Safety risks of interstitial lung disease upon real-world usage of Janus kinase inhibitors and biologics for patients with autoimmune diseases: epidemiological study using nationwide electronic medical record database in Japan.

Although Janus kinase inhibitor (JAKi) therapy is used for patients with autoimmune diseases (AD), one safety concern, interstitial lung disease (ILD), is life-threatening. We evaluated actual usage of JAKi and safety upon JAKi treatment, in an epidemiological retrospective cohort study utilizing the electronic medical record database in Japan. Among 391,565 AD patients, we analyzed data of new-users receiving JAKi or tumor necrosis factor alpha inhibitor (TNFi)/biologics during the period July 2013-May 2022. ILD (ICD10: J70.2, J70.3, J70.4 and J84) criteria were defined: new-ILD (1) and new-ILD (2) which differed in the latter's prompter therapeutics cessation upon ILD development. We analyzed ILD occurrence and death, ILD cumulative incidence by the Kaplan-Meier method, and hazard ratio (HR) by the Cox model, for 957 JAKi and 3931 TNFi users. JAKi use has become widespread amidst additional drug-development. Among JAKi users, two-year new-ILD (2) incidence, at 1.4%, was higher than for TNFi users (risk ratio: new-ILD (2) 1.75, death 2.31). Cumulative incidence (2.9% in 20.48 days) was also significantly higher (log-rank test p = .013, HR 2.23 (95% CI 1.16-4.27)); risk factors estimated by HR included JAKi (2.14), rheumatoid arthritis (4.94), diabetes mellitus (2.67) and cerebrovascular disease (2.86). ILD screening is essential.

The effects of BPA-BNCT on normal bone: determination of the CBE value in mice‡.

Boron neutron capture therapy (BNCT) with p-boronophenylalanine (BPA) is expected to have less effect on the decrease in normal bone strength than X-ray therapy. However, the compound biological effectiveness (CBE) value necessary to convert the boron neutron capture reaction (BNCR) dose into a bioequivalent X-ray dose has not been determined yet. The purpose of this study was to evaluate the influence of BNCT on normal bone in mice and to elucidate the CBE factor. We first searched the distribution of BPA in the normal bone of C3H/He mice and then measured the changes in bone strength after irradiation. The CBE value was determined when the decrease in bone strength was set as an index of the BNCT effect. The 10B concentrations in the tibia after subcutaneous injection of 125, 250 and 500 mg/kg BPA were measured by prompt gamma-ray spectroscopy and inductively coupled plasma (ICP)-atomic emission spectrometry. The 10B mapping in the tibia was examined by alpha-track autoradiography and laser ablation-ICP-mass spectrometry. The 10B concentration increased dose-dependently; moreover, the concentrations were maintained until 120 min after BPA administration. The administered 10B in the tibia was abundantly accumulated in the growth cartilage, trabecular bone and bone marrow. The bone strength was analyzed by a three-point bending test 12 weeks after irradiation. The bending strength of the tibia decreased dose-dependently after the irradiation of X-ray, neutron and BNCR. The CBE factor was obtained as 2.27 by comparing these dose-effect curves; the value determined in this study will enable an accurate dosimetry of normal bone.

Prenatal blood lead levels and Birth Weight: a Meta-analysis study.

Purpose: Lead, a known toxic metal, causes several adverse reproductive effects, including low birth weight. Fortunately, the exposure level has sharply decreased during the recent decades, but a definitive safe level did not introduce for pregnant women yet. The current meta-analysis study aimed to conduct a quantitative estimation of maternal and umbilical cord blood lead effects on birth weight. Methods: Two researchers have independently searched the scientific literature for retrieving related studies using the PRISMA criteria for data extraction. Twenty-one full-text articles were selected from primary 5006 titles, limited by the English language and published between 1991 and 2020 on humans. Results: The pooled mean of maternal and umbilical cord blood lead levels were 6.85 µg/dL (95% CI: 3.36-10.34) and 5.41 µg/dL (95%CI: 3.43-7.40), respectively. The correlation coefficient analysis showed a significant inverse association between the mean maternal blood lead level and birth weight, which was confirmed by Fisher Z-Transformation analysis (-0.374, 95% CI: -0.382, -0.365, p < 0.01). In addition, a significantly lower birth weight (∆: 229 gr, p < 0.05) was found in the relatively high level of maternal blood lead than in low-level exposure (> 5 µg/dL vs. ≤ 5 µg/dL, respectively). Conclusion: In short, the present study findings suggest an increasing maternal blood lead levels could be a potential risk factor for reducing birth weight. Thus, pregnant women should avoid lead exposure, as much as possible. Supplementary information: The online version contains supplementary material available at 10.1007/s40201-022-00843-w.

