Quantitative Measurement of Phthalate Exposure Biomarker Levels in Diaper-Extracted Urine of Japanese Toddlers and Cumulative Risk Assessment: An Adjunct Study of JECS Birth Cohort.

Phthalate exposure monitoring and risk assessment in non-toilet-trained children are rarely reported. This adjunct study of the Japan Environment and Children's Study assessed cumulative health risks in 1.5-year-old toddlers in the Aichi regional subcohort by biomonitoring 16 urinary metabolites of eight phthalate plasticizers. Overnight urine was extracted from toddlers' diapers (n = 1077), and metabolites were quantified using ultraperformance liquid chromatography coupled with tandem mass spectrometry. The analyses' quality was assured by running quality control samples. The highest geometric mean concentration was found for mono-(2-ethyl-5-carboxypentyl) phthalate, followed by mono-isobutyl phthalate (23 and 21 µg/L, respectively). Di-2-ethylhexyl phthalate (DEHP) and di-butyl phthalate exhibited higher risks [hazard quotient (HQ) > 1] than the cutoff level in a small proportion of toddlers; 8 and 14% of toddlers were at cumulative risk of multiple phthalates beyond the cutoff level [hazard index, (HI) > 1], based on the tolerable daily intake of the European Food Safety Authority and the United States Environmental Protection Agency Reference Dose. HI > 1 for antiandrogenicity in creatinine-unadjusted and -adjusted estimations were exhibited by 36 and 23% of the children, respectively. Thus, identifying exposure sources and mitigating exposure are necessary for risk management. Additionally, continuous exposure assessment and evaluation of health outcomes, especially antiandrogenic effects, are warranted.

Interpreting biomonitoring data: Introducing the international human biomonitoring (i-HBM) working group's health-based guidance value (HB2GV) dashboard.

Human biomonitoring (HBM) data measured in specific contexts or populations provide information for comparing population exposures. There are numerous health-based biomonitoring guidance values, but to locate these values, interested parties need to seek them out individually from publications, governmental reports, websites and other sources. Until now, there has been no central, international repository for this information. Thus, a tool is needed to help researchers, public health professionals, risk assessors, and regulatory decision makers to quickly locate relevant values on numerous environmental chemicals. A free, on-line repository for international health-based guidance values to facilitate the interpretation of HBM data is now available. The repository is referred to as the "Human Biomonitoring Health-Based Guidance Value (HB2GV) Dashboard". The Dashboard represents the efforts of the International Human Biomonitoring Working Group (i-HBM), affiliated with the International Society of Exposure Science. The i-HBM's mission is to promote the use of population-level HBM data to inform public health decision-making by developing harmonized resources to facilitate the interpretation of HBM data in a health-based context. This paper describes the methods used to compile the human biomonitoring health-based guidance values, how the values can be accessed and used, and caveats with using the Dashboard for interpreting HBM data. To our knowledge, the HB2GV Dashboard is the first open-access, curated database of HBM guidance values developed for use in interpreting HBM data. This new resource can assist global HBM data users such as risk assessors, risk managers and biomonitoring programs with a readily available compilation of guidance values.

Claims-based algorithms for common chronic conditions were efficiently constructed using machine learning methods.

Identification of medical conditions using claims data is generally conducted with algorithms based on subject-matter knowledge. However, these claims-based algorithms (CBAs) are highly dependent on the knowledge level and not necessarily optimized for target conditions. We investigated whether machine learning methods can supplement researchers' knowledge of target conditions in building CBAs. Retrospective cohort study using a claims database combined with annual health check-up results of employees' health insurance programs for fiscal year 2016-17 in Japan (study population for hypertension, N = 631,289; diabetes, N = 152,368; dyslipidemia, N = 614,434). We constructed CBAs with logistic regression, k-nearest neighbor, support vector machine, penalized logistic regression, tree-based model, and neural network for identifying patients with three common chronic conditions: hypertension, diabetes, and dyslipidemia. We then compared their association measures using a completely hold-out test set (25% of the study population). Among the test cohorts of 157,822, 38,092, and 153,608 enrollees for hypertension, diabetes, and dyslipidemia, 25.4%, 8.4%, and 38.7% of them had a diagnosis of the corresponding condition. The areas under the receiver operating characteristic curve (AUCs) of the logistic regression with/without subject-matter knowledge about the target condition were .923/.921 for hypertension, .957/.938 for diabetes, and .739/.747 for dyslipidemia. The logistic lasso, logistic elastic-net, and tree-based methods yielded AUCs comparable to those of the logistic regression with subject-matter knowledge: .923-.931 for hypertension; .958-.966 for diabetes; .747-.773 for dyslipidemia. We found that machine learning methods can attain AUCs comparable to the conventional knowledge-based method in building CBAs.

