenic potential of BFDGE was confirmed by the Bhas 42 cell transformation assay, which showed that BFDGE has both promoter and initiator activity, in vitro. A single dermal application of BFDGE was associated with minor contact hypersensitivity symptoms. In contrast, repeated dermal exposure to BFDGE for 2 weeks induced persistent acute inflammation with features similar to inflammation in human psoriasis. This is the first report evaluating the toxicity of BFDGE in animals, and we showed that BFDGE carries a health risk of inducing skin dermatitis similar to that in human psoriasis in an exposure period-dependent manner.

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.

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.

Structural Dynamics of Amyloid-ß Protofibrils and Actions of Anti-Amyloid-ß Antibodies as Observed by High-Speed Atomic Force Microscopy.

Amyloid-ß (Aß) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used high-speed atomic force microscopy to observe the structural dynamics of Aß42 PF at the single-molecule level and the effect of lecanemab, an anti-Aß PF antibody with the positive results from Phase 3 Clarity AD. PF was found to be a curved nodal structure with stable binding angle between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PFs and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Aß aggregation process.

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.

Gestational Weight Gain Growth Charts Adapted to Japanese Pregnancies Using a Bayesian Approach in a Longitudinal Study: The Japan Environment and Children's Study.

BACKGROUND: Tracking gestational weight gain (GWG) during pregnancy makes it possible to optimize pregnancy outcomes, and GWG growth curves are well suitable for this purpose. The GWG guidelines for Japanese were revised in 2021. However, currently, there are no GWG growth curves to guide women on how to gain weight to meet these guidelines. METHODS: Using data on 96,631 live births from the Japan Environment and Children's Study (JECS), we created descriptive GWG percentile curves estimating the trajectory of GWG required to meet the GWG guidelines stratified by pre-pregnancy body mass index (BMI). For both analyses, Bayesian mixed models with restricted cubic splines adjusted for maternal characteristics were used. RESULTS: GWG curves substantially differed by pre-pregnancy BMI and were higher among multiparas and those with lower maternal age and with no previous disease. We estimated that underweight, normal weight, overweight, and obese women who gain 8.4 to 11.1 kg, 6.4 to 9.1 kg, 3.8 to 6.5 kg, and <1.9 kg at 30 weeks of gestation are on the trajectory to reach the new guidelines at 40 weeks of gestation. CONCLUSION: We provide GWG percentiles curves for Japanese women, as well as GWG trajectory curves to meet the new GWG recommendations. These results may help pregnant women monitor weight during pregnancy.

Association between COVID-19 infection rates by region and implementation of non-pharmaceutical interventions: a cross-sectional study in Japan.

BACKGROUND: During a pandemic, non-pharmaceutical interventions (NPIs) play an important role in protecting oneself and others from infection. There are large regional differences in COVID-19 infection rates in Japan. We hypothesized that the local infection incidence may affect adherence to individual NPIs. METHODS: This cross-sectional study was conducted online among full-time workers in Japan in December 2020. The questionnaire asked the respondents to identify their habits regarding seven common NPIs (wearing masks, washing hands after the bathroom, disinfecting hands when entering indoors, gargling when returning home, ventilating the room, disinfecting or washing hands after touching frequently touched surfaces, carrying alcohol sanitizers when outdoors). RESULTS: A total of 27 036 participants were analyzed. Compared with the region with the lowest infection rate, five of the seven NPIs showed statistically significant trends across regional infection levels, the two exceptions being wearing masks and washing hands after the bathroom. Multivariate adjustment did not change these trends. CONCLUSIONS: This study found that NPIs were more prevalent in regions with higher incidence rates of COVID-19 in Japanese workers. The findings suggest that the implementation of NPIs was influenced not only by personal attributes but also by contextual effects of the local infection level.

Occupational Factors Associated with Telemedicine Use in the Japanese Working-Age Population: A Web-Based Study Conducted during the COVID-19 Pandemic.

Telemedicine has significant potential for helping workers access medical treatment. To improve workers' access to telemedicine, it is important to analyze current utilization rates and influencing factors. Therefore, the purpose of this study is to evaluate the associations between occupational factors and telemedicine use. A 1-year follow-up study of 4,882 full-time workers receiving regular treatment in Japan was conducted from December 2020 to December 2021. Occupational factors associated with the use of telemedicine were evaluated by multivariate logistic regression analysis. In total, 191 participants had experience of using telemedicine (3.9%). The most common comorbidity was hypertension (37.0%), followed by back pain and arthritis (19.8%) and depression and psychiatric disorders (14.5%). Managers and executives [adjusted odds ratio (aOR) = 1.92, 95% confidence interval (CI): 1.68-3.43, P < = 0.026], finance industry workers (aOR = 2.61, 95% CI: 1.24-5.49, P = 0.011), and individuals with experience of teleworking (aOR = 2.08, 95% CI: 1.52-2.85, P < 0.001) were more likely to use telemedicine. Telemedicine usage was least common among workers aged 50-59 years (aOR = 0.35, 95% CI: 0.22-0.57, P < 0.001) and those with long working hours (≥ 9.0 hours/day) (aOR = 0.59, 95% CI: 0.38-0.93, P < 0.022). The utilization rate of telemedicine in Japan is still low. This study identified occupational factors related to the use of telemedicine, such as worker's age, employee status, working hours, and experience of teleworking. Our findings suggest that flexible work arrangements could promote widespread use of telemedicine.