Association between serum concentrations of perfluoroalkyl substances and global DNA methylation levels in peripheral blood leukocytes of Japanese women: A cross-sectional study.

Global DNA methylation levels in peripheral blood leukocytes can be a biomarker for cancer risk; however, levels can be changed by various factors such as environmental pollutants. We investigated the association between serum concentrations of perfluoroalkyl substances (PFASs) and global DNA methylation levels of leukocytes in a cross-sectional study using the control group of a Japanese breast cancer case-control study [397 women with a mean age of 54.1 (SD 10.1) years]. Importantly, our analysis distinguished branched PFAS isomers as different from linear isomers. The serum concentrations of 20 PFASs were measured by in-port arylation gas-chromatography negative chemical ionization mass spectrometry. Global DNA methylation levels in peripheral blood leukocytes were measured using a luminometric methylation assay. Associations between log10-transformed serum PFAS concentrations and global DNA methylation levels were evaluated by regression coefficients in multivariable robust linear regression analyses. Serum concentrations of 13 PFASs were significantly associated with increased global DNA methylation levels in leukocytes. Global DNA methylation was significantly increased by 1.45 %-3.96 % per log10-unit increase of serum PFAS concentration. Our results indicate that exposure to PFASs may increase global DNA methylation levels in peripheral blood leukocytes of Japanese women.

Predictors of Major Adverse Cardiovascular and Cerebrovascular Events After Acute Coronary Syndromes: A Retrospective Observational Study Using YoMDB Database.

Objectives: Despite the rapid aging of the population in Japan, clinical predictors for major adverse cerebrovascular and cardiovascular events (MACCE) in patients with new onset of acute coronary syndromes (ACS) have not been well studied. This study therefore aimed to identify the predictors of MACCE in the first onset of ACS patients requiring care. Materials and Methods: Using the Yokohama Original Medical Database, we identified 3,373 patients who experienced a first onset of ACS and had certified care information from April 2014 to March 2016. The incidence proportion of MACCE from June 2014 to March 2018 was retrospectively investigated. Each patient's independence of daily living (IDL) was classified as one of three categories (reference, mild and severe). Results: Predictors of MACCE were identified using multivariate logistic regression analysis. Impaired IDL was associated with increased MACCE, with adjusted odds ratios for reference, mild and severe of 1.00, 1.35 (95% confidence intervals 1.14-1.60) and 2.12 (95% confidence intervals 1.61-2.80; P for trend < 0.001), respectively. Conclusions: This study revealed that male sex, chronic kidney disease, atrial fibrillation, high-intensity statin use, low-intensity statin use, and lower IDL (representing less independence) were the predictors of MACCE requiring care for a first onset of ACS. Further research will be required to understand the results of interventions for the identified predictors of MACCE.

Comparison of lithium levels between suicide and non-suicide fatalities: Cross-sectional study.

