Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function.

MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs), which promote synaptic development. Mutations in MDGAs are implicated in various neuropsychiatric diseases. MDGAs bind NLGNs in cis on the postsynaptic membrane and physically block NLGNs from binding to NRXNs. In crystal structures, the six immunoglobulin (Ig) and single fibronectin III domains of MDGA1 reveal a striking compact, triangular shape, both alone and in complex with NLGNs. Whether this unusual domain arrangement is required for biological function or other arrangements occur with different functional outcomes is unknown. Here, we show that WT MDGA1 can adopt both compact and extended 3D conformations that bind NLGN2. Designer mutants targeting strategic molecular elbows in MDGA1 alter the distribution of 3D conformations while leaving the binding affinity between soluble ectodomains of MDGA1 and NLGN2 intact. In contrast, in a cellular context, these mutants result in unique combinations of functional consequences, including altered binding to NLGN2, decreased capacity to conceal NLGN2 from NRXN1ß, and/or suppressed NLGN2-mediated inhibitory presynaptic differentiation, despite the mutations being located far from the MDGA1-NLGN2 interaction site. Thus, the 3D conformation of the entire MDGA1 ectodomain appears critical for its function, and its NLGN-binding site on Ig1-Ig2 is not independent of the rest of the molecule. As a result, global 3D conformational changes to the MDGA1 ectodomain via strategic elbows may form a molecular mechanism to regulate MDGA1 action within the synaptic cleft.

A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Developmental trajectories at a high risk for childhood overweight/obesity.

BACKGROUND: The associations between developmental patterns (trajectories) in children and maternal factors have been widely investigated, but paternal effects on these trajectories are unclear. This study aimed to determine child and parental factors involved in developmental trajectories at high risk for causing adverse cardiovascular (CV) profiles in children. METHODS: We analyzed longitudinal anthropometric data from birth to the present and CV profiles of 1,832 healthy volunteers (51% girls) aged 3-15 years who participated in a nationwide study between July 2012 and January 2014. Six trajectory latent class growth models were developed using body mass index z- scores. Predictors for being in developmental trajectories at high risk for causing adverse CV profiles were determined by multivariate regression analysis. RESULTS: The mean±standard deviation number of anthropometric data points was 12±3 for both boys and girls. Among the six trajectories, the infantile onset and continual increase groups had significantly worse levels of many CV profiles than those in the remaining groups. Paternal overweight/obesity was an independent predictor for boys being in the infantile onset group and for girls being in the continual increase group. Additionally, maternal pre-pregnancy overweight/obesity in boys and maternal excessive gestational weight gain in girls were independent predictors for being in the infantile onset group. Having no sibling in boys and an older maternal age were independent predictors for being in the continual increase group. CONCLUSIONS: Interventions to prevent childhood obesity should include strategies that focus on fathers and mothers as well as those that focus on children with certain types of familial background.

Workplace factors associated with willingness to undergo human immunodeficiency virus testing during workplace health checkups.

BACKGROUND: To examine workplace factors associated with willingness to undergo human immunodeficiency virus (HIV) testing during workplace health checkups. METHODS: This cross-sectional study used an Internet-based self-administered questionnaire to obtain data from a pool of 24,287 Japanese workers. Binary and multiple logistic regression analyses evaluated the association between workplace factors and HIV testing. Data were adjusted for sex, age, marital status, education, and history of HIV testing. RESULTS: We gathered information from 4,143 (17.1%) respondents, of whom 1,129 (27.3%) were willing to be tested for HIV as part of a workplace health checkup. The participants were 20-59 years old. Approximately half of the participants were male (49.9%), half were married (48.9%), and half had completed higher education (47.6%). Workplace hepatitis testing was offered to 15.6% of the respondents, and most participants underwent health checkups without their colleagues (52.1%) at a medical facility (60.2%). Willingness to undergo HIV testing was positively correlated with having an increased risk of occupational blood exposure (vs. not at risk, adjusted odds ratio [OR]: 1.74, 95% confidence interval [CI]: 1.41-2.15) or working in medical and welfare roles (vs. manufacturing, OR: 1.40, 95% CI: 1.07-1.84). The presence of occupational health staff at the workplace (vs. their absence, adjusted OR: 1.35, 95% CI: 1.16-1.59) and hepatitis testing (vs. not testing, adjusted OR: 2.02, 95% CI: 1.66-2.44) increased willingness to undergo HIV testing. CONCLUSIONS: A pilot HIV-testing program involving individuals at an increased risk of occupational blood exposure and undergoing hepatitis tests in workplaces providing occupational health staff support is recommended.

