PD-1 blockade therapy augments the antitumor effects of lymphodepletion and adoptive T cell transfer.

Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.

The preventive effect of internet-based cognitive behavioral therapy for prevention of depression during pregnancy and in the postpartum period (iPDP): a large scale randomized controlled trial.

BACKGROUND: Prevention of perinatal depression beginning from the antenatal period is essential. Therefore, this study aimed to investigate the effectiveness of recently developed internet-delivered cognitive behavioral therapy (iCBT) for preventing the onset of a major depressive episode (MDE) in the third trimester and at 3 months postpartum. METHODS: This is a two-arm, parallel-group, general-information controlled, randomized controlled trial. Participants were 5017 pregnant women at 16-20 weeks' gestation without MDE at baseline. They were randomly assigned to an iCBT (intervention; n = 2509) or general-information (control; n = 2508) group, stratified by psychological distress at baseline. The primary outcomes were the numbers of new MDE onsets, measured using the World Health Organization Composite International Diagnostic Interview 3.0, at 32 weeks' gestation and at 3 months postpartum. RESULTS: New MDE onset was reported by 59 participants (2.35%) in the intervention group and 73 (2.91%) in the control group during follow-up. Compared with the control group, the hazard ratio (HR) of MDE in the intervention group was 0.85 (95% CI 0.61-1.20), which was not significantly different. Among participants who scored between 5 and 8 on K6 at baseline, 10 (1.37%) in the intervention group reported new onset of MDE, compared with 28 (3.81%) in the control group, and the HR of MDE was 0.38 (95%CI 0.19-0.79). CONCLUSIONS: No intervention effect was found for iCBT in preventing new onset of perinatal MDE. iCBT might prevent perinatal depression only among pregnant women with subthreshold depressive symptoms. TRIAL REGISTRATION: UMIN000038190.

Effects of Smartphone-Based Stress Management on Improving Work Engagement Among Nurses in Vietnam: Secondary Analysis of a Three-Arm Randomized Controlled Trial.

BACKGROUND: Work engagement is important for employee well-being and work performance. However, no intervention study has investigated the effect of an eMental Health intervention on work engagement among workers in low- and middle-income countries (LMICs). OBJECTIVE: The aim of the study was to examine the effects of a newly developed smartphone-based stress management program (ABC Stress Management) on improving work engagement among hospital nurses in Vietnam, an LMIC. METHODS: Full-time registered nurses (n=949) were randomly assigned to one of 2 intervention groups or a control group. The intervention groups were a 6-week, 6-lesson program offering basic cognitive behavioral therapy (CBT-based stress management skills), provided in either free-choice (program A) or fixed order (program B). Work engagement was assessed at baseline and 3-month and 7-month follow-ups in each of the 3 groups. RESULTS: The scores of work engagement in both intervention groups improved from baseline to 3-month follow-up, and then decreased at the 7-month follow-up, while the score steadily increased from baseline to 7-month follow-up in the control group. Program B showed a significant intervention effect on improving work engagement at the 3-month follow-up (P=.049) with a small effect size (Cohen d= 0.16; 95% CI 0.001 to 0.43]). Program A showed nonsignificant trend (d=0.13; 95% CI -0.014 to 0.41; P=.07) toward improved engagement at 3 months. Neither program achieved effectiveness at the 7-month follow-up. CONCLUSIONS: The study demonstrated that a fixed order (program B) delivery of a smartphone-based stress management program was effective in improving work engagement in nurses in Vietnam. However, the effect was small and only temporary. Further improvement of this program is required to achieve a greater effect size and more sustained, longer lasting impact on work engagement. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000033139; tinyurl.com/55gxo253. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2018-025138.

The effect of a behavioral activation program on improving mental and physical health complaints associated with radiation stress among mothers in Fukushima: a randomized controlled trial.

