Home visitors' needs and perceptions of the benefits of a home visiting program for childcare support in Japan: A qualitative study of home visitors.

BACKGROUND: The Home Visiting Program for Childcare Support (HV-CCS; "Yoiku Shien Homon Jigyo" in Japanese) has targeted families in need of parenting support and those at risk of child maltreatment in Japan. OBJECTIVE: The aim of this study was to explore the needs and perceptions of benefits of home visitors in HV-CCS. PARTICIPANTS AND SETTING: Sixteen home visitors agreed to participate in the interview. METHODS: This study conducted 1-hour semi-structured interviews with 16 home visitors and analyzed approximately 18 h of interview data using thematic analysis. RESULTS: The findings suggested that home visitors required training to enhance individual skills and knowledge about mental health of caregivers or children. Additionally, they required environmental support, particularly for transportation expenses and parking places. Multidisciplinary communicative support is also necessary, as well as system to improve the process of support. Home visitor perceived the HV-CCS as beneficial in preventing child maltreatment by improving parenting skills and home environment, providing psychological support for mothers, and entering families' intimate spaces. CONCLUSIONS: To ensure the continuity and improvement of home visits for parents and children in Japan, it is essential to address the identified needs of home visitors.

Validity and Reproducibility of a Food Frequency Questionnaire for Dietary Assessment in Japanese People.

A 76-item food frequency questionnaire (FFQ) was developed to investigate nutritional epidemiology in urban residents in Japan. The authors prepared two food models-a life-size three-dimensional model and a life-size two-dimensional photograph-to assess the FFQ portion size. The validity of the FFQ was verified using the two food models by comparing them with 16-d weighted dietary records (WDRs). Validation was conducted by comparing the FFQ1 findings with those obtained with the WDR, which is regarded as the gold standard, and reproducibility was verified by comparing the findings from FFQ2 and FFQ1. After completion of the WDR, the participants were randomized into two groups. In one group, the FFQ was conducted using life-size three-dimensional models (3D-FFQ) to estimate the portion size. In the other group, the FFQ was administered using life-size photo collection (2D-FFQ). Regarding validity, the median values (range) of Pearson's correlation coefficients for the energy and nutrient intake of the 32 items by the WDR and FFQ1 were r=0.53 (0.30-0.68) in the 3D-FFQ and r=0.57 (0.33-0.87) in the 2D-FFQ. When FFQs with 2D or 3D food models and two different portion sizes were compared with regard to the intake of certain food groups, energy, and nutrients, both the 2D-FFQ and 3D-FFQ provided good correlation coefficients with the WDR.

Comparison of the specimen quality of endobronchial ultrasound-guided intranodal forceps biopsy using standard-sized forceps versus mini forceps for lung cancer: A prospective study.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic procedure with adequate performance; however, its ability to provide specimens of sufficient quality and quantity for treatment decision-making in advanced-stage lung cancer may be limited, primarily due to blood contamination. The use of a 0.96-mm miniforceps biopsy (MFB) permits true histological sampling, but the resulting small specimens are unsuitable for the intended applications. Therefore, we introduced a 1.9-mm standard-sized forceps biopsy (SFB) and compared its utility to that of MFB. METHODS: We prospectively enrolled patients from three institutions who presented with hilar/mediastinal lymphadenopathy and suspected advanced-stage lung cancer, or those who were already diagnosed but required additional tissue specimens for biomarker analysis. Each patient underwent MFB followed by SFB three or four times through the tract created by TBNA using a 22-gauge needle on the same lymph node (LN). Two pathologists assessed the quality and size of each specimen using a virtual slide system, and diagnostic performance was compared between the MFB and SFB groups. RESULTS: Among the 60 enrolled patients, 70.0% were diagnosed with adenocarcinoma. The most frequently targeted sites were the lower paratracheal LNs, followed by the interlobar LNs. The diagnostic yields of TBNA, MFB and SFB were 91.7%, 93.3% and 96.7%, respectively. The sampling rate of high-quality specimens was significantly higher in the SFB group. Moreover, the mean specimen size for SFB was three times larger than for MFB. CONCLUSION: SFB is useful for obtaining sufficient qualitative and quantitative specimens.

Preoperative factors affecting the two-year postoperative patient-reported outcome in single-level lumbar grade I degenerative spondylolisthesis.

