Exploring early discontinuation of mental health outpatient treatment: language, demographics and clinical characteristics among migrant populations in Japan.

BACKGROUND: The fast-growing migrant population in Japan and globally poses challenges in mental healthcare, yet research addressing migrants mental health treatment engagement remains limited. OBJECTIVE: This study examined language proficiency, demographic and clinical characteristics as predictors of early treatment discontinuation among migrants. METHODS: Electronic health record data from 196 adult migrants, identified from 14 511 patients who received mental health outpatient treatment during 2016 and 2019 at three central hospitals in the Tokyo-Yokohama metropolitan region of Japan, were used. We conducted multivariable regression models to identify predictors of early discontinuation within 3 months. FINDINGS: The study cohort (65% women, age range: 18-90 years, from 29 countries or regions) included 23% non-Japanese speakers. Japanese and non-Japanese speakers had similar discontinuation rates (26% vs 22%). Multivariable models revealed younger age (OR=0.97; 95% CI: 0.95, 0.99; p=0.016) and those with a primary diagnosis other than a schizophrenia spectrum disorder (OR=3.99; 95% CI: 1.36, 11.77; p=0.012) or a neurotic, stress-related and somatoform disorder (OR=2.79; 95% CI: 1.14, 6.84; p=0.025) had higher odds of early discontinuation. These effects were more pronounced among the Japanese speakers with significant language-by-age and language-by-diagnoses interactions. CONCLUSION: Younger age and having a primary diagnosis other than a schizophrenia spectrum disorder or a neurotic, stress-related and somatoform disorder increased vulnerability for discontinuing mental health treatment early in Japanese-speaking migrants but not for migrants with limited Japanese proficiency. CLINICAL IMPLICATIONS: Understanding language needs within a context of mental health treatment should go beyond assumed or observed fluency. Unmet language needs might increase vulnerability for treatment disengagement among migrants. Targeted clinical efforts are crucial for enhancing early treatment engagement and informing health practices in Japan and countries with growing migrant populations

Perceptions and attitudes of users and non-users of mental health services concerning mental illness and services in Japan

ObjectivesThere is a global movement to develop and implement community-based integrated mental health systems. The present study attempted to clarify the perceptions and attitudes of users and non-users of mental health services concerning mental illness and services in Japan.MethodsA new questionnaire was developed for this internet survey. Data from 500 outpatients with depression and 500 healthy subjects were sampled according to the demographics of the Japanese population.ResultsOver 90% of healthy subjects and over 70% of patients were unaware of the common age of onset or lifetime prevalence of mental illness. Over 90% of the healthy subjects and about 70% of the patients could not describe any services where they would feel comfortable discussing mental health problems. In both groups, “adolescents and young adults” were ranked first as a target population for mental health and illness policies. The top requirement for the integrated care systems was the promotion and awareness of correct knowledge of mental illness in both the healthy subjects and patients.ConclusionSocietal requirements could include disseminating correct knowledge, awareness-raising actions for society, and implementing services where people, especially young people, can easily consult and receive support in the community

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity

<div><p>Centromere-associated protein E (CENP-E) regulates both chromosome congression and the spindle assembly checkpoint (SAC) during mitosis. The loss of CENP-E function causes chromosome misalignment, leading to SAC activation and apoptosis during prolonged mitotic arrest. Here, we describe the biological and antiproliferative activities of a novel small-molecule inhibitor of CENP-E, Compound-A (Cmpd-A). Cmpd-A inhibits the ATPase activity of the CENP-E motor domain, acting as a time-dependent inhibitor with an ATP-competitive-like behavior. Cmpd-A causes chromosome misalignment on the metaphase plate, leading to prolonged mitotic arrest. Treatment with Cmpd-A induces antiproliferation in multiple cancer cell lines. Furthermore, Cmpd-A exhibits antitumor activity in a nude mouse xenograft model, and this antitumor activity is accompanied by the elevation of phosphohistone H3 levels in tumors. These findings demonstrate the potency of the CENP-E inhibitor Cmpd-A and its potential as an anticancer therapeutic agent.</p></div

PK/PD and antitumor efficacy of Cmpd-A in a COLO205 xenograft nude mouse model.

<p>(A) Expression of pHH3 in COLO205 xenografts at the indicated time points after the intraperitoneal administration of Cmpd-A at a dose of 100 mg/kg. (B) Time-dependent PK and PD of Cmpd-A. The green, blue, and red lines indicate plasma concentration, tumor concentration, and tumor pHH3 intensity, respectively. The pHH3 intensity was quantified using the results shown in (A). (C) Immunohistochemistry of pHH3 in the tumor sections from COLO205 xenograft nude mice 24 h after the intraperitoneal administration of Cmpd-A at 100 mg/kg. Black arrows indicate misaligned chromosomes in sections from COLO205 xenografts treated with Cmpd-A. (D) Antitumor efficacy of Cmpd-A in the COLO205 xenograft nude mouse model. COLO205 xenografted nude mice intraperitoneally injected with Cmpd-A at 100 mg/kg or vehicle three times (at 0, 8, and 24 h) on the first day of the study. Representative tumors 8 days after the administration of vehicle or Cmpd-A are shown. (E) Efficacy data plotted as the mean tumor volume (mm³ ± standard error of the mean; n = 5) in COLO205 xenograft nude mice treated with Cmpd-A (red) or vehicle (black). Statistical analysis was performed using Student’s t-test. Differences were considered significant at P ≤ 0.05 (*) and P ≤ 0.01 (**). (F) Bodyweight comparison of COLO205 xenograft nude mice 8 days after the administration of Cmpd-A (red) or vehicle (black). Data are presented as mean ± standard deviation (n = 5). Statistical analysis was performed using Student’s t-test. Differences were considered significant at P ≤ 0.05 (*) and P ≤ 0.01 (**).</p

Cmpd-A induces prolonged mitotic arrest accompanied by SAC activation.