BACKGROUND: Mothers living with small children in Fukushima prefecture may experience radiation anxiety and related symptoms after the Fukushima Dai'ich Nuclear Power Plant Accident. A behavioral activation (BA) program was developed to improve their psychosomatic symptoms. The purpose of this randomized controlled trial was to examine the effectiveness of a BA program for improving psychological distress and physical symptoms among mothers with preschool children in Fukushima-prefecture 3 years after the Fukushima Daiichi Nuclear Power Plant accident. METHODS: Participants were recruited from mothers living with a preschool child(ren) in Fukushima city and surrounding areas though a newspaper advertisement, posters, and flyers. Participants allocated to the intervention group received a newly developed group-based BA program, which consisted of two 90- min lessons with a 1-week interval. Psychological distress and physical symptoms as a primary outcome, and radiation anxiety and positive well-being (liveliness and life satisfaction) as a secondary outcome, were measured at baseline, 1- and 3-month follow-ups. RESULTS: Participants were randomly allocated to either an intervention or a control group (18 and 19, respectively). The BA program showed a marginally significant intervention effect on psychological distress (p = 0.051) and physical symptoms (p = 0.07) at 1-month follow-up, while the effect became smaller at 3-month follow-up. The effect sizes at 1-month were medium to large (-0.72 and -0.56, respectively). There was a significant intervention effect on increasing liveliness at 3-month follow-up (p = 0.02); and there were marginally significant effects on life satisfaction at 1- and 3-month follow-ups (both p = 0.09). CONCLUSIONS: This BA program may be effective for improving psychological distress, physical symptoms, and well-being, at least for a short duration, among mothers with preschool children after the nuclear power plant accident in Fukushima, while a further large-scale study is needed. TRIAL REGISTRATION: The UMIN Clinical Trials Registry (UMIN-CTR; ID = UMIN000014081 ). Registered 27 May 2014.

The Effect of the Imacoco Care Psychoeducation Website on Improving Psychological Distress Among Workers During the COVID-19 Pandemic: Randomized Controlled Trial.

BACKGROUND: The prolonged COVID-19 pandemic has affected mental health among workers. Psychoeducational intervention via a website could be effective for primary prevention of mental illness among workers in the current COVID-19 pandemic. OBJECTIVE: The aim of this randomized controlled trial is to examine the effect of a newly developed online psychoeducational website named Imacoco Care on reducing psychological distress and fear about COVID-19 infection among workers. METHODS: Participants in the study were recruited from registered members of a web survey company in Japan. Participants who fulfilled the eligibility criteria were randomly allocated to the intervention or control group. Participants in the intervention group were invited to access the Imacoco Care program within a month after the baseline survey. The Kessler Psychological Distress Scale (K6) and the Fear of COVID-19 Scale (FCV-19S) scores were obtained at baseline and at 1- and 3-month follow-ups. RESULTS: A total of 1200 workers were randomly allocated to the intervention and control groups (n=600 [50%] per group). The Imacoco Care intervention group showed a significant favorable effect on K6 scores (P=.03) with a small effect size (ES; Cohen d=-0.14) and an adverse effect on FCV-19S scores (P=.01) with a small ES (Cohen d=0.16) at 3-month follow-up. In the per protocol analysis (including only participants who had read the Imacoco Care content at least 1 time), the Imacoco Care intervention group also showed a significant favorable effect on reducing K6 scores (P=.03), while an adverse effect on FCV-19S scores was not significant (P=.06) in the intervention group at 3-month follow-up. CONCLUSIONS: A web-based psychoeducation approach may be effective for improving psychological distress among workers; however, it may be important not only to distribute information but also to encourage active engagement with the content of the program to prevent adverse effects of psychoeducational intervention. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000042556; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000048548.

The Survey Measure of Psychological Safety and Its Association with Mental Health and Job Performance: A Validation Study and Cross-Sectional Analysis.