Background: The choice of operative method for lumbar spinal stenosis with Meyerding grade I degenerative spondylolisthesis remains controversial. The purpose of this study was to identify the preoperative factors affecting the 2-year postoperative patient-reported outcome in Meyerding grade I degenerative spondylolisthesis. Methods: Seventy-two consecutive patients who had minimally invasive decompression alone (D group; 28) or with fusion (DF group; 44) were enrolled. The parameters investigated were the Japanese Orthopaedic Association back pain evaluation questionnaire as patient-reported assessment, and L4 slippage (L4S), lumbar lordosis (LL), and lumbar axis sacral distance (LASD) as an index of sagittal alignment for radiological evaluation. Data collected prospectively at 2 years postoperatively were examined by statistical analysis. Results: Sixty-two cases (D group; 25, DF group; 37) were finally evaluated. In multiple logistic regression analysis, preoperative L4S and LASD were extracted as significant preoperative factors affecting the 2-year postoperative outcome. Patients with preoperative L4S of 6 mm or more have a lower rate of improvement in lumbar spine dysfunction due to low back pain (risk ratio=0.188, p=.043). Patients with a preoperative LASD of 30 mm or more have a higher rate of improvement in lumbar dysfunction due to low back pain (risk ratio=11.48, p=.021). The results of multiple logistic analysis by operative method showed that there was a higher rate of improvement in lumbar spine dysfunction due to low back pain in patients with preoperative LASD of 30 mm or more in DF group (risk ratio=172.028, p=.01). Conclusions: Preoperative L4S and LASD were extracted as significant preoperative factors affecting patient-reported outcomes at 2 years postoperatively. Multiple logistic analyses by the operative method suggested that DF may be advantageous in improving lumbar dysfunction due to low back pain in patients with preoperative LASD of 30 mm or more.

Clinical significance of KL-6 in immune-checkpoint inhibitor treatment for non-small cell lung cancer.

PURPOSE: Krebs von den Lungen-6 (KL-6) functions as a tumor marker, as well as a diagnostic tool for interstitial pneumonia (IP). However, the significance of KL-6 in the immune-checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC), especially in patients without IP, is unknown. METHODS: This multicenter, retrospective study, which included patients with advanced NSCLC who received ICI therapy, analyzed the association between serum KL-6 values and ICI efficacy and the association between serum KL-6 values and ICI-induced interstitial lung disease (ILD) occurrence, focusing primarily on patients without IP. RESULTS: In total, 322 patients had available KL-6 values before ICI therapy. Among 202 patients without IP who received ICI monotherapy, the high-KL-6 group (≥ 500 U/mL) showed significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-KL-6 group (< 500 U/mL) (median: 2.1 vs. 3.6 months, p = 0.048; median: 9.2 vs. 14.5 months, p = 0.035). There was no significant difference in response rate between the KL-6 high and low groups (19% vs. 29%, p = 0.14). In the multivariate analysis, high KL-6 was a significant predictor of poor PFS (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.10-2.11, p = 0.012) and OS (HR, 1.51; 95% CI 1.07 - 2.13, p = 0.019) for patients treated with ICI monotherapy. There was no significant difference in the occurrence rate of ILD between the high KL-6 and low KL-6 groups in patients with (20% vs. 15%, p = 1.00) or without IP (12% vs. 12%, p = 1.00). CONCLUSION: In ICI monotherapy for NSCLC without IP, elevated serum KL-6 levels were associated with poorer outcomes.

Vimentin expression correlates with immune checkpoint inhibitor efficacy in non-small cell lung cancer.

BACKGROUND: Although vimentin is often expressed in non-small cell lung cancer (NSCLC), the association between vimentin expression and immune-checkpoint inhibitor (ICI) efficacy remains unclear. METHODS: This retrospective multicenter study enrolled patients with NSCLC who received ICI treatment between December 2015 and July 2020. The authors constructed tissue microarrays and performed immunohistochemical staining with vimentin. They analyzed the relationship between vimentin expression rate and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Immunohistochemically evaluable specimens on microarray blocks were available for 397 patients, of whom 343 (86%) were negative (<10%), 30 (8%) were positive (10%-49%), and 24 (6%) were highly positive (≥50%) for vimentin expression. Both rates of programmed death-ligand 1 (PD-L1) tumor proportion score ≥1% and ≥50% were significantly higher in the vimentin-positive group (≥10%) than the vimentin-negative group (<10%) (96% vs. 78%, p = .004; 64% vs. 42%, p = .006, respectively). In patients treated with ICI monotherapy, ORR, PFS, and OS were significantly better in the vimentin-positive group (10%-49%) than in the vimentin-negative group (<10%) (54% vs. 25%, p = .003, median = 7.9 vs. 3.2 months, p = .011; median = 27.0 vs. 13.6 months, p = .015, respectively), whereas there was no significant difference in PFS and OS between the vimentin highly positive group (≥50%) and the vimentin-negative group (<10%) (median = 3.4 vs. 3.2 months, p = .57; median = 7.2 vs. 13.6 months, p = .086, respectively). CONCLUSIONS: Vimentin expression correlated with PD-L1 expression and ICI efficacy. PLAIN LANGUAGE SUMMARY: We constructed tissue microarrays and performed immunohistochemical staining with vimentin on 397 patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitor (ICI). The vimentin-positive group who were treated with ICI monotherapy showed significantly better objective response rate, progression-free survival, and overall survival than the vimentin negative group. The measurement of vimentin expression will aid in determining appropriate immunotherapy strategies.