Dopaminergic neurons establish a distinctive axonal arbor with a majority of non-synaptic terminals.

Chemical neurotransmission typically occurs through synapses. Previous ultrastructural examinations of monoamine neuron axon terminals often failed to identify a pre- and postsynaptic coupling, leading to the concept of "volume" transmission. Whether this results from intrinsic properties of these neurons remains undefined. We find that dopaminergic neurons in vitro establish a distinctive axonal arbor compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons. While most dopaminergic varicosities are active and contain exocytosis proteins like synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in dopaminergic terminals that are in proximity to a target cell. Finally, we found that the proteins neurexin-1αSS4- and neuroligin-1A+B play a critical role in the formation of synapses by dopamine (DA) neurons. Our findings suggest that DA neurons are endowed with a distinctive developmental connectivity program.

Revisiting the Geographical Distribution of Thyroid Cancer Incidence in Fukushima Prefecture: Analysis of Data From the Second- and Third-round Thyroid Ultrasound Examination.

BACKGROUND: After the first-round (Preliminary Baseline Survey) ultrasound-based examination for thyroid cancer in response to the accident at the Fukushima Daiichi Nuclear Power Plant in 2011, two rounds of surveys (Full-scale Survey) have been carried out in Fukushima Prefecture. Using the data from these surveys, the geographical distribution of thyroid cancer incidence over 6 or 7 years after the disaster was examined. METHODS: Children and adolescents who underwent the ultrasound-based examinations in the second- and/or third-round (Full-scale) survey in addition to the first-round survey were included. With a discrete survival model, we computed age, sex, and body mass index standardized incidence ratios (SIRs) for municipalities. Then, we employed spatial statistics to assess geographic clustering tendency in SIRs and Poisson regression to assess the association of SIRs with the municipal average absorbed dose to the thyroid gland at the 59-municipality level. RESULTS: Throughout the second- and third-round surveys, 99 thyroid cancer cases were diagnosed in the study population of 252,502 individuals. Both flexibly shaped spatial scan statistics and maximized excess events test did not detect statistically significant spatial clustering (P = 0.17 and 0.54, respectively). Poisson regression showed no significant dose-response relationship: the estimated relative risks of lowest, middle-low, middle-high, and highest areas were 1.16 (95% confidence interval [CI], 0.52-2.59), 0.55 (95% CI, 0.31-0.97), 1.05 (95% CI, 0.79-1.40), and 1.24 (95% CI, 0.89-1.74). CONCLUSION: There was no statistical support for geographic clustering or regional association with radiation dose measures of the thyroid cancer incidence in the cohort followed up to the third-round survey (fiscal years 2016-2017) in Fukushima Prefecture.

Association of marital status and access to dental care among the Japanese population: a cross-sectional study.