OBJECTIVES: This study validated the Japanese version of O'Donovan et al.'s (2020) composite measure of the psychological safety scale and examined the associations of psychological safety with mental health and job-related outcomes. METHODS: Online surveys were administered twice to Japanese employees in teams of more than three members. Internal consistency and test-retest reliability were tested using Cronbach's α and intra-class correlation coefficient (ICC), respectively. Structural validity was examined using confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Convergent validity was tested using Pearson's correlation coefficients. Multiple linear regression analyses were conducted to examine the relationship between psychological safety and psychological distress, work engagement, job performance, and job satisfaction. RESULTS: Two hundred healthcare workers and 200 non-healthcare workers were analyzed. Internal consistency, test-retest reliability, and convergent validity were acceptable. CFA demonstrated poor fit, and EFA yielded a two-factor structure, with team leader as one factor and peers and team forming the second factor. The total score showed significant and expected associations with all outcomes in the adjusted model for all workers. CONCLUSIONS: The Japanese version of the measure of the psychological safety scale presented good reliability and validity. Psychological safety is important for employees' mental health and performance.

Effectiveness of an Internet-Based Machine-Guided Stress Management Program Based on Cognitive Behavioral Therapy for Improving Depression Among Workers: Protocol for a Randomized Controlled Trial.

BACKGROUND: The effect of an unguided internet-based cognitive behavioral therapy (iCBT) stress management program on depression may be enhanced by applying artificial intelligence (AI) technologies to guide participants adopting the program. OBJECTIVE: The aim of this study is to describe a research protocol to investigate the effect of a newly developed iCBT stress management program adopting AI technologies on improving depression among healthy workers during the COVID-19 pandemic. METHODS: This study is a two-arm, parallel, randomized controlled trial. Participants (N=1400) will be recruited, and those who meet the inclusion criteria will be randomly allocated to the intervention or control (treatment as usual) group. A 6-week, six-module, internet-based stress management program, SMART-CBT, has been developed that includes machine-guided exercises to help participants acquire CBT skills, and it applies machine learning and deep learning technologies. The intervention group will participate in the program for 10 weeks. The primary outcome, depression, will be measured using the Beck Depression Inventory II at baseline and 3- and 6-month follow-ups. A mixed model repeated measures analysis will be used to test the intervention effect (group × time interactions) in the total sample (universal prevention) on an intention-to-treat basis. RESULTS: The study was at the stage of recruitment of participants at the time of submission. The data analysis related to the primary outcome will start in January 2022, and the results might be published in 2022 or 2023. CONCLUSIONS: This is the first study to investigate the effectiveness of a fully automated machine-guided iCBT program for improving subthreshold depression among workers using a randomized controlled trial design. The study will explore the potential of a machine-guided stress management program that can be disseminated online to a large number of workers with minimal cost in the post-COVID-19 era. TRIAL REGISTRATION: UMIN Clinical Trials Registry（UMIN-CTR) UMIN000043897; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050125. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/30305.

Internet-based acceptance and commitment therapy programme 'Happiness Mom' for well-being: a protocol for a randomised controlled trial.

INTRODUCTION: This randomised controlled trial (RCT) aims to examine the effects of an internet-delivered acceptance and commitment therapy (iACT) programme ('Happiness Mom') on the psychological well-being of working mothers. METHODS AND ANALYSIS: The target population of the RCT will be employed mothers with at least one preschool child. Participants who fulfil the study's eligibility criteria will be randomly assigned either to an iACT intervention group (n=200) or to a wait-list control group (n=200). Participants in the intervention groups will be asked to complete the programme within 12 weeks of the baseline survey. The intervention programme contains eight modules based on ACT. Primary outcomes are six components of psychological well-being, based on Ryff's theory. Secondary outcomes are intention to leave their job, work engagement, work performance, sick leave days, psychological distress, euthymia, positive emotions, job and life satisfaction, social support and parental burn-out. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Research Ethics Review Board of Graduate School of Medicine, the University of Tokyo (No. 2019134NI). If the intervention programmes are found to be significantly beneficial, the programmes can be made available for all working mothers with preschool children in Japan. DISCUSSION: This study will contribute to the development of an internet-based self-care programme that is effective, feasible, low cost and accessible to improve the well-being of working mothers. TRIAL REGISTRATION NUMBER: UMIN000039918.