Ecological studies have suggested the protective effect of micro-dose lithium in drinking water against suicide, however, the association between body lithium level and suicide is unknown. We aimed to compare body lithium levels between suicide and non-suicide fatalities. This cross-sectional study included 12 suicides and 16 non-suicides who were examined or dissected at the Tokyo Medical Examiner's Office from March 2018 to June 2021. The aqueous humor lithium concentration was measured twice using inductively coupled plasma mass spectrometry. Analysis of covariance (ANCOVA) was used to compare the lithium concentration between suicides and non-suicides. Mixed-effects model was conducted to account for all lithium concentration data. The aqueous humor lithium concentration did not change after death (t(7) = -0.70, [Formula: see text], SE = 0.03, 95% CI = [-0.09, 0.05], P = 0.51, Cohen's d = 0.01). The aqueous humor lithium concentration was lower in suicides (mean 0.50 µg/L (variance s2 0.04)) than in non-suicides (mean 0.92 µg/L (s2 0.07)) (t(26) = 4.47, [Formula: see text], SE = 0.09, 95% CI = [0.22 to 0.61], P < 0.001, Cohen's d = 1.71). The ANCOVA showed that death by suicide was significantly associated with lower lithium concentration (F(1, 24) = 8.57, P = 0.007), and the effect size was large (ηp2 = 0.26). The random intercept model showed a significant effect of suicide on aqueous humor lithium concentration (b = -0.261, SE = 0.102, 95% CI = [-0.471 to -0.051], t(24) = -2.568, P = 0.017). The results of this study demonstrate that even micro-dose lithium is associated with suicide death. Clinical studies are warranted to examine the effects of micro-dose lithium on suicide prevention.

Preliminary efficacy of cognitive-behavioral therapy on emotion regulation in adults with autism spectrum disorder: A pilot randomized waitlist-controlled study.

Previous studies have demonstrated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in children on the autism spectrum. However, no studies have elucidated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in autistic adults. The aim of the present pilot study was to explore the preliminary clinical utility of a group-based cognitive-behavioral therapy program designed to address emotion regulation skills in autistic adults. We conducted a clinical trial based on a previously reported protocol; 31 participants were randomly allocated to the intervention group and 29 to the waitlist control group. The intervention group underwent an 8-week program of cognitive-behavioral therapy sessions. Two participants from the intervention group withdrew from the study, leaving 29 participants (93.5%) in the group. Compared with the waitlist group, the cognitive-behavioral therapy group exhibited significantly greater pre-to-post (Week 0-8) intervention score improvements on the attitude scale of the autism spectrum disorder knowledge and attitude quiz (t = 2.21, p = 0.03, d = 0.59) and the difficulty describing feelings scale of the 20-item Toronto Alexithymia Scale (t = -2.07, p = 0.04, d = -0.57) in addition to pre-to-follow-up (Week 0-16) score improvements on the emotion-oriented scale of the Coping Inventory for Stressful Situations (t = -2.14, p = 0.04, d = -0.59). Our study thus provides preliminary evidence of the efficacy of the group-based cognitive-behavioral therapy program on emotion regulation in autistic adults, thereby supporting further evaluation of the effectiveness of the cognitive-behavioral therapy program in the context of a larger randomized clinical trial. However, the modest and inconsistent effects underscore the importance of continued efforts to improve the cognitive-behavioral therapy program beyond current standards.

Spatial localization of cadmium and metallothionein in the kidneys of mice at the early phase of cadmium accumulation.

Chronic exposure to cadmium (Cd) leads to an accumulation of Cd in the kidneys. Metallothionein (MT) is a low-molecular-weight protein having a high affinity for Cd. Cd bound to MT in serum is filtered through the glomeruli of kidney nephrons and reabsorbed by endocytosis into the proximal tubules from the luminal side. Accumulation of Cd in renal cells induces MT synthesis, leading to long-term deposition of Cd and the suppression of Cd toxicity. Recently, many studies have investigated the tissue distribution of metals using laser ablation ICP-MS (LA-ICP-MS). However, little information has been available regarding renal Cd distribution. Hence, we dually investigated the renal distribution of Cd by LA-ICP-MS and that of MT by immunohistochemistry to clarify the dose- and time-dependent changes in the distributions of Cd and MT in mice exposed to Cd from drinking water for 1, 2, and 4 months. Both Cd and MT exhibited characteristic heterogeneous distribution patterns in the renal cortex. The accumulation of Cd and MT near the surface of the cortex suggests a preferential accumulation of Cd in the surface nephrons. MT distribution was more pronounced in the proximal tubules than in the distal tubules, and there were clear differences in MT immunostaining even among the proximal tubules. The heterogeneous localization of MT may reflect the nephron-specific accumulation of Cd. Combining elemental imaging of Cd with immunostaining of MT proved a successful strategy to reveal the characteristic renal Cd distribution, especially in the early stages of Cd accumulation.