Knowledge, Experience, and Perceptions of Generic Drugs among Middle-Aged Adults and their Willingness-to-Pay: A Nationwide Online Survey in Japan.

Promoting generic drugs can reduce the financial burden on patients and improve healthcare finances. The insurers have been conducting promotional efforts, such as direct-mail campaigns, but little is known about the public's perception of generic drugs and effective message strategies for promotion. In 2018, we conducted a web-based survey of middle-aged Japanese men and women that investigated: (i) their perceptions of generic drugs, (ii) the association between perceptions and willingness-to-pay for brand-name drugs relative to generic drugs, and (iii) potentially effective forms of information provision to alter individuals' perceptions. Of the 1,005 respondents, over half perceived generic drugs as having the same level of efficacy and safety as brand-name drugs. While willingness-to-pay was dispersed among respondents, two factors were associated with small willingness-to-pay: (a) perceiving generic drugs as having the same level of efficacy and safety as brand-name drugs and (b) perceiving that promoting the use of generic drugs is important for controlling medical expenditures. Moreover, presenting potential savings over five years by choosing generic drugs was a potentially effective tool for altering perceptions, relative to showing monthly savings. Our findings suggest that certain parts of the population still have high willingness-to-pay for brand-name drugs, and strategic communication to alter perception could be effective in promoting the use of generic drugs among those who are price-inelastic.

Safety assessment of the prophylactic use of silicone gel sheets (Lady Care®) for the prevention of hypertrophic scars following caesarean section.

This study aimed to investigate the side effects of silicone gel sheet (Lady Care®) and evaluate its prophylactic efficacy in preventing abnormal scarring. Sixty women who underwent caesarean section were recruited from September 2016 to September 2017 in this prospective study. Lady Care® was applied from the 2nd to the 6th postoperative months. Side effects of Lady Care® were evaluated through medical examinations and questionnaires. A plastic surgeon diagnosed abnormal scarring. Pruritus was diagnosed in 25 (47.2%) patients; folliculitis, four (7.5%); dry skin, four (7.5%); contact dermatitis, three (5.7%); wound infection, two (3.8%); and epidermolysis, one (1.9%), albeit with mild severity. Following Lady Care® application, no abnormal scarring and mild hypertrophic scarring was observed in 32 (64.0%) and 18 (36.0%) patients respectively. Of seven patients with pre-existing hypertrophic scars, only two showed hypertrophic scarring after Lady Care® application. Our findings support the safety and prophylactic efficacy of Lady Care®.Impact StatementWhat is already known on this subject? The incidence of abnormal scarring, i.e. keloid or hypertrophic scar formation after caesarean section (CS) is reported to be ∼41%. Abnormal or excessive scar formation can lead to functional limitations, pruritus, pain and cosmetic issues. Studies have also shown a prophylactic effect of the application of silicone materials against the development of hypertrophic and keloid scars, though prohibitive cost and lack of adhesiveness of such gel sheets are known factors limiting their usage.What the results of this study add? The new silicone gel sheet 'Lady Care®' has strong adhesive properties and is consequently not easily peeled off. Furthermore, it is easy to use and economically efficient.What the implications are of these findings for clinical practice and/or further research? This is the first clinical trial on the application of Lady Care® silicone gel sheet for the prevention of CS scarring. Our findings support the safety and prophylactic efficacy of Lady Care®.

Cumulative exposure assessment of neonicotinoids and an investigation into their intake-related factors in young children in Japan.