Effect of smartphone-based stress management programs on depression and anxiety of hospital nurses in Vietnam: a three-arm randomized controlled trial.

There are growing concerns on stress among nurses in low- and middle-income countries (LMICs) in South-East Asia. It is important to improve mental health among nurses in these countries. The objective of this study was to examine the efficacy of two types of newly developed smartphone-based stress management programs in improving depressive and anxiety symptoms among hospital nurses in Vietnam. This study was a three-arm (including two intervention groups and one control group) randomized trial. Participants were recruited from nurses in a large general hospital in Hanoi, Vietnam. Two types (free-choice and fixed sequential order) of smartphone-based stress management programs were developed. Participants were randomly allocated to Program A (a free-choice, multimodule stress management), Program B (a fixed-order, internet cognitive behavioral therapy, iCBT), or a control group (treatment as usual). The depressive and anxiety symptoms were measured by using the Depression Anxiety and Stress Scales at baseline, 3-, and 7-month follow-up surveys. 951 participants were randomly allocated to each of the three groups. Program B showed a statistically significant effect on improving depressive symptoms at 3-month (p = 0.048), but not at 7-month (p = 0.92); Cohen's d was - 0.18 (95% CI - 0.34 to - 0.02) and 0.03 (95% CI - 1.00 to 1.05), respectively. Program A failed to show a significant intervention effect on any of the outcomes at 3- or 7-month follow-up (p > 0.05). Despite the small effect size, the present fixed-order iCBT program seems effective in improving depression of hospital nurses in Vietnam. A public health impact of the intervention can be scalable, when considering its accessibility and minimal cost.Trial registration number: The study protocol is registered at the UMIN Clinical Trials Registry (UMINCTR; ID = UMIN000033139). Registered date of the protocol is 1st Jul. 2018. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037796.

The effects of training managers on management competencies to improve their management practices and work engagement of their subordinates: A single group pre- and post-test study.

OBJECTIVES: The aim of this study was to investigate the effect of a training program for managers on their management competencies and work engagement of their subordinate workers and to investigate the mediating effect of management competencies on the subordinate work environment. METHODS: A training program, developed based on the UK Health and Safety Executive management competencies framework, was offered to managers in a finance company in Japan. Management competency was assessed at baseline and 1 month after the intervention. Work engagement was assessed at baseline and at a 1-year follow-up. Multilevel correlations between changes in components of management competency and changes in subordinate work engagement were analyzed. RESULTS: Although 6 of 12 components of management competency increased significantly following the intervention, significant intervention effect on subordinate work engagement was not found. Among 12 components of management competency, the integrity of managers showed significant multilevel correlation with work engagement of their subordinates. Subgroup analyses revealed that this multilevel correlation increased when a manager and a subordinate differed in gender. CONCLUSIONS: The results of this study indicated that the training program developed in this study effectively improved the management competency of managers and that integrity of managers may facilitate work engagement of subordinate workers, especially when a manager and a subordinate are of different genders. Thus, a training program focused on improving the integrity of managers could enhance the work engagement of employees.

Effects of a Transdiagnostic Preventive Intervention on Anxiety and Depression Among Workers in Japan: A Pre- and Posttest Study.

OBJECTIVE: This study examined the effectiveness of a newly developed transdiagnostic preventive intervention for anxiety and depressive symptoms among workers in a pre- and posttest study design. METHODS: Participants were recruited from six companies and one medical clinic. The program was developed based on Unified Protocol. The outcomes were anxiety symptoms (GAD7), depressive symptoms (BDI-II), and psychological distress (K6), measured at baseline, 3-week, and 6-week follow-up. A mixed model for repeated measures was conducted for the whole sample and for a subgroup with higher psychological distress. RESULTS: Among 75 participants, this program showed no significant effects on improving any outcome in the whole sample, but a significant improvement of psychological distress among the high-distress subgroup. CONCLUSIONS: The program may be effective in improving psychological distress among those who have high symptom levels.