BACKGROUND: Health disparities according to marital status have been reported worldwide. Although spouses provide an important social network that influences heath behaviors, limited studies have examined the association between marital status and access to dental care. Therefore, this study aimed to analyze the association between marital status and access to dental care. METHODS: A secondary analysis of the 2013 Comprehensive Survey of Living Conditions in Japan which is a national survey, was performed in this study. Out of 367,766 respondents, 4111 respondents, aged over 40 years who selected oral symptoms as their most concerning subjective symptom were recruited as participants. The independent variable of interest was marital status-married or non-married (single, divorced, widowed); and the dependent variable was access to dental care. We performed Poisson regression analyses stratified by sex with adjustment for age, educational status, employment, equivalent household expenditure, and smoking habits. RESULTS: Among respondents who reported oral symptoms, 3024 were married, and 1087 were non-married. Further, 29.4% and 40.4% of married and non-married men, respectively, did not receive dental treatment for their symptoms. Meanwhile, 27.5% and 25.0% of married and non-married women, respectively, did not receive dental treatment for their symptoms. The prevalence ratio for not receiving dental treatment was significantly higher among non-married men (prevalence ratio: 1.33; 95% confidence interval: 1.14-1.56) than among married men. However, no significant association was observed among women. CONCLUSIONS: Non-married men were highly unlikely to receive dental treatment than married men, while no significant association was observed among women. The results implicate the importance of implementing a public dental health policy for protecting the dental health of non-married individuals.

[Validation of using disqualification from long-term care insurance registry as a proxy of death].

Objectives　The national database for long-term care insurance (LTCI) of Japan (Kaigo DB) enables researchers to access comprehensive data from its LTCI registry, eligibility assessment records, claims for service usage, and information about service providers. However, studies regarding the death or mortality of beneficiaries cannot be conducted because Kaigo DB does not contain death records, and researchers are not allowed to link Kaigo DB to other databases, such as national death records. Therefore, we aimed to assess the validity of using an insurer's disqualification from an LTCI beneficiary as a proxy of death.Methods　We used 510,751,798 monthly beneficiary records between April 2007 and March 2017 from the LTCI registry, while excluding data for ineligible persons for LTCI benefit or those younger than 65 years. We identified insurer cases disqualified from LTCI beneficiaries and linked them to national death records using deterministic linkage methods by dates of birth and death, sex, and residence. We considered the cases as positive if they were disqualified and their record was linked to a death. We used sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) as validity indices.Results　We identified 5,986,991 (1.17%) disqualified and 5,295,961 death cases. Sensitivity, specificity, PPV, and NPV of disqualification for death were 100%, 99.86%, 88.46%, and 100%, respectively. After stratification, PPV of disqualification was between 85% and 88% before 2012, 91% after 2012, 91.9% in men, and 85.9% in women. PPV increased with age (65-69 years: 80.6%, 70-74 years: 86.7%, 75-79 years: 86.4%, 80-84 years: 86.7%, 85-89 years: 88.0%, 90-94 years: 90.6%, and 95+ years: 93.4%) and level of care needed (support level: 72.2%, care level (CL) 1: 79.7%, CL2: 85.9%, CL3: 89.3%, CL4: 92.3%, and CL5: 94.0%).Conclusions　Disqualification from the LTCI registry is an inappropriate measure to estimate mortality accurately because it has a 10% false-positive rate. However, it appears sufficiently valid to use disqualification as a proxy outcome of death, although the main effect or confounding of a possible predictor of death could be slightly underestimated.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

Prevention services via public long-term care insurance can be effective among a specific group of older adults in Japan.

BACKGROUND: To evaluate the effects of prevention services provided by long-term care insurance (LTCI) for older adults who require support from LTCI in Kashiwa City, Japan. METHODS: We conducted an analysis using the following population-based longitudinal data in Kashiwa City between April 2012 and March 2015: Data of National Health Insurance and LTCI claims, the survey for certification of LTCI, the register, and premium tier classification. All data was linked using the pre-assigned anonymous identifying numbers. We analyzed the Cox regression model using the time for the deteriorations of levels of certified care need in LTCI as an outcome and the use of preventive care services as the primary exposure among participants aged 75 years or older, who had either support levels 1 or 2 at the beginning of this analysis. The study was further stratified by both age and initial support level. RESULTS: The final analysis included 1289 participants. The primary result showed, among all participants, that preventive service was not effective (hazard ratio 0.96, 95% confidence interval 0.78-1.19). In our sub-analysis, the preventive service was effective in avoiding deteriorations only among those aged 85 and older with support level 1 (HR 0.65, 95% CI 0.43-0.97) out of four groups. CONCLUSIONS: The preventive services of LTCI in Kashiwa City showed a significant effect on the deterioration among subjects aged 85 or older, whose disability level were low (support level 1). Our results suggest that the prevention services provided by LTCI may not be effective for all older individuals; to provide these services efficiently, local governments, as insurers of LTCI, will need to identify the specified groups that may benefit from the preventive services. Additionally, it is necessary to re-examine what preventive interventions may be effective, or redesign the health system if necessary, for those who were not affected by the intervention.