Development of the Japanese version of the Depression Literacy Scale.

BACKGROUND: Depression is a major social concern in Japan. It is therefore necessary to develop a scale in Japanese that can assess depression literacy. AIMS: The present study aimed to develop the Japanese version of the Depression Literacy Scale (D-Lit-J), and examined its validity and reliability. METHODS: Three groups were administered the D-Lit-J, including 117 first-year university English literature students, 112 first-year medical school students, and 53 psychiatrists. Among these, 112 (95.7%), 112 (100%), and 29 subjects (54.7%) returned completed questionnaires, respectively. The total D-Lit-J scores were compared between the three groups to assess known-group validity, and internal reliability was examined by calculating Cronbach's alpha coefficients. Medical students were asked to complete the questionnaire a second time, 3 weeks later (11 students did not respond), to assess the test-retest reliability using the intra-class correlation coefficient. RESULTS: The total D-Lit-J scores (mean ± SD) were 7.61 ± 4.18, 9.51 ± 4.37, and 17.7 ± 3.15, for English literature students, medical students, and psychiatrists, respectively, and there were significant differences between the three groups (p < .05). The Cronbach's alpha coefficients ranged from .800 to .834 in all students, and was .764 in psychiatrists, revealing a good internal consistency. The intra-class correlation coefficient of the scale was .769. CONCLUSIONS: The D-Lit-J showed a credible known-group validity, with good internal and test-retest reliabilities. Additional studies with a greater variety of subjects and that examine concurrent or discriminant validity will be necessary in the future.

Burnout and poor perceived health in flexible working time in Japanese employees: the role of self-endangering behavior in relation to workaholism, work engagement, and job stressors.

The study aim was to examine whether flexible working time was associated with burnout and poor perceived health in relation to the work-related psychological/behavioral factors of self-endangering work behavior (SEWB), workaholism, work engagement, and job stressors. We analyzed data obtained from an Internet survey of 600 full-time Japanese employees. We also proposed a causal model using path analysis to investigate the overall relationships of burnout and perceived health to psychological/behavioral factors. The results indicated that flexible working time was associated with adverse work-related consequences and factors such as increased burnout, working hours, SEWB, workaholism, and job demands, and with positive factors such as improvement of work engagement. The path analysis suggested that burnout was caused by workaholism both directly and via SEWB, and by low job decision latitude, and was reduced by work engagement. Similarly, it was observed that poor health was caused by workaholism via SEWB, and reduced by work engagement. Thus, SEWB is driven by workaholism and plays a key role in the adverse health consequences of flexible working time. For workers to benefit from flexible working time, it is important to improve workaholism, SEWB, and low job decision latitude, and to develop work engagement in the workplace.

Improvement of spatial resolution of elemental imaging using laser ablation-ICP-mass spectrometry.

Laser ablation-ICP-mass spectrometer (LA-ICPMS) now becomes one of the most principal analytical technique for mapping analysis for major to trace elements in rocks, minerals, functional materials, or biological tissue samples. In this study, imaging analysis was conducted with coupling of small volume cell and off-set laser ablation protocol to improve the spatial resolution. Combination of newly designed small volume cell and in-torch gas mixing protocols provides faster washout time of the signals (about 0.8 s for reducing 238U being one part in a hundred, 1% level). This is very important to improve the spatial resolution in a direction of laser scanning. Moreover, combination of small distances between the laser-line scan (laser pitch distance) and preferential and total ablation of only biological tissue samples placed on glass substrate results in laser ablation of smaller areas than the size of laser ablation pit (shaving ablation). With the shaving ablation, laser-line scanning with narrower-band width (e.g., 2 µm) can be achieved even by the laser beam of 8 µm diameter. To demonstrate the practical usage of the present technique, imaging analysis of Gd-ethylenediamine tetra-methylene phosphonic acid-doped mouse bone was conducted. Preferential distribution of Gd at the edge of the apatite cell was more clearly identified by the present technique. Combination of the shorter washout system setup and the shaving ablation protocol enables us to improve the spatial resolution of the elemental imaging obtained with the LA-ICPMS technique.