Relationship between placental hemodynamics and placental histological analysis in third trimester.

AIM: To investigate whether vascularization index (VI), flow index (FI), and vascularization flow index (VFI) correlate with the pathological structure of the placenta and whether there were any differences in VI, FI, VFI, and placental pathological structure between the normal and preeclampsia (PE) groups. METHODS: Fifty-five pregnant women (normal group, n = 27; PE group, n = 28) underwent VI, FI, and VFI at four locations in the placenta during the second and third trimesters. Two hematoxylin and eosin (HE)-stained specimens of the postpartum placenta were prepared. We randomly selected two of these locations and used ImageJ, an open-source image package, to quantify intervillous blood vessels (IBV), intervillous spaces (IS), and intervillous blood vessels + intervillous spaces (IBV + IS) per unit placenta and analyzed their correlation with VI, FI, and VFI. RESULTS: There was no positive correlation between VI, FI, VFI, IBV, IS, and IBV + IS. There were no significant differences in VI, FI, and VFI between the normal and PE groups; however, there were significant differences in IBV, IS, and IBV + IS in the PE group compared to those in the normal group. CONCLUSIONS: Placental hemodynamics measured by VI, FI, and VFI were not positively correlated with placental morphology in the third trimester. There were no differences in the VI, FI, and VFI in the third trimester between the normal and PE groups, suggesting that these may reflect placental circulatory insufficiency.

The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by Aß Oligomers.

In Alzheimer's disease (AD), accumulation of amyloid ß-protein (Aß) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aß has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aß-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aß oligomers (Aßo), which include high-molecular-weight (HMW) Aßo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 µM) on Aßo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca2+ ([Ca2+]i). GT863 inhibited the Aßo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca2+]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aßo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aßo exposure.

Association between maternal fish consumption during pregnancy and preterm births: the Japan Environment and Children's Study.

BACKGROUND: Fish are a rich source of essential nutrients that protect against preterm birth. However, as fish can absorb environmental pollutants, their consumption can also increase the risk of preterm birth. This study aimed to assess whether maternal fish consumption during pregnancy is associated with preterm birth in a nationwide large Japanese cohort that consumed relatively high amounts and many types of fish. METHODS: This study included 81,428 mother-child pairs enrolled in a nationwide prospective Japanese birth cohort study. Fish consumption was assessed using a validated food frequency questionnaire. Multivariate logistic regression was used to investigate the association of total consumption of fish, fatty fish and lean fish, fish paste, and seafood and clams with preterm birth, adjusted for potential confounders. RESULTS: There was no association between overall fish consumption and preterm births. However, the highest quintile of fish paste consumption was significantly associated with an increased risk of preterm birth (odds ratio [OR]: 1.11; 95% confidence interval [CI: 1.04, 1.17]). The consumption of baked fish paste at least three times per week was significantly associated with preterm birth (OR: 1.20; 95% CI: 1.03, 1.40). Consumption of other types of fish, except fish paste, was not significantly associated with preterm birth risk. CONCLUSIONS: Fish paste consumption may increase the risk of preterm birth. Further studies are required to confirm this association.

A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure.

BACKGROUND: Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score, attention-deficit hyperactivity disorder and autism spectrum disorder in children when it is administered during pregnancy. Prenatal VPA exposure has been reported to affect neurogenesis and neuronal migration and differentiation. In addition, growing evidence has shown that microglia and brain immune cells are activated by VPA treatment. However, the role of VPA-activated microglia remains unclear. METHODS: Pregnant female mice received sodium valproate on E11.5. A microglial activation inhibitor, minocycline or a CCR5 antagonist, maraviroc was dissolved in drinking water and administered to dams from P1 to P21. Measurement of microglial activity, evaluation of neural circuit function and expression analysis were performed on P10. Behavioral tests were performed in the order of open field test, Y-maze test, social affiliation test and marble burying test from the age of 6 weeks. RESULTS: Prenatal exposure of mice to VPA induced microglial activation and neural circuit dysfunction in the CA1 region of the hippocampus during the early postnatal periods and post-developmental defects in working memory and social interaction and repetitive behaviors. Minocycline, a microglial activation inhibitor, clearly suppressed the above effects, suggesting that microglia elicit neural dysfunction and behavioral disorders. Next-generation sequencing analysis revealed that the expression of a chemokine, C-C motif chemokine ligand 3 (CCL3), was upregulated in the hippocampi of VPA-treated mice. CCL3 expression increased in microglia during the early postnatal periods via an epigenetic mechanism. The CCR5 antagonist maraviroc significantly suppressed neural circuit dysfunction and post-developmental behavioral disorders induced by prenatal VPA exposure. CONCLUSION: These findings suggest that microglial CCL3 might act during development to contribute to VPA-induced post-developmental behavioral abnormalities. CCR5-targeting compounds such as maraviroc might alleviate behavioral disorders when administered early.