<p>(A) Cell cycle histogram of synchronous HeLa cells treated with Cmpd-A (200 nM) or DMSO. Cmpd-A was added at the G2 phase (7 h after dT block release), and the cells were collected at the indicated time points for FACS analysis. (B) pHH3 in synchronous HeLa cells treated with Cmpd-A (200 nM) or DMSO. Cmpd-A was added at the G2 phase (7 h after dT block release), and the cells were collected 12 h after dT block release. Representative results are shown. (C) pHH3 elevation in synchronous HeLa cells treated with Cmpd-A (200 nM) or DMSO. Cmpd-A was added at the G2 phase (7 h after dT block release), and the cells were collected at the indicated time points for FACS analysis of pHH3 staining. The graph indicates quantified pHH3-positive cells (mean ± standard deviation; n = 3). Red and blue lines indicate Cmpd-A- and DMSO-treated HeLa cells, respectively. (D) Immunoblotting of mitosis markers in synchronous HeLa cells treated with Cmpd-A or DMSO. The cells were treated with Cmpd-A or DMSO as described in Fig 2A and collected 12 h after dT block release for immunoblotting.</p

Cmpd-A exhibits potent antiproliferative activity in multiple cancer cell lines.

<p>(A) Antiproliferative activity of Cmpd-A in multiple cancer cell lines. DU145, COLO205, NIH-OVCAR3, RKO, ES2, SK-OV3, PC-3, SW620, and CAPAN-2 cell lines were treated with Cmpd-A for 3 days at the indicated concentrations. The relative ATP concentration was calculated based on the chemiluminescence compared with the 0 nM chemiluminescence value (control). Data are presented as mean ± standard deviation (n = 3). (B) Correlation between the antiproliferative activity of Cmpd-A and CENP-E mRNA expression in cancer cell lines. The X and Y axes indicate the relative ATP level at 300 nM Cmpd-A treatment and CENP-E mRNA levels in the 14 indicated cancer cell lines, respectively. The relative ATP concentration was calculated based on chemiluminescence compared with the 0 nM chemiluminescence value (control) in each cell line. The raw data of CENP-E mRNA expression was downloaded from the Cancer Cell Line Encyclopedia (<a href="http://www.broadinstitute.org/ccle/data/browseData" target="_blank">http://www.broadinstitute.org/ccle/data/browseData</a>) and processed with MAS 5.0 algorithm.</p

CENP-E inhibitor Cmpd-A induces chromosome misalignment during mitosis.

<p>(A) Cmpd-A is a time-dependent inhibitor with an ATP competitive-like behavior. Red and black lines indicate the dose-dependent activity of Cmpd-A in the presence of low (1.25 μM) and high (500 μM) concentrations of ATP, respectively. The blue line indicates the activity of Cmpd-A with a high concentration of ATP, following 1 h of preincubation with CENP-E. The X-axis and Y-axis indicate the concentration of Cmpd-A and % inhibition of CENP-E ATPase activity, respectively. (B) Representative mitotic HeLa cells treated with Cmpd-A (200 nM) or DMSO. Arrows indicate misaligned chromosomes. Blue, green, and red signals indicate 4′,6-diamidino-2-phenylindole (DAPI)-stained DNA, α-tubulin, and CENP-B (kinetochores), respectively. (C) Quantitative analysis of mitotic morphology in the DMSO- or Cmpd-A-treated HeLa cells. The cells were treated for 3 h with 200 nM Cmpd-A or DMSO after dT block release. The DMSO- and Cmpd-A-treated mitotic cells (105 and 106 cells, respectively) were then counted. (D) Inter-kinetochore distance of aligned and misaligned chromosomes in HeLa cells treated with Cmpd-A or DMSO. Prometaphase (left) and metaphase (middle) cells were used as controls for misaligned and aligned chromosomes, respectively. The inter-kinetochore distance was measured between the outer kinetochore markers (HEC1) of individual chromosomes. Statistical analysis was performed using Student’s t-test. Differences were considered significant at P ≤ 0.05 (*) and P ≤ 0.01 (**).</p

Time-dependent antiproliferative activity of Cmpd-A in HeLa cells.

<p>(A) Experimental schemes to asses time-dependent antiproliferative activity of Cmpd-A. HeLa cells were treated with Cmpd-A at the indicated concentrations for 4, 8, 24, 48, and 72 h (red arrows) and then the cells were cultured in Cmpd-A-free medium for 72 h (black arrows). Cells were collected 72 h after treatment for cell viability analysis. (B) Time-dependent antiproliferative activity of Cmpd-A in HeLa cells. The relative ATP concentration was calculated based on chemiluminescence compared with the 0 nM chemiluminescence value (control). Data are presented as mean ± standard deviation (n = 8). (C) Quantitative RT-PCR analysis of CENP-E in cancer cell lines and human skin fibroblasts (MRC5). CENP-E expression ratios were quantified using GAPDH expression in each cell line as a control. Data are presented as mean ± standard deviation (n = 3).</p