Hokkaido birth cohort study in Japan on the growth trajectory of children born with low birth weight until 7 years of age.

BACKGROUND: Low birth weight (LBW) is a significant global health concern with potential health risks and developmental implications for infants. Catch-up growth, an accelerated growth following an inhibition period, may partially compensate for growth deficits in LBW children. AIMS: This study investigated the prevalence of LBW and catch-up growth in height, weight, and body mass index (BMI) among LBW children in Japan, identified factors associated with LBW, and explored the potential for catch-up growth at different ages up to seven years. STUDY DESIGN AND SUBJECTS: The Hokkaido birth cohort study included 20,926 pregnant Japanese women recruited during their first trimester from 37 hospitals and clinics. Follow-up assessments were conducted in children up to seven years of age, tracking LBW children's growth and development using the Maternal and Child Health Handbook, and providing valuable insights into catch-up growth patterns. OUTCOME MEASURES: LBW was defined as a neonatal birth weight of <2500 g. The primary outcomes were catch-up growth in height, weight, and BMI at different ages. Z-scores were calculated to assess growth parameters with catch-up growth, defined as a change in z-score (> 0.67) between two time points. RESULTS AND CONCLUSIONS: A LBW was prevalent in 7.6 % of the cohort, which was lower than that reported in other Japanese studies. Among LBW children, 19.3 % achieved catch-up growth in height by age seven, and 10.6 % in weight. Catch-up growth in LBW children could partially offset these deficits. Further research will help understand the long-term outcomes and inform interventions for healthy development.

The association between prenatal per-and polyfluoroalkyl substance levels and Kawasaki disease among children of up to 4 years of age: A prospective birth cohort of the Japan Environment and Children's study.

Kawasaki disease (KD) is common among pediatric patients and is associated with an increased risk of later cardiovascular complications, though the precise pathophysiology of KD remains unknown. Per- and polyfluoroalkyl substances (PFAS) have gathered notoriety as the causal pathogens of numerous diseases as well as for their immunosuppressive effects. The present epidemiological study aims to assess whether PFAS may affect KD risk. We evaluated research participants included in the ongoing prospective nationwide birth cohort of the Japan Environment and Children's Study (JECS). Among the over 100,000 pregnant women enrolled in the JECS study, 28 types of PFAS were measured in pregnancy in a subset of participants (N = 25,040). The JECS followed their children born between 2011 and 2014 (n total infants = 25,256; n Kawasaki disease infants = 271), up to age four. Among the 28 types of PFAS, those which were detected in >60 % of participants at levels above the method reporting limit (MRL) were eligible for analyses. Multivariable logistic regressions were implemented on the seven eligible PFAS, adjusting for multiple comparison effects. Finally, we conducted Weighted Quantile Sum (WQS) and Bayesian kernel machine regression (BKMR) to assess the effects of the PFAS mixture on KD. Therefore, we ran the BKMR model using kernel mechanical regression equations to examine PFAS exposure and the outcomes of KD. Upon analysis, the adjusted multivariable regression results did not reach statistical significance for the seven eligible substances on KD, while odds ratios were all under 1.0. WQS regression was used to estimate the mixture effect of the seven eligible PFAS, revealing a negative correlation with KD incidence; similarly, BKMR implied an inverse association between the PFAS mixture effect and KD incidence. In conclusion, PFAS exposure was not associated with increased KD incidence.

Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children's Study.