Lack of catch-up in weight gain may intermediate between pregnancies with hyperemesis gravidarum and reduced fetal growth: the Japan Environment and Children's Study.

BACKGROUND: Women with nausea and vomiting of pregnancy (NVP) have higher birth weight infants, while those with hyperemesis gravidarum, a severe manifestation of NVP, have lower birth weight infants. We aimed to investigate the associations between maternal weight loss (a consequence of hyperemesis gravidarum), NVP, and infant birth weight. METHODS: This study was a secondary analysis of a nationwide birth cohort in Japan. Singleton pregnancies delivered at 28-41 weeks of gestation were included in the analysis. Women were categorized based on their weight change in the 1st trimester (as a proportion to their pre-pregnancy weight: > + 3%, > 0 to + 3%, > -3 to 0%, > -5 to -3%, ≤ -5%) and severity of NVP (no nausea, only nausea, vomiting but able to eat, vomiting and unable to eat). The effects of weight change and severity of NVP on infant birth weight and small for gestational age (SGA) were assessed using regression models. We further examined how these effects could be modified by maternal weight gain up to the 2nd trimester. RESULTS: Among 91,313 women, 5,196 (5.7%) lost ≥ 5% of their pre-pregnancy weight and 9,983 (10.9%) experienced vomiting and were unable to eat in the 1st trimester. Women with weight loss ≥ 5% in the 1st trimester had infants 66 (95% CI: 53, 78) g lighter and higher odds of SGA (aOR: 1.29; 95% CI: 1.14, 1.47) than women who gained > 3% during the same period. However, when adjusting for weight gain up to the 2nd trimester, women with weight loss ≥ 5% in the 1st trimester had infants 150 (95% CI: 135, 165) g heavier and lower odds of SGA (aOR: 0.39; 95% CI: 0.33, 0.46) than those who gained > 3% during the same period. In contrast, women with more severe NVP tended to have infants with larger birth weight and lower odds of SGA compared to women without NVP. These trends were strengthened when adjusting for weight gain up to the 2nd trimester. CONCLUSIONS: Our study suggests the possibility that reduced fetal growth in pregnancies with hyperemesis gravidarum may be caused by the lack of catch-up in gestational weight gain up to the 2nd trimester.

Effect of COVID-19 infection related experiences on social behaviors when a state of emergency is declared: a cohort study.

BACKGROUND: Restricting the movement of the public to gathering places and limiting close physical contact are effective measures against COVID-19 infection. In Japan, states of emergency have been declared in specific prefectures to reduce public movement and control COVID-19 transmission. We investigated how COVID-19 infection related experiences including people with a history of infection, people with a history of close contact, and people whose acquaintances have been infected, affected self-restraint from social behaviors during the second state of emergency in Japan. METHODS: A prospective cohort study was conducted among workers aged 20-65 years using data from an internet survey. The baseline survey was conducted on December 22-25, 2020, and a follow-up survey was on February 18-19, 2021. There were 19,051 participants who completed both surveys and were included in the final analysis. We identified eight social behaviors: (1) eating out (4 people or fewer); (2) eating out (5 people or more); (3) gathering with friends and colleagues; (4) day trip; (5) overnight trip (excluding visiting home); (6) visiting home; (7) shopping for daily necessities; and (8) shopping for other than daily necessities. We set self-restraint regarding each social behavior after the second state of emergency was declared in January 2021 as the dependent variable, and COVID-19 infection related experiences as independent variables. Odds ratios were estimated using multilevel logistic regression analyses nested in the prefecture of residence. RESULTS: Significant differences by COVID-19 infection related experiences were identified: compared to people without COVID-19 related experiences, people with a history of COVID-19 were less likely self-restraint from most social behaviors. People whose acquaintance had been diagnosed with COVID-19 were significantly more likely to refrain from most social behaviors. There was no significant difference in any social behaviors for people with a history of close contact only. CONCLUSION: To maximize the effect of a state of emergency, health authorities should disseminate information for each person in the target population, taking into account potential differences related to the infection related experiences.