Effects of Trace Elements on Anthropometric Characteristics of Children: Cobalt and Childhood Body Mass Index.

Objectives: There are many reports on the effects of trace elements on human anthropometric characteristics. Among these elements, cobalt has consistently shown an inverse relationship with obesity risk. In the present study, we aimed to investigate the relationship between urinary levels of trace elements, focusing on cobalt, and childhood obesity, as indicated by the body mass index (BMI) in early adolescents, focusing on the participants' gender. Design: A cross-sectional study was conducted in the Tokyo Teen Cohort study. Based on urinary samples, we obtained the anthropometric characteristics (weight and height) and potential covariates associated with childhood BMI for 1542 children (mean age=12 years; 860 boys and 682 girls). Methods: Concentrations of urinary cobalt and 17 other trace elements were measured using inductively coupled plasma-mass spectrometry or inductively coupled plasma-atomic emission spectrometry. Results: Pearson's correlation coefficient revealed an inverse relationship between the log of cobalt concentrations in the urine and the BMI for the boys (r=-0.125, p<0.001) and girls (r=-0.082, p=0.033). Multivariate analysis, adjusted for various covariates, reconfirmed the correlation between urine cobalt and the childhood BMI, only in the boys (beta=-0.14, p<0.001). Conclusions: Among the 18 elements measured in the children's urine, cobalt may exhibit sufficient potency to decrease the risk of childhood obesity, particularly in boys. Future studies are required to clearly determine the magnitude of the effect and the underlying mechanism(s).

Development of the Japanese Version of the Self-Endangering Work Behavior (J-SEWB) Scale.

Objective: The concept of self-endangering work behavior (SEWB) was recently proposed to describe problematic behaviors to cope with heavy workloads and self-management. Although SEWB may enable workers to achieve immediate goals, it risks health and long-term work capacity. In this study, we developed a Japanese version of the SEWB (J-SEWB) scale, which was originally in German, and verified its validity and reliability. Materials: The original SEWB scale consisted of 21 items, constituting five subscales: "Intensification of working hours," "Prolongation/extension of working hours," "Refraining from recovery/leisure activities," "Working despite illness," and "Use of stimulating substances." We translated the scale into Japanese, then checked the wording using back-translation. Methods: The J-SEWB scale and questions for working conditions and sociodemographic variables was administered via an online survey with 600 participants registered with an internet survey company in Japan. Cronbach's α coefficients were calculated for each subscale to assess internal consistency. Construct validity was examined using principal factor analysis with equamax rotation. An analysis of variance evaluated the relationships of J-SEWB scores with working conditions and sociodemographic variables. Results: Cronbach's α coefficients ranged from 0.846 to 0.964 for five subscales, and 0.957 for all 21 items (total J-SEWB score) in 600 participants. The factor analysis identified five factors, classifying 21 items into corresponding subscales. Total J-SEWB scores were significantly higher for flexible work as well as longer working hours. Conclusions: The J-SEWB scale appears to be an effective tool for assessing SEWB in Japanese employees, with satisfactory reliability and construct validity.

Serum perfluoroalkyl substances and breast cancer risk in Japanese women: A case-control study.