Exposure levels of neonicotinoids (NEO) in young children remain unknown, despite their widespread use and the plausible vulnerability of toddlers to environmental toxicants. Herein we aimed to clarify the exposure levels and sources of NEOs in young Japanese children. Disposable diapers were collected from 1036 children (16-23 months old) participating in an adjunct study of the Japan Environment and Children's Study between 2015 and 2016. Six NEOs and one metabolite in urine extracted from a diaper from each child were analyzed using high-performance liquid chromatography-tandem mass spectrometry. A relative potency factor approach was used to assess the cumulative exposure to NEOs equivalent to dinotefuran levels (DINRPF). The 95th percentile urinary concentration of DINRPF was 157 µg/L and 380 µg/g creatinine (Cr). Receiver operating characteristic curve analyses for the propensity scores of the possible exposure-related factors revealed that the discriminatory powers determining whether Cr-adjusted and Cr-unadjusted DINRPF concentrations exceeding the 95th percentile values were higher for the amount of each foodstuff ingested on the survey day (areas under the curve were 0.62 and 0.75, respectively) than for the exposure-related behaviors (0.60 and 0.71, respectively) or for mothers' attitudes toward food selection and preparation (0.54 and 0.57, respectively). Use of a mosquito coil, insect repellent, and mothproof net for a screen door, and playing on a lawn were associated with increased urinary NEO levels (odds ratio [OR]: 2.0-2.9), while care about the child's nutritional balance by mothers reduced urinary NEO levels (OR: 0.23-0.41). To the best of our knowledge, this is the first study that dealt with urinary concentrations and possible exposure sources of NEOs in a large number of young children. Attention to the children's behavior and diet might result in the reduction of a high exposure to NEOs in young children.

Direct Assessment of Single-Cell DNA Using Crudely Purified Live Cells: A Proof of Concept for Noninvasive Prenatal Definitive Diagnosis.

Noninvasive testing techniques are often used for fetal diagnosis of genetic abnormalities but are limited by certain characteristics, including noninformative results. Thus, novel methods of noninvasive definitive diagnosis of fetal genetic abnormalities are needed. The aim of this study was to develop a single-cell DNA analysis method with high sensitivity and specificity that enables direct extraction of genetic information from live fetal cells in a crude mixture for simultaneous evaluation. Genomic DNA from circulating fetal CD45-CD14- cells, an extremely rare cell type, extracted from 10-mL samples of maternal peripheral blood, was extracted using a single-cell-based droplet digital (sc-dd) PCR system with a modified amount of polymerase. A hexachloro-6-carboxyfluorescein-labeled RPP30 probe was used as an internal control and a 6-carboxyfluorescein-labeled SRY probe as a target. The results indicated that no droplets generated with samples from pregnant women carrying female fetuses were positive for both probe signals, whereas droplets prepared with samples from pregnant women carrying male fetuses were positive for both probe signals. The latter was considered a direct assessment of genetic information from single circulating male fetal cells. Thus, the modified sc-ddPCR system allows the detection of genetic information from rare target cells in a crudely purified cell population. This research also serves as a proof of concept for noninvasive prenatal definitive diagnosis.

Cohort profile: Aichi regional sub-cohort of the Japan Environment and Children's Study (JECS-A).

PURPOSE: Effects of fetal, perinatal and childhood environment on the health of children at birth and during later life have become a topic of concern. The Aichi regional sub-cohort of the Japan Environment and Children's Study (JECS-A) is an ongoing birth cohort of pregnant women and their children which has been used to provide unique data, as adjunct studies of JECS, on multifaceted potential factors affecting children's health. PARTICIPANTS: The JECS-A is part of the JECS which follows a total of 100 000 pairs of children and their mothers (fathers' participation is optional) across 15 regions in Japan. In JECS-A, of the 8134 pregnant women living in Ichinomiya City and Nagoya City, Japan, a total of 5721 pregnant women and their 5554 children were included. Sociodemographic and psychological data as well as biological specimens were collected from the pregnant women and their spouses (if available) in the cohort during their pregnancy. Information on children included in the JECS-A was collected from their mothers and includes demographic, behavioural, childcare, psychological and psychiatric data. Urine extracted from disposable diapers and anthropometric data were also obtained from the children. FINDINGS TO DATE: A similar distribution trend for age at delivery was confirmed between the pregnant women enrolled in the JECS-A and the national statistics of the relevant areas. However, differences in education level and household income were observed. A total of 5502 children remained in the cohort at 18 months after delivery. Compared with the national statistics, the basic demographics of the children in the cohort represented the population in the study areas. FUTURE PLANS: The enrolled children in the JECS-A will be followed until the age of 13 years. The studies that come from JECS-A will complement JECS and bring novel results with a high level of generalisability.