Combined Treatment with Curcumin and Ferulic Acid Suppressed the Aß-Induced Neurotoxicity More than Curcumin and Ferulic Acid Alone.

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-ß (Aß)-induced neuronal cytotoxicity. The effect of Cur or FA on Aß aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aß exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD.

The Sympathetic Nervous System Contributes to the Establishment of Pre-Metastatic Pulmonary Microenvironments.

Emerging evidence suggests that neural activity contributes to tumor initiation and its acquisition of metastatic properties. More specifically, it has been reported that the sympathetic nervous system regulates tumor angiogenesis, tumor growth, and metastasis. The function of the sympathetic nervous system in primary tumors has been gradually elucidated. However, its functions in pre-metastatic environments and/or the preparation of metastatic environments far from the primary sites are still unknown. To investigate the role of the sympathetic nervous system in pre-metastatic environments, we performed chemical sympathectomy using 6-OHDA in mice and observed a decrease in lung metastasis by attenuating the recruitment of myeloid-derived suppressor cells. Furthermore, we note that neuro-immune cell interactions could be observed in tumor-bearing mouse lungs in conjunction with the decreased expression of Sema3A. These data indicate that the sympathetic nervous system contributes to the preparation of pre-metastatic microenvironments in the lungs, which are mediated by neuro-immune cell interactions.

COVID-19 vaccination coverage by company size and the effects of workplace vaccination program in Japan: a cohort study.

BACKGROUND: Vaccination is considered the most effective control measure against COVID-19. Vaccine hesitancy and equitable vaccine allocation are important challenges to disseminating developed vaccines. To promote COVID-19 vaccination coverage, the government of Japan established the workplace vaccination program. However, while it appears that the program was effective in overcoming vaccine hesitancy, the program may have hindered the equitable allocation of vaccines because it mainly focused on employees of large companies. We investigated the relationship between company size and COVID-19 vaccination completion status of employees and the impact of the workplace vaccination program on this relationship. METHODS: We conducted an internet-based prospective cohort study from December 2020 (baseline) to December 2021. The data were collected using a self-administered questionnaire survey. Briefly, 27,036 workers completed the questionnaire at baseline and 18,560 at follow-up. After excluding ineligible respondents, we finally analyzed the data from 15,829 participants. At baseline, the participants were asked about the size of the company they worked for, and at follow-up they were asked about the month in which they received their second COVID-19 vaccine dose and the availability of a company-arranged vaccination opportunity. RESULTS: In each month throughout the observation period, the odds of having received a second COVID-19 vaccine dose were significantly lower for small-company employees than for large-company employees in the sex- and age-adjusted model. This difference decreased after adjusting for socioeconomic factors, and there was no significant difference after adjusting for the availability of a company-arranged vaccination opportunity. CONCLUSIONS: The workplace vaccination program implemented in Japan to control the COVID-19 pandemic may have been effective in overcoming vaccine hesitancy in workers; however, it may have caused an inequitable allocation of vaccines between companies of different sizes. Because people who worked for small companies were less likely to be vaccinated, it will be necessary to enhance support of vaccination for this population in the event of future infectious disease outbreaks. TRIAL REGISTRATION: Not applicable.

Association between willingness to receive the COVID-19 vaccine and sources of health information among Japanese workers: a cohort study.

BACKGROUND: It is important to achieve herd immunity by vaccinating as many people as possible to end the COVID-19 pandemic. We investigated the relationship between willingness to receive vaccination and sources of health information among those who did not want to be vaccinated against COVID-19. METHODS: This prospective cohort study collected data using a self-administered questionnaire survey. The baseline survey was conducted during December 22-25, 2020, and the follow-up survey during February 18-19, 2021. Participants were aged 20-65 years and worked at the time of the baseline survey (N = 33,087). After excluding 6,051 invalid responses, we included responses from 27,036 participants at baseline. In total, 19,941 people responded to the follow-up survey (74% follow-up rate). We excluded 7,415 participants who answered "yes" to the question "If a COVID-19 vaccine becomes available, would you like to get it?" in the baseline survey. We finally analyzed 12,526 participants. RESULTS: The odds ratio for change in willingness to be vaccinated from "no" to "yes" differed by source of health information. Compared with workers that used TV as a source of information, significantly fewer people who reported getting information from the Internet and friends/colleagues were willing to get the vaccine. CONCLUSIONS: It is important to approach workers who do not watch TV when implementing workplace vaccination programs. It is likely that willingness to be vaccinated can be increased through an active company policy whereby the top management recommend vaccination, coupled with an individual approach by occupational health professionals. TRIAL REGISTRATION: Not applicable.