Internet-based cognitive-behavioural therapy for prevention of depression during pregnancy and in the post partum (iPDP): a protocol for a large-scale randomised controlled trial.

INTRODUCTION: The objective of this randomised controlled trial (RCT) is to examine the effects of smartphone-based cognitive-behavioural therapy (CBT) in preventing the onset of major depressive episodes (MDE) among pregnant women. METHODS AND ANALYSIS: The target study population will be pregnant women of 16-20 weeks gestation who are currently users of 'Luna Luna Baby', the most widely used app for pregnant women in Japan. Those who meet the eligibility criteria will be randomly allocated to the 6-module internet CBT programme that was newly developed for pregnant women (n=2500), or to a treatment-as-usual control group (n=2500). Participants in the intervention groups will be required to complete the programme by 32 weeks gestation. The primary outcomes are the number of new onsets of MDE, measured by using WHO Composite International Diagnostic Interview 3.0 at 32 weeks gestation and 3 months post partum. Survival analysis will be conducted to test for the effectiveness of the intervention on the time to the onset of MDE. ETHICS AND DISSEMINATION: The study plan has been approved by the Research Ethics Review Board of the Graduate School of Medicine/Faculty of Medicine, the University of Tokyo (2019150NI). If the intervention programmes are found to produce a significant positive effect in this RCT, these programmes can be made available for all users of the app in the future. TRIAL REGISTRATION NUMBER: UMIN000038190; Pre-results.

Effects of two types of smartphone-based stress management programmes on depressive and anxiety symptoms among hospital nurses in Vietnam: a protocol for three-arm randomised controlled trial.

INTRODUCTION: Due to an increasing demand for healthcare in low-income and middle-income countries in Asia, it is important to develop a strategy to manage work-related stress in healthcare settings, particularly among nurses in these countries. The purpose of this three-arm randomised controlled trial (RCT) is to examine the effects of a newly developed smartphone-based multimodule stress management programme on reducing severity of depressive and anxiety symptoms as primary outcomes at 3-month and 7-month follow-ups among hospital nurses in Vietnam. METHODS AND ANALYSIS: The target study population will be registered nurses working in a large general hospital (which employs approximately about 2000 nurses) in Vietnam. They will be invited to participate in this study. Participants who fulfil the eligibility criteria will be randomly allocated to the free-choice, multimodule stress management (intervention group A, n=360), the internet cognitive behavioural therapy (iCBT), that is, fixed-order stress management (intervention group B, n=360), or a treatment as usual control group (n=360). Two types (free-choice and fixed sequential order) of smartphone-based six-module stress management programmes will be developed. Participants in the intervention groups will be required to complete one of the programmes within 10 weeks after the baseline survey. The primary outcomes are depressive and anxiety symptoms, measured by using the Depression Anxiety and Stress Scales (DASS) at 3-month and 7 month follow-ups. ETHICS AND DISSEMINATION: The study procedures have been approved by the Research Ethics Review Board of Graduate School of Medicine/Faculty of Medicine, the University of Tokyo (no 11991) and the Ethical Review Board for Biomedical Research of Hanoi University of Public Health (no 346/2018/YTCC-HD3). If a significant effect of the intervention programmes will be found in the RCT, the programmes will be made available to all nurses in the hospital including the control group. If the positive effects are found in this RCT, the e-stress management programmes will be disseminated to all nurses in Vietnam. TRIAL REGISTRATION NUMBER: UMIN000033139; Pre-results.

Telephone cognitive-behavioral therapy for subthreshold depression and presenteeism in workplace: a randomized controlled trial.

BACKGROUND: Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight-session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT). METHODS: We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study. RESULTS: The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, -0.21 to 0.52, and p = 0.50, ES = 0.02, -0.34 to 0.39, respectively). CONCLUSION: Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd. TRIAL REGISTRATION: ClinicalTrials.gov NCT00885014.