Cost-Effectiveness of Behavior Modification Intervention for Patients With Chronic Kidney Disease in the FROM-J Study.

OBJECTIVES: Chronic kidney disease (CKD) is a significant public health problem. An advanced, or innovative, CKD care system of clinical practice collaboration among general physicians (GPs), nephrologists, and other healthcare workers achieved behavior modification in patients with Stage 3 CKD in the Frontier of Renal Outcome Modifications in Japan (FROM-J) study. This behavior modification intervention consisted of educational sessions on nutrition and lifestyle, as well as encouragement of patients' regular visits. The intervention contributed to slowing CKD progression. This study aimed to evaluate the cost-effectiveness of the widespread diffusion of the behavior modification intervention proven effective by the FROM-J study. METHODS: A cost-effectiveness analysis was carried out to compare the behavior modification intervention with the current practice recommended by the latest CKD clinical guidelines for GPs. A Markov model with a societal perspective under Japan's health system was constructed. We assumed that the behavior modification intervention proven effective by the FROM-J study would be initiated by GPs for targeted patient cohorts-patients aged 40-74 years with Stage 3 CKD-as a part of the innovative CKD care system. RESULTS: The incremental cost-effectiveness ratio for the behavior modification intervention compared with current guideline-based practice was calculated as 145,593 Japanese yen (¥; $1,324 United States dollars [$]) per quality-adjusted life year (QALY). CONCLUSIONS: Using the suggested value of social willingness to pay for a one-QALY gain in Japan of ¥5 million (US$45,455) as the threshold to judge cost-effectiveness, the behavior modification intervention is cost-effective. Our results suggest that diffusing the behavior modification intervention proven effective by the FROM-J study could be justifiable as an efficient use of finite healthcare resources. GPs could be encouraged to initiate this intervention by revising the National Health Insurance fee schedule and strengthening clinical guidelines regarding behavior modification interventions.

[The relationship between information sources, media, and "anxiety about the effects of radiation on future generations" in Hamadori and Fukushima Prefecture's evacuation areas after the nuclear accident].

Objectives　Nine years after the accident at the TEPCO Fukushima Daiichi Nuclear Power Plant in March 2011, anxiety about the effects of radiation on future generations persists. We considered the possibility that information from mass media sources and the Internet might influence this anxiety. Thus, this study examined the relationship between information sources and anxiety; based on the results, we consider the necessary measures to reduce this anxiety.Methods　We conducted a mail-based survey by distributing an anonymous self-administered questionnaire to 2,000 Fukushima Prefecture residents aged 20 to 79. We randomly selected 500 residents from Aizu, Nakadori, Hamadori, and the evacuation areas, and compared the data obtained from Hamadori and the evacuation areas. The objective variable was anxiety about the effects (of radiation) on future generations, while the explanatory variables were trusted sources and media the respondents used to get information on radiation. Other variables assessed included health status and knowledge of radiation. We conducted univariate analysis of combined data to assess the relationship between anxiety and the questionnaire items. This was followed by multiple regression analysis with anxiety as the objective variable and those showing significant differences in the univariate analysis as the explanatory ones. We then conducted multiple regression analysis, that included the interaction means between explanatory variables and evacuation areas.Results　Of the 500, 201 respondents were from Hamadori (40.2%) and 192 from the evacuation areas (38.4%). Multiple regression analysis revealed that anxiety was significantly lower among those who trusted government ministries and those who were healthy. Anxiety was also significantly lower among those who correctly answered the question on the genetic influence of radiation, while it was significantly higher among those who correctly answered the question on the dose-response model of radiation-induced cancer. In Hamadori, anxiety was significantly higher among those who watched private national television. In the evacuation areas, the result was the same as that of the combined data.Conclusion　Different information sources and media were significantly associated with anxiety about the effects of radiation on future generations. Therefore, media sensationalism should be reduced to prevent anxiety among citizens. Our findings highlight the importance of selecting information sources and media that disseminate accurate information, as well as the need to improve media literacy among citizens. Furthermore, a dose-response model of radiation-induced cancer must be communicated in a way that is not misleading. Receiving accurate information on the genetic effects of radiation can reduce anxiety among citizens.