BACKGROUND: The association between prenatal metal exposure and congenital anomalies is unclear. We aimed to examine the association between exposure to cadmium, lead, mercury, selenium, and manganese and physical abnormalities. METHODS: Data from 89,887 pregnant women with singleton pregnancies who participated in the Japan Environment and Children's Study (JECS) were used. The correlation between maternal blood metal concentrations and physical abnormalities during the second or third trimester was investigated using logistic regression models. Physical anomalies included those observed at birth or at 1 month, primarily from ICD-10 Chapter 17, particularly congenital anomalies associated with environmental factors (e.g., hypospadias, cryptorchidism, cleft lip and palate, digestive tract atresia, congenital heart disease, and chromosomal abnormalities) and minor abnormalities. RESULTS: After adjusting for covariates, the OR (95% CIs) of physical abnormalities for a one-unit rise in Mn concentrations in all individuals were 1.26 (1.08, 1.48). The OR (95% CIs) of physical abnormalities in the 4th quartile (≥18.7 ng/g) were 1.06 (1.01, 1.13) (p-value for the trend = 0.034) compared with those in the 1st quartile (≤12.5 ng/g). CONCLUSION: In Japan, maternal blood Mn concentrations above threshold during pregnancy may slightly increase the incidence of physical abnormalities. IMPACT: Physical abnormalities (including minor anomalies and congenital anomalies) are associated with prenatal manganese concentrations. They are not associated with cadmium, lead, mercury, and selenium concentrations.

Cross-sectional associations between early mobile device usage and problematic behaviors among school-aged children in the Hokkaido Study on Environment and Children's Health.

BACKGROUND: Concerns have been raised about the adverse health impacts of mobile device usage. The objective of this cross-sectional study was to examine the association between a child's age at the first use of a mobile device and the duration of use as well as associated behavioral problems among school-aged children. METHODS: This study focused on children aged 7-17 years participating in the Hokkaido Study on Environment and Children's Health. Between October 2020 and October 2021, the participants (n = 3,021) completed a mobile device use-related questionnaire and the strengths and difficulties questionnaire (SDQ). According to the SDQ score (normal or borderline/high), the outcome variable was behavioral problems. The independent variable was child's age at first use of a mobile device and the duration of use. Covariates included the child's age at the time of survey, sex, sleep problems, internet addiction, health-related quality of life, and history of developmental concerns assessed at health checkups. Logistic regression analysis was performed for all children; the analysis was stratified based on the elementary, junior high, and senior high school levels. RESULTS: According to the SDQ, children who were younger at their first use of a mobile device and used a mobile device for a longer duration represented more problematic behaviors. This association was more pronounced among elementary school children. Moreover, subscale SDQ analysis showed that hyperactivity, and peer and emotional problems among elementary school children, emotional problems among junior high school children, and conduct problems among senior high school children were related to early and long usage of mobile devices. CONCLUSIONS: Elementary school children are more sensitive to mobile device usage than older children, and early use of mobile devices may exacerbate emotional instability and oppositional behaviors in teenagers. Longitudinal follow-up studies are needed to clarify whether these problems disappear with age.

Prediction of Oral Drug Absorption in Rats from In Vitro Data.

PURPOSE: In drug discovery, rats are widely used for pharmacological and toxicological studies. We previously reported that a mechanism-based oral absorption model, the gastrointestinal unified theoretical framework (GUT framework), can appropriately predict the fraction of a dose absorbed (Fa) in humans and dogs. However, there are large species differences between humans and rats. The purpose of the present study was to evaluate the predictability of the GUT framework for rat Fa. METHOD: The Fa values of 20 model drugs (a total of 39 Fa data) were predicted in a bottom-up manner. Based on the literature survey, the bile acid concentration (Cbile) and the intestinal fluid volume were set to 15 mM and 4 mL/kg, respectively, five and two times higher than in humans. LogP, pKa, molecular weight, intrinsic solubility, bile micelle partition coefficients, and Caco-2 permeability were used as input data. RESULTS: The Fa values were appropriately predicted for highly soluble drugs (absolute average fold error (AAFE) = 1.65, 18 Fa data) and poorly soluble drugs (AAFE = 1.57, 21 Fa data). When the species difference in Cbile was ignored, Fa was over- and under-predicted for permeability and solubility limited cases, respectively. High Cbile in rats reduces the free fraction of drug molecules available for epithelial membrane permeation while increasing the solubility of poorly soluble drugs. CONCLUSION: The Fa values in rats were appropriately predicted by the GUT framework. This result would be of great help for a better understanding of species differences and model-informed preclinical formulation development.