Influence of Smoking History on the Effectiveness of Immune-checkpoint Inhibitor Therapy for Non-small Cell Lung Cancer: Analysis of Real-world Data.

BACKGROUND/AIM: There is no real-world data in an Asian population to investigate the difference between the outcome of immune-checkpoint inhibitor (ICI) monotherapy and combination therapy for non-small cell lung cancer (NSCLC) based on smoking status. In this study, we investigated the correlation between smoking status and the efficacy of ICI therapy for NSCLC patients. PATIENTS AND METHODS: This multicentre retrospective study enrolled patients with recurrent or metastatic NSCLC who were treated using ICI therapy between December 2015 and July 2020. We analysed the objective response rate (ORR) of patients who received ICI monotherapy or combination therapy, based on smoking status using Fisher's exact test, and progression-free survival (PFS) and overall survival (OS) based on smoking status using the Kaplan-Meier method, the log-rank test, and Cox proportional hazards model. RESULTS: A total of 487 patients were included in the study. In the ICI monotherapy group, non-smokers showed significantly lower ORR and shorter PFS and OS than smokers (10% vs. 26%, p=0.002; median: 1.8 vs. 3.8 months, p<0.001; median: 8.0 vs. 15.4 months, p=0.026). In the ICI combination therapy group, non-smokers showed significantly longer OS than smokers (median: not reached vs. 26.3 months, p=0.045), and there was no significant difference in ORR and PFS between non-smokers and smokers (63% vs. 51%, p=0.43; median: 10.2 vs. 9.2 months, p=0.81). In the multivariate analysis of patients who received ICI combination therapy, the "non-smoker" status was not significantly associated with PFS [hazard ratio (HR)=1.31; 95% confidence interval (CI)=0.70-2.45, p=0.40] and OS (HR=0.40; 95% CI=0.14-1.13, p=0.083). CONCLUSION: Non-smokers showed worse outcomes than smokers with ICI monotherapy, but not with ICI combination therapy.

Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer.

It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune-checkpoint inhibitors and antiangiogenic agents. This retrospective, multicenter study included patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti-vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression-free survival, and overall survival in patients receiving immune-checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression-free survival, and overall survival were significantly worse in patients treated with immune checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs 30%, p = 0.028; median = 2.2 vs 3.6 months, p = 0.012; median = 7.9 vs 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without antiangiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells.

The new imaging findings: "Passing spine" without kissing.

ABSTRACT: Case-control studies by examining the lumbar spine computed tomography (CT) findings focusing on the spinous processes."Passing spine" was defined as a lumbar degenerative change observed on CT images. In contrast, kissing spine, which is also an image finding, has been acknowledged as an established clinical condition. Therefore, we compared the passing spine group and the kissing spine group to investigate whether the 2 groups belong to a similar disease group; this would help explain the clinical and imaging characteristics of patients with passing spine.Previous studies have described the gradual increase in the height and thickness of the lumbar vertebral spinous processes that can occur in individuals aged >40 years, and reported that this progressive degeneration can lead to a condition termed "kissing spine."We examined the CT imaging of 373 patients with lumbar spinal disease and divided patients into 2 groups, the kissing spine (K) group and the passing spine (P) group, and compared the clinical (age, sex, presence/absence of lower extremity pain) and imaging data (localization of kissing or passing spine, intervertebral disc height at the level of kissing or passing spine, lumbar lordosis (LL) angle, presence/absence of vacuum phenomenon (VP) in the intervertebral discs and spondylolisthesis at the level of kissing or passing spine between the 2 groups.Compared with patients with kissing spine, patients with passing spine had an increased incidence of lower extremity pain, lower intervertebral disc height at the level of passing spine, relatively static LL, and VP commonly observed in the intervertebral discs at the level of passing spine.Because the clinical and imaging characteristics of patients with passing spine are different from those of patients with kissing spine, passing spine might be a pathological condition distinct from kissing spine.