Factors Influencing the Proportion of Non-examinees in the Fukushima Health Management Survey for Childhood and Adolescent Thyroid Cancer: Results From the Baseline Survey.

BACKGROUND: After the Fukushima Daiichi Nuclear Power Plant accident, a preliminary ultrasound-based screening for thyroid cancer was conducted to establish a baseline for subsequent evaluations. In this survey, we assessed the relationship between the proportion of non-examinees and characteristics of the target populations. METHODS: After summarizing a regional difference of non-examinees among the population of 359,200 (primary evaluation) and 2,246 (confirmatory testing) individuals who were living in Fukushima Prefecture on March 11, 2011, we estimated odds ratios (ORs) for each characteristic, including age, sex, area of residence, and moving after the accident, based on the proportion of non-examinees for the primary examination and the confirmatory testing, using a multivariate logistic regression model. RESULTS: The dataset included 64,117 non-examinees (primary evaluation) and 194 (confirmatory testing). The logistic regression result indicated that girls were not likely to be non-examinees compared to boys, with adjusted OR of 0.80 (95% confidence interval [CI], 0.78-0.81) for the primary evaluation. Odds were lowest for children 6-10 years old (OR 0.26; 95% CI, 0.25-0.27), and higher for those 11-15 years old (OR 1.28; 95% CI, 1.25-1.32) and over 16 years old (OR 5.30; 95% CI, 5.16-5.43) when compared to children 0-5 years old. Individuals residing in the western part of the prefecture showed higher ORs. There was a higher proportion of non-examinees among those who moved after the accident compared to those who did not in the primary evaluation (OR 1.72; 95% CI, 1.64-1.79). CONCLUSIONS: In addition to demographic characteristics, a change of residence could be a potential factor that influenced the proportion of non-examinees. Our results will help proper interpretation of reports and prospective management of the survey.

A significance of school screening electrocardiogram in the patients with ventricular noncompaction.

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.

Correction to: Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG).

In the October 2018 issue of International Journal of Clinical Oncology.

Effect of reduced formal care availability on formal/informal care patterns and caregiver health: a quasi-experimental study using the Japanese long-term care insurance reform.

BACKGROUND: It is unclear how formal long-term care (LTC) availability affects formal /informal caregiving patterns and caregiver health. We tested the impact of reduced formal LTC availability on formal LTC service use, intensity of informal caregiving, and caregiver health. METHODS: Using a representative, repeated cross-sectional sample of Japanese caregivers providing care to co-resident family members from 2001 to 2016, we applied a difference-in-differences approach by observing caregivers before and after the major reform of the public Japanese LTC insurance (LTCI) in 2006. The reform reduced coverage benefits for non-institutionalized older persons with low care needs, but not for those with high care needs. We analyzed 12,764 caregivers aged ≥30 years (mean age 64.3 ± 11.8 years, 73.5% women) and measured indicators of formal LTC use, hours of informal caregiving, and caregiver self-reported health outcomes after propensity score matching to balance caregivers' background characteristics. RESULTS: We found the 2006 LTCI reform relatively reduced the use of formal LTC services and relatively increased the percentage of experiencing long hours of informal caregiving (> 3 h per day) among the caregivers for seniors with low care needs compared to those for seniors with high care needs. The effects of the LTCI reform for the caregivers for seniors with low care needs were 2.2 percentage point higher on caregivers' experiencing poor self-rated health (95% confidence interval [CI]: 0.7-3.7; p = 0.01), 2.7 percentage point higher on experiencing symptoms of a depressive state (95%CI: 0.5-4.8; p = 0.03), and 4.7 percentage point higher on experiencing symptoms of musculoskeletal diseases (95%CI, 3.6-5.7; p < 0.001), compared to those for seniors with high care needs. CONCLUSIONS: Reduced formal care availability under the Japanese LTCI reform increased hours of informal caregiving corresponding to reduced use of formal LTC and deteriorated multiple dimensions of caregiver health. Our findings may highlight the importance of enhancing the availability of formal LTC services for caregiver health.