BACKGROUND: Perfluoroalkyl substances (PFASs) may contribute to causing breast cancer; however, associations between exposure to PFASs and risk of breast cancer are controversial. OBJECTIVES: In the present study, we newly distinguished branched isomers of PFASs from their linear isomers and aimed to investigate the association between serum PFAS concentrations and breast cancer risk in Japanese women. METHODS: We used a case-control design to study 405 eligible matched pairs attending four hospitals in Nagano Prefecture, Japan from May 2001 to September 2005. We used in-port arylation gas-chromatography mass spectrometry with negative chemical ionization to measure serum concentrations of 20 PFAS congeners. We calculated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer and its hormone-receptor subtypes by quartiles or tertiles of serum PFASs. RESULTS: After multivariable adjustment for breast cancer risk factors, we found that serum concentrations of 20 PFAS congeners were significantly inversely associated with risk of breast cancer. Comparing the extreme quartiles of linear isomers of perfluorooctane sulfonate or perfluorooctanoic acid, ORs were 0.15 (95% CI: 0.07, 0.33 P for trend <0.0001) and 0.21 95% CI: 0.10, 0.44 P for trend <0.0001). Among postmenopausal women, whereas we found the linear isomer of perfluorotridecanoic acid to be inversely associated with breast cancer risk, a medium degree of exposure to the branched isomer of perfluorotridecanoic acid was associated with a marginally increased risk of breast cancer (OR [95% CI] = 1.74 [0.98, 3.09]). DISCUSSION: In our case-control study, we found overall no association between serum PFAS concentrations and increased risk of breast cancer. Many inverse associations between serum PFAS concentrations and breast cancer risk were found.

Prenatal blood levels of some toxic metals and the risk of spontaneous abortion.

High-level toxic metal exposure has become rare in the recent years. Although, it has not known whether relatively lower exposure may adversely affect human reproductive system. Spontaneous abortion (SA) is a serious reproductive problem, which, in many cases, the cause(s) is not clearly understood. To assess the relationship between prenatal blood level of metals and SA risk, we compared blood concentration of some heavy metals in samples taken from mothers recruited in Tehran Environment and Neurodevelopmental Defects (TEND) study conducted on apparently healthy pregnant women in Tehran, Iran who subsequently experienced spontaneous abortion with mothers who their pregnancy ended to live births. During early gestation, 206 women were enrolled to the survey and followed up till fetal abortion or baby deliveries occur. Blood metal concentrations were measured using an inductively coupled plasma mass spectrometer. The mean blood levels of lead, antimony, and nickel were higher in SA than ongoing pregnancy; however, this difference was not statistically significant. When adjusted for covariates, the logistic regression analysis showed significant association between maternal age and the risk of SA in all models. Among toxic metals only antimony had a noticeable positive relation with the risk of SA (OR: 1.65, 95% CI:1.08-2.52, P value: 0.02). Pearson's correlation coefficient showed significant (P < 0.05) positive correlations among prenatal blood metals levels, except for nickel. Although the present study failed to provide strong evidence for the effects of toxic metals on the occurrence of SA at the relatively low-levels, these metals should be avoided in women who plan pregnancy and/or during the early stages of gestation to prevent the chance of adverse effects.

Investigation of clinical target volume segmentation for whole breast irradiation using three-dimensional convolutional neural networks with gradient-weighted class activation mapping.

This study aims to implement three-dimensional convolutional neural networks (3D-CNN) for clinical target volume (CTV) segmentation for whole breast irradiation and investigate the focus of 3D-CNNs during decision-making using gradient-weighted class activation mapping (Grad-CAM). A 3D-UNet CNN was adopted to conduct automatic segmentation of the CTV for breast cancer. The 3D-UNet was trained using three datasets of left-, right-, and both left- and right-sided breast cancer patients. Segmentation accuracy was evaluated using the Dice similarity coefficient (DSC). Grad-CAM was applied to trained CNNs. The DSCs for the datasets of the left-, right-, and both left- and right-sided breasts were on an average 0.88, 0.89, and 0.85, respectively. The Grad-CAM heatmaps showed that the 3D-UNet used for segmentation determined the CTV region from the target-side breast tissue and by referring to the opposite-side breast. Although the size of the dataset was limited, DSC ≥ 0.85 was achieved for the segmentation of breast CTV using the 3D-UNet. Grad-CAM indicates the applicable scope and limitations of using a CNN by indicating the focus of such networks during decision-making.