Measurement of personal radio frequency exposure in Japan: The Hokkaido Study on the Environment and Children's health.

The opportunities for exposure to radiofrequency electromagnetic fields (RF-EMF) among children are increasing. Children's exposure to RF-EMF in Japan was recorded using a personal exposure meter (ExpoM-RF), and factors associated with the exposure examined. A total of 101 children, aged 10-15 years old, participated in the prospective birth cohort "Hokkaido study". RF-EMF data were recorded in the 700 MHz-5.8 GHz frequency range for 3 days. The recorded data were summarized into six groups of frequency bands: downlink from mobile phone base stations (DL), uplink from mobile phones to a base station (UL), Wireless Local Area Network (LAN), terrestrial digital TV broadcasting (digital TV), 2.5 GHz and 3.5 GHz Time Division Duplex (TDD), 1.9 GHz TDD, and total (the summation of power density in all measured frequency bands). A questionnaire was used to document the internet environment (at home) and mobile phone usage. Personal RF-EMF exposure in Japanese children was lower than that reported in studies in Europe. The DL signals from mobile phone base stations were the most significant contributors to total exposure, while Wireless LAN and digital TV were only higher at home. The urban residence was consistently associated with increases in the four groups of frequency bands (DL, UL, digital TV, and TDD). TDD level has several associations with mobile phone usage (calls using mobile phones, video viewing, text message service, and online game). The association between inattention/hyperactivity subscale of the Strengths and Difficulties Questionnaire (SDQ) and higher Wireless LAN exposure at nighttime was also noted. Further studies with additional data will shed light on factors involved in RF-EMF exposure among Japanese children.

Impact of prenatal exposure to mercury and selenium on neurodevelopmental delay in children in the Japan environment and Children's study using the ASQ-3 questionnaire: A prospective birth cohort.

Neurodevelopmental delay is associated with neurodevelopmental disorders. Prenatal metal exposure can potentially cause neurodevelopmental delays in children. This study examines whether prenatal exposure to mercury (Hg) and selenium (Se) is associated with the risk of neurodevelopmental delays in children up to 4 years of age. Children enrolled in a prospective birth cohort of the Japan Environment and Children's Study were examined. Hg and Se levels in maternal (nchild = 48,731) and cord (nchild = 3,083) blood were analyzed by inductively coupled plasma-mass spectrometry. Neurodevelopmental delays were assessed in children between the ages of 0.5 to 4 years using the Ages and Stages Questionnaires, Third Edition. The association between exposure and outcomes was examined using the generalized estimation equation models. In maternal blood, compared to participants with Se levels in the first quartile (83.0 to < 156 ng/g), the odds ratio (95 % confidence intervals) for problem-solving ability in children of mothers in the third (168 to < 181 ng/g) and fourth quartiles (181 to 976 ng/g) were 1.08 (1.01 to 1.14) and 1.10 (1.04 to 1.17), respectively. Furthermore, communication, gross and fine motor skills, and problem-solving delays were also observed. However, prenatal Hg levels in maternal and cord blood and Se levels in the latter were not associated with neurodevelopmental delays in children. Thus, the findings of this study suggest an association between Se levels in maternal blood and slightly increased risks of neurodevelopmental delays in children up to the age of 4 years.

Association between maternal caffeine intake during pregnancy and child development at 6 and 12 months: The Japan Environment and Children's Study.