A phase II JN-I-10 efficacy study of IDRF-based surgical decisions and stepwise treatment intensification for patients with intermediate-risk neuroblastoma: a study protocol.

BACKGROUND: Few clinical trials have been reported for patients with intermediate-risk neuroblastoma because of the scarcity of the disease and the variety of clinical and biological characteristics. A multidisciplinary treatment that consists of multidrug chemotherapy and surgery is expected to lead to a good prognosis with few complications. Therefore, a clinical trial for patients with intermediate-risk tumors was designed to establish a standard treatment that reduces complications and achieves good outcomes. METHODS: We planned a prospective phase 2, single-arm study of the efficacy of image-defined risk factors (IDRF)-based surgical decision and stepwise treatment intensification for patients with intermediate-risk neuroblastomas. For the localized tumor group, IDRF evaluations will be performed after each three-course chemotherapy, and surgery will be performed when appropriate. For patients with metastatic tumors, a total of five chemotherapy courses will be performed, and primary lesions will be removed when the IDRF becomes negative. The primary endpoint is 3-year progression-free survival rate, and the secondary endpoints include 3-year progression-free survival rates and overall survival rates of the localized group and the metastasis group and the incidence of adverse events. From international results, 75% is considered an appropriate 3-year progression-free survival rate. If this trial's expected 3-year progression-free survival rate of 85% is statistically greater than 75% in the lower limit of the 95.3% confidence interval, with an accuracy 10% (85 ± 10%), both groups require more than 65 patients. DISCUSSION: This study is the first clinical trial on the efficacy of IDRF-based surgical decision and stepwise treatment intensification for patients with intermediate-risk neuroblastomas. We expect that this study will contribute to the establishment of a standard treatment for patients with intermediate-risk neuroblastoma. TRIAL REGISTRATION: UMIN000004700, jRCTs051180203; Registered on December 9, 2010.

Promoting physical activity through walking to treat childhood obesity, mainly for mild to moderate obesity.

BACKGROUND: There are no randomized controlled trials examining the effect of walking on childhood obesity. METHODS: A randomized controlled trial was conducted between August 2014 and April 2015 in Japan. Elementary school children aged 6 to 12 years with a percentage overweight (%OW) of ≥20% were recruited. One hundred and ninety children wanted to participate in the program, and all were accepted. After viewing a video that promoted physical activity through walking, participants were randomly assigned to three groups: walking (≥10 000 steps on school holidays), limiting screen time (<90 min on weekdays and <150 min on school holidays), and a control group (no intervention). The primary outcome was a decrease in %OW after 3 months' intervention. Per protocol analysis was performed using 156 participants who fulfilled the inclusion criteria of a %OW ≥20%. RESULTS: The mean %OW was 35 ± 7% before intervention. The mean reduction in %OW after intervention in the walking (n = 59), limiting ST (n = 46), and control (n = 51) groups were -4.06 ± 4.84, -1.97 ± 4.62, and -1.81 ± 3.64 percentage points, respectively. Reduction in %OW was significantly larger in the walking group than in the control group: adjusted mean difference, -2.18 percentage points (95% confidence interval, -3.85 to -0.52), P = 0.002. The intervention in children also had favorable effects on the lifestyles of their parents. The intention-to-treat analysis of all 190 participants showed comparable results. CONCLUSION: Promoting physical activity through walking on school holidays may be an additional strategy for treating elementary school children with obesity.