Can income-based co-payment rates improve disparity? The case of the choice between brand-name and generic drugs.

BACKGROUND: Higher income population tend to prefer brand-name to generic drugs, which may cause disparity in access to brand-name drugs among income groups. A potential policy that can resolve such disparity is imposing a greater co-payment rate on high-income enrollees. However, the effects of such policy are unknown. We examined how patients' choice between brand-name and generic drugs are affected by the unique income-based co-payment rates in Japan; 10% for general enrollees and 30% for those with high income among the elderly aged 75 and over. METHODS: We drew on cross-sectional price variation among commonly prescribed 311 drugs using health insurance claims data from a large prefecture in Japan between October 2013 and September 2014 to identify between-income-group differences in responses to differentiated payments. RESULTS: Running 311 multivariate logistic regression models controlling individual demographics, the median estimate indicated that high-income group was 3% (odds ratio = 0.97) less likely to choose a generic drug than the general-income group and the interquartile estimates ranged 0.92-1.02. The multivariate feasible generalized least squares model indicated high-income group's higher likelihood to choose brand-name drugs than the general-income group without co-payment rate differentiation (p < 0.001). Such gap in the likelihood was attenuated by 0.4% (p = 0.027) with an US$1 increase in the difference in additional payment/month for brand-name drugs between income groups - no gap with US$10 additional payment/month. This attenuation was observed in drugs for chronic diseases only, not for acute diseases. CONCLUSIONS: Income-based co-payment rates appeared to reduce disparity in access to brand-name drugs across income groups, in addition to reducing total medical expenditure among high-income group who shifted from brand-name drugs to generic ones due to larger drug price differences.

Novel Method for Rapid Assessment of Cognitive Impairment Using High-Performance Eye-Tracking Technology.

A rapid increase in the number of patients with dementia has emerged as a global health challenge. Accumulating evidence suggests that early diagnosis and timely intervention can delay cognitive decline. The diagnosis of dementia is commonly performed using neuropsychological tests, such as the Mini-Mental State Examination (MMSE), administered by trained examiners. While these traditional neuropsychological tests are valid and reliable, they are neither simple nor sufficiently short as routine screening tools for dementia. Here, we developed a brief cognitive assessment utilizing an eye-tracking technology. The subject views a series of short (178 s) task movies and pictures displayed on a monitor while their gaze points are recorded by the eye-tracking device, and the cognitive scores are determined from the gaze plots data. The cognitive scores were measured by both an eye tracking-based assessment and neuropsychological tests in 80 participants, including 27 cognitively healthy controls (HC), 26 patients with mild cognitive impairment (MCI), and 27 patients with dementia. The eye tracking-based cognitive scores correlated well with the scores from the neuropsychological tests, and they showed a good diagnostic performance in detecting patients with MCI and dementia. Rapid cognitive assessment using eye-tracking technology can enable quantitative scoring and the sensitive detection of cognitive impairment.

The Utility of Decision Trees in Oncofertility Care in Japan.

PURPOSE: To identify the utility and issues associated with the use of decision trees in oncofertility patient care in Japan. METHODS: A total of 35 women who had been diagnosed with cancer, but had not begun anticancer treatment, were enrolled. We applied the oncofertility decision tree for women published by Gardino et al. to counsel a consecutive series of women on fertility preservation (FP) options following cancer diagnosis. Percentage of women who decided to undergo oocyte retrieval for embryo cryopreservation and the expected live-birth rate for these patients were calculated using the following equation: expected live-birth rate = pregnancy rate at each age per embryo transfer × (1 - miscarriage rate) × No. of cryopreserved embryos. RESULTS: Oocyte retrieval was performed for 17 patients (48.6%; mean ± standard deviation [SD] age, 36.35 ± 3.82 years). The mean ± SD number of cryopreserved embryos was 5.29 ± 4.63. The expected live-birth rate was 0.66. CONCLUSIONS: The expected live-birth rate with FP indicated that one in three oncofertility patients would not expect to have a live birth following oocyte retrieval and embryo cryopreservation. While the decision trees were useful as decision-making tools for women contemplating FP, in the context of the current restrictions on oocyte donation and the extremely small number of adoptions in Japan, the remaining options for fertility after cancer are limited. In order for cancer survivors to feel secure in their decisions, the decision tree may need to be adapted simultaneously with improvements to the social environment, such as greater support for adoption.