Tumor microenvironment disparity in multiple primary lung cancers: Impact of non-intrinsic factors, histological subtypes, and genetic aberrations.

INTRODUCTION: Multiple primary lung cancers (MPLCs) occur in common carcinogenetic risks such as lifestyle, biological aging, immune responses, hormones, and metabolism. Although MPLCs harbor various genetic profiles within the same individuals, differences in the tumor microenvironment (TME) are unclear. We investigated the impact of genetic aberrations, non-intrinsic factors, and pathological subtypes on tumor immunity. MATERIALS AND METHODS: In total, 73 surgically resected specimens from 32 patients with MPLC were analyzed. PD-L1 expression in tumor cells (TCs) and immune cells (ICs), CD3-positive tumor-infiltrating lymphocytes (TILs), CD8/CD3 ratios, and FOXP3-positive TILs that compose TMEs were evaluated by immunohistochemistry and classified on a score of 0-2. 38 tumors were sequenced for somatic mutations in 409 cancer-associated genes. RESULTS: Females and never or light smokers had a higher incidence of PD-L1-negative tumors and a higher concordance rate. PD-L1 positivity in TCs and ICs was significantly less frequent in EGFR-mutated than in wild-type tumors. Differences in the score of TMEs were observed between the KRAS-mutated-only tumor and the KRAS and TP53-co-mutated tumors, and between the KRAS-mutated-only tumor and the KRAS and STK11-co-mutated tumors. Significantly more FOXP3-high TILs were observed in invasive pathological subtypes than in non-invasive ones. CONCLUSION: Comparing TMEs among MPLCs revealed that non-smokers or light smokers and females were unlikely to express PD-L1 regardless of tumor site and confirmed that the EGFR mutations and co-occurring KRAS and STK11 or TP53 mutations were associated with TME. Pathological subtypes may impact the efficacy of immune therapy due to their potential correlations with regulatory T cells.

Mutational landscape of multiple primary lung cancers and its correlation with non-intrinsic risk factors.

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Paired mutational analyses were performed to obtain a census of mutational events in MPLC and assess their relationship with non-intrinsic risk factors. Thirty-eight surgical specimens from 17 patients diagnosed as MPLC were used. Extracted DNAs were sequenced for somatic mutations in 409 cancer-associated genes from a comprehensive cancer panel. We statistically analysed the correlation between each driver mutation frequency and non-intrinsic risk factors using Fisher's exact test, and whether genetic mutations occurred concomitantly or randomly in MPLC using an exact test. Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases. EGFR mutations were significantly more frequent in never or light smokers and females. Concomitant EGFR or KRAS mutations in MPLCs were significantly more frequent than expected by chance (P = .0023 and .0049, respectively) suggesting a more prominent role of non-intrinsic risk factors in EGFR and KRAS mutations than other mutations, which occurred more randomly. Concomitant EGFR or KRAS mutations were particularly prominent in never or light smokers and males.

Can smoking duration alone replace pack-years to predict the risk of smoking-related oncogenic mutations in non-small cell lung cancer? A cross-sectional study in Japan.

OBJECTIVE: To investigate whether smoking duration alone can replace pack-years to predict the risk of oncogenic mutations in non-small cell lung cancer (NSCLC). DESIGN: A cross-sectional study using the baseline dataset from the Japan Molecular Epidemiology for Lung Cancer Study. SETTING: Forty-three medical institutions nationwide in Japan. PARTICIPANTS: From July 2012 to December 2013, 957 patients with newly diagnosed stage I-IIIB NSCLC who underwent surgery were enrolled, and molecular analyses were performed on 876 samples (from 441 ever-smokers and 435 never-smokers). MAIN OUTCOMES MEASURED: We calculated the area under the receiver operating characteristic curve (AUC) values using logistic regression to compare between the predictive values of smoking duration and pack-years for mutational frequencies in the v-Ki-ras2 Kirsten rat sarcoma (KRAS), tumour suppressor p53 (TP53), and epidermal growth factor receptor (EGFR) genes and for cytosine-to-adenine base substitution (C>A). RESULTS: For predicting KRAS mutations, the AUC values for smoking duration and pack-years were 0.746 (95% CI 0.682 to 0.800) and 0.759 (95% CI 0.700 to 0.810), respectively (p=0.058). For predicting KRAS mutations in smokers, the AUC values for smoking duration and pack-years were 0.772 (95% CI 0.697 to 0.833) and 0.787 (95% CI 0.714 to 0.845), respectively (p=0.036). There were no significant differences between the AUC values for smoking duration and pack-years in terms of predicting TP53 and EGFR mutations and C>A. Pack-years was a significantly better predictor of KRAS mutations than smoking duration. CONCLUSION: Smoking duration was not significantly different from pack-years in predicting the likelihood of smoking-related gene mutations. Given the recall bias in obtaining smoking information, smoking duration alone should be considered for further investigation as a simpler alternative to pack-years.

Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.

OBJECTIVES: Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. MATERIALS AND METHODS: Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). RESULTS: Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P =  0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P =  0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. CONCLUSION: EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer.

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) as first-line treatment in 70 patients with advanced EGFR-mutant non-small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28-8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death-1 ligand-1 (PD-L1), as high (50% or more) or low (less than 50%), and ligand-2 (PD-L2) expression, respectively. The extent of CD8+ tumor-infiltrating lymphocytes was evaluated on a scale of 0-3, with 0-1 as low and 2-3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD-L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD-L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression-free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR-TKIs differed according to the TME, and the phenotype with high PD-L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.

Japanese orthopaedic association cervical myelopathy evaluation questionnaire (JOACMEQ): Part 5. Determination of responsiveness.

BACKGROUND: In 1999, the Japanese Orthopaedic Association decided to develop a new Cervical Myelopathy Evaluation Questionnaire (JOACMEQ). The final version of the JOACMEQ, comprising 24 questions and five domains (cervical spine function (CF); upper extremity function (UF); lower extremity function (LF); bladder function (BF); and quality of life (QOL)), was established after three nationwide investigations. The fourth investigation, reported in this paper, was performed to confirm the responsiveness of the questionnaire. METHODS: A total of 137 patients with cervical myelopathy were included in the study. Each patient was interviewed twice using the JOACMEQ before and after treatment. At the second interview, the patients self-rated their condition in five domains for "worse," "somewhat worse," "no change," "somewhat better," or "better," and these scores were defined as the external assessment rating. The difference of the points in five domains between the first and the second interview was calculated against each external assessment. Based on the results, substantial clinical benefit (SCB) thresholds for the JOACMEQ were determined. RESULTS: The statistically significant median values of the acquired points were 17.5 for CF, 16.0 and 21.0 for UF, 27.0 and 20.5 for LF, 13.0 for BF, and 29.0 for QOL. After consideration of the results, the committee decided that an acquired point ≥20 could be interpreted as representing an SCB threshold for the JOACMEQ. CONCLUSION: We have concluded that a treatment can be judged to be effective for a patient if 1) The patient give all answers for the questions necessary to calculate the functional score of a domain and an increase of ≥20 points is obtained for that score, or 2) The functional score after treatment is > 90 points even if the answer for the unanswered questions was supposed to be the worst possible choice.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Applying a meal coding system to 16-d weighed dietary record data in the Japanese context: towards the development of simple meal-based dietary assessment tools.

Data on the combination of foods consumed simultaneously at specific eating occasions are scarce, primarily due to a lack of assessment tools. We applied a recently developed meal coding system to multiple-day dietary intake data for assessing its ability to estimate food and nutrient intakes and characterise meal-based dietary patterns in the Japanese context. A total of 242 Japanese adults completed sixteen non-consecutive-day weighed dietary records, including 14 734 eating occasions (3788 breakfasts, 3823 lunches, 3856 dinners and 3267 snacks). Common food group combinations were identified by meal type to identify a range of generic meals. Dietary intake was calculated on the basis of not only the standard food composition database but also the substituted generic meal database. In total, eighty generic meals (twenty-three breakfasts, twenty-one lunches, twenty-four dinners and twelve snacks) were identified. The Spearman correlation coefficients between food group intakes calculated based on the standard food composition database and the substituted generic meal database ranged from 0·26 to 0·85 (median 0·69). The corresponding correlations for nutrient intakes ranged from 0·17 to 0·82 (median 0·61). A total of eleven meal patterns were established using principal components analysis, and these accounted for 39·1 % of total meal variance. Considerable variation in patterns was seen in meal type inclusion and choice of staple foods (bread, rice and noodles) and drinks, and also in meal constituents. In conclusion, this study demonstrated the usefulness of a meal coding system for assessing habitual diet, providing a scientific basis towards the development of simple meal-based dietary assessment tools.