External Radiation Dose, Obesity, and Risk of Childhood Thyroid Cancer After the Fukushima Daiichi Nuclear Power Plant Accident: The Fukushima Health Management Survey.

BACKGROUND: The 2011 Great East Japan Earthquake led to a nuclear accident at Fukushima Daiichi Nuclear Power Plant. This study examines the associations of radiation dose and lifestyle factors with incidence of thyroid cancer in Fukushima. METHODS: We designed a prospective study with 300,473 participants aged 18 years or younger, who underwent thyroid examinations from October 2011. Follow-up surveys were conducted through June 2017, and 245,530 participants (123,480 men and 122,050 women, 82% follow-up) received follow-up examinations. Fukushima Prefecture was divided into five areas based on individual external radiation dose. We calculated relative risks and 95% confidence intervals (CIs) for thyroid cancer in each area, with area of lowest dose as reference, using age-adjusted Poisson regression models. We also calculated risks associated with overweight and obesity. RESULTS: The incidence per 100,000 for Groups A (highest dose), B, C, D, and E (lowest dose) were 13.5, 19.2, 17.3, 9.0, and 8.3, respectively. Compared with Group E, the age-adjusted risks (95% CIs) were 1.62 (0.59, 4.47) for group A, 2.32 (0.86, 6.24) for group B, 2.21 (0.82, 5.94) for group C, and 1.02 (0.36, 2.86) for group D. Obesity was positively associated with thyroid cancer incidence; the multivariable-adjusted risk of thyroid cancer was 2.23 (1.01, 4.90) for obese individuals compared with nonobese individuals. CONCLUSION: Regional differences in radiation dose were not associated with increased risk of thyroid cancer among children in Fukushima within 4 to 6 years after the nuclear power plant accident. Obesity may be an important factor for further follow-up in Fukushima.

Results of a prospective clinical trial JN-L-10 using image-defined risk factors to inform surgical decisions for children with low-risk neuroblastoma disease: A report from the Japan Children's Cancer Group Neuroblastoma Committee.

BACKGROUND: The present study sought to reduce the incidence of treatment complications of low-risk neuroblastoma by using image-defined risk factors (IDRFs) to inform the timing of surgical resection. PROCEDURES: Eligible patients included children (<18 years of age) with stage 1 or 2 disease, children (<365 days of age) with stage 3 disease, and infants with stage 4S disease. In IDRF-negative cases, treatment was completed with surgical resection alone. In IDRF-positive cases, the timing of surgery was determined based on the IDRFs after low-dose chemotherapy with 2-3 of the following four drugs: vincristine, cyclophosphamide, pirarubicin, and carboplatin. The outcome measures were overall survival, progression-free survival, and adverse events. This study was registered with the UMIN Clinical Trials Registry (number 000004355). RESULTS: Of the 60 patients screened between 2010 and 2013, 58 eligible patients were enrolled; 32 were identified as IDRF negative at diagnosis while 26 were identified as IDRF positive and underwent induction chemotherapy. The 3-year overall and progression-free survival rates of the 58 patients were 100% and 82.8% (95% confidence interval: 70.3-90.3), respectively. Neutropenia was the most frequently reported grade 3 or 4 chemotherapy-related form of toxicity (41.7%). With regard to surgical complications, 2.5% of all patients developed pleural effusion and ascites as early complications, while only 2.5% developed renal atrophy as a long-term complication. No fatal toxicities were observed. CONCLUSION: Using IDRFs to inform surgical decision making for the treatment of low-risk neuroblastoma improved prognosis and reduced the incidence of long-term complications.