Dual ring multilayer ionization chamber and theory-based correction technique for scanning proton therapy.

PURPOSE: To develop a multilayer ionization chamber (MLIC) and a correction technique that suppresses differences between the MLIC and water phantom measurements in order to achieve fast and accurate depth dose measurements in pencil beam scanning proton therapy. METHODS: The authors distinguish between a calibration procedure and an additional correction: 1-the calibration for variations in the air gap thickness and the electrometer gains is addressed without involving measurements in water; 2-the correction is addressed to suppress the difference between depth dose profiles in water and in the MLIC materials due to the nuclear interaction cross sections by a semiempirical model tuned by using measurements in water. In the correction technique, raw MLIC data are obtained for each energy layer and integrated after multiplying them by the correction factor because the correction factor depends on incident energy. The MLIC described here has been designed especially for pencil beam scanning proton therapy. This MLIC is called a dual ring multilayer ionization chamber (DRMLIC). The shape of the electrodes allows the DRMLIC to measure both the percentage depth dose (PDD) and integrated depth dose (IDD) because ionization electrons are collected from inner and outer air gaps independently. RESULTS: IDDs for which the beam energies were 71.6, 120.6, 159, 180.6, and 221.4 MeV were measured and compared with water phantom results. Furthermore, the measured PDDs along the central axis of the proton field with a nominal field size of 10 × 10 cm(2) were compared. The spread out Bragg peak was 20 cm for fields with a range of 30.6 and 3 cm for fields with a range of 6.9 cm. The IDDs measured with the DRMLIC using the correction technique were consistent with those that of the water phantom; except for the beam energy of 71.6 MeV, all of the points satisfied the 1% dose/1 mm distance to agreement criterion of the gamma index. The 71.6 MeV depth dose profile showed slight differences in the shallow region, but 94.5% of the points satisfied the 1%/1 mm criterion. The 90% ranges, defined at the 90% dose position in distal fall off, were in good agreement with those in the water phantom, and the range differences from the water phantom were less than ±0.3 mm. The PDDs measured with the DRMLIC were also consistent with those that of the water phantom; 97% of the points passed the 1%/1 mm criterion. CONCLUSIONS: It was demonstrated that the new correction technique suppresses the difference between the depth dose profiles obtained with the MLIC and those obtained from a water phantom, and a DRMLIC enabling fast measurements of both IDD and PDD was developed. The IDDs and PDDs measured with the DRMLIC and using the correction technique were in good agreement with those that of the water phantom, and it was concluded that the correction technique and DRMLIC are useful for depth dose profile measurements in pencil beam scanning proton therapy.

A review of hazardous chemical toxicity studies utilizing genetically-modified animals--their applications for risk assessment.

Studies on the mechanisms of chemical toxicity carried out using knockout mice lacking genes of enzymes for drug metabolism or nuclear receptor proteins were reviewed, and the studies were compared with the respective conventional mechanistic studies. While the toxicity of many hazardous chemicals was observed only in wild-type or knockout mice, which clearly showed that their toxicity was involved in the enzyme or receptor, some chemicals exhibited the same degree of toxicity in two genotypes, i.e., in both the wild strain and knockout mice, demonstrating that the enzymes or receptors are not involved in their toxicity. The use of genetically-modified animals presents not only the advantage of simultaneous evaluation of toxicity endpoints and mechanisms, but also suggests significant benefits over conventional methods using several chemicals to elucidate toxicity mechanisms. Elucidation of the mechanism of toxicity will provide useful information for risk assessment, and the use of genetically-modified animals for this purpose will lead to the advancement of this assessment.