Validation study of a self-administered diet history questionnaire for estimating amino acid intake among Japanese adults.

BACKGROUND AND OBJECTIVES: Despite growing interest in the association between dietary amino acid intake and optimal health, validated dietary questionnaires that can estimate amino acid intake have been scarce. We examined the validity of amino acid intakes estimated using a self-administered diet history questionnaire (DHQ) comparing with 16-day semi-weighed dietary records (DR). METHODS AND STUDY DESIGN: A total of 184 Japanese men and women completed a four-day DR and a DHQ four times, once in each season. Dietary amino acid intakes were estimated as crude, energy-adjusted, and percentage of total protein intake (% protein) using an amino acid database of Japanese foods. The validity of dietary amino acid intake estimated by the first-time DHQ was examined using the mean of 16 days' DRs as reference. RESULTS: Mean intakes of almost all amino acids estimated by DHQ were significantly lower than those estimated by the DR for energy-adjusted values in both sexes. Although mean amino acid intakes estimated by DHQ were significantly higher than those estimated by the DR for % protein value, the differences between the DR and DHQ were slight (-0.04 to 0.39% protein for men, -0.05 to 0.37% protein for women). Pearson correlation coefficients between DHQ and the DR showed reasonable ranking ability in % protein values for men (interquartile range (Q1-Q3): 0.31-0.47) and energy-adjusted values for women (interquartile range (Q1-Q3): 0.40-0.45). CONCLUSION: DHQ showed acceptable ability to estimate mean amino acid intake and to rank individuals in a population according to their amino acid intake for using in large-scale epidemiological studies.

Low-dose irradiation of mouse embryos increases Smad-p21 pathway activity and preserves pluripotency.

PURPOSE: To study the outcomes of mouse preimplantation embryos irradiated with low doses of X-rays (≤ 1 Gy) and investigate apoptosis and pluripotency of the irradiated embryos. METHODS: Mouse embryos at the 2-cell stage were collected for in vitro culture. After reaching the 8-cell stage, embryos were irradiated with various low doses of X-rays (0-1 Gy). Blastocysts with a normal appearance were transferred into a pseudopregnant uterus. The developmental rate to blastocysts and the survival rate following embryo transfer were examined. Expression levels of p21, Smad2, Foxo1, Cdx2, Oct4, and Nanog genes were measured by RT-PCR. Apoptotic cells in mouse blastocysts were examined immunofluorescently by staining for cleaved caspase-3. RESULTS: More than 90% of non-irradiated and low-dose X-ray-irradiated preimplantation embryos developed to morphologically normal blastocysts that could be implanted and survive in the uterus. However, embryos irradiated with X-rays had more apoptotic cells in a dose-dependent manner. Expression of p21, Smad2, and Foxo1 genes in X-ray-irradiated embryos was increased significantly, while expression of Cdx2, Oct4, and Nanog genes was maintained in comparison with non-irradiated embryos. CONCLUSIONS: Although irradiated embryos contained apoptotic cells, the low doses of irradiation did not disturb development of 8-cell stage embryos to blastocysts or their survival in utero. The underlying mechanisms might involve anti-apoptotic systems, including the Smad-p21 pathway, and preservation of pluripotency.

[DIAN/DIAN-J/DIAN-TU].

The Dominantly Inherited Alzheimer's Network (DIAN) observational study compared pathophysiological markers between mutation carriers and non-carriers in autosomal dominant Alzheimer's disease. This study revealed that changes in the biomarkers in the mutation carrier's brain start as early as 20 or even 25 years prior to the onset of symptoms. Doctors of the DIAN-Japan team have successfully implemented the DIAN study in Japan (DIAN-J) with effort and enthusiasm. The DIAN-J study is completely compatible with the DIAN study. All members of the DIAN-J team were certified by the NIH and Washington University. The DIAN researchers started a prevention trial (DIAN-TU) testing two monoclonal antibodies in 2013. Together with the DIAN global members including the Japanese team, they will start the new DIAN-TU NexGen Trial testing a BACE inhibitor in 2017. The API study is another clinical trial of anti-amyloid monoclonal antibody therapy for family members of patients with early-onset familial AD who carry the PSEN1 E280A mutation. This study has shown the same biomarker changes that were reported in the DIAN study.