BACKGROUND: Caffeine intake by pregnant women may have neurodevelopmental effects on the fetus due to adenosine antagonism. However, there are insufficient data and inconsistent results from epidemiological studies on the effect of maternal caffeine intake on child development. AIMS: This study examined the association between mothers' estimated caffeine intake during pregnancy and their children's score on the Japanese version of the Ages & Stages Questionnaires™ (J-ASQ) at 6 and 12 months of age. STUDY DESIGN: The study is a part of nationwide prospective birth-cohort study: the Japan Environment and Children's Study. SUBJECTS: In total, 87,106 participants with the Food Frequency Questionnaire (FFQ) data and J-ASQ at 6 or 12 months of age were included in the study. OUTCOME MEASURES: The data were analyzed by logistic regression analysis to determine whether the scores of the five subscales on the J-ASQ were below the cutoff point as the dependent variable. RESULTS: The results showed that children born to mothers who consumed >300 mg caffeine per day had a 1.11-fold increased odds of gross motor developmental delay at 12 months of age (adjusted odds ratio [AOR] = 1.114 [95 % CI: 1.013-1.226]). CONCLUSIONS: Issues in gross motor development can emerge prior to future developmental issues. Therefore, further studies on developmental outcomes in older children, including the future outcomes of the children who participated in this study, are needed.

Hypertensive Disorders during Pregnancy and Anthropometric Measurement of Children up to 7 Years of Age: The Hokkaido Birth Cohort Study in Japan.

Hypertensive disorders during pregnancy (HDP) increase the risk of offspring with a low birth weight, preterm birth and small-for-gestational age; however, evidence of the anthropometric measurements during early childhood remains limited. We aimed to understand the associations between maternal HDP and anthropometric measurements of children aged up to seven years in a Japanese cohort. In total, 20,926 mother-infant pairs participated in the Hokkaido Study on Environment and Children's Health, Japan, from 2002 to 2013. Medical reports were used to confirm HDP exposure, while weight, height, height z score, and weight z score were the outcomes. The prevalence of HDP in the study population was 1.7%. The birth height of male children born to HDP mothers was smaller as compared to those born to non-HDP mothers. When adjusted with covariates, the linear regressions showed significant changes in birth weight (ß: -79.3; 95% confidence interval [CI]: -154.8, -3.8), birth height (-0.67; 95% CI: -1.07, -0.26), weight at seven years (1.21; 95% CI: 0.13, 2.29), and weight gain between four and seven years (1.12; 95% CI: 0.28, 1.96) of male children exposed to HDP. Differences were more significant in male children than female. Our study showed that despite low birth weight, male children exposed to HDP caught up with their growth and gained more weight by seven years of age compared with male children not exposed to HDP, whereas no such differences were observed in female children; however, this finding requires replication.

Association between the Concentrations of Metallic Elements in Maternal Blood during Pregnancy and Prevalence of Abdominal Congenital Malformations: The Japan Environment and Children's Study.

Abdominal congenital malformations are responsible for early mortality, inadequate nutrient intake, and infant biological dysfunction. Exposure to metallic elements in utero is reported to be toxic and negatively impacts ontogeny. However, no prior study has sufficiently evaluated the effects of exposure to metallic elements in utero on abdominal congenital malformations. The aim of the present study was to evaluate associations between metallic elements detected in maternal blood during pregnancy and congenital abdominal malformations. Data from participants in the Japan Environment and Children's Study was used in the present study, and contained information on singleton and live birth infants without congenital abnormalities (control: n = 89,134) and abdominal malformations (case: n = 139). Heavy metals such as mercury (Hg), lead (Pb), cadmium (Cd), and trace elements of manganese (Mn) and selenium (Se) were detected in maternal serum samples during mid- and late-gestation. Infant congenital abnormalities were identified from delivery records at birth or one month after birth by medical doctors. In a multivariate analysis adjusted to account for potential confounders, quartiles of heavy metals and trace elements present in maternal blood were not statistically correlated to the prevalence of abdominal congenital malformations at birth. This study is the first to reveal the absence of significant associations between exposure levels to maternal heavy metals and trace elements in utero and the prevalence of abdominal congenital malformations in a large cohort of the Japanese population. Further studies are necessary to investigate the impact of exposure to heavy metals and trace elements via maternal blood in offspring after birth.

Hokkaido birth cohort study on environment and children's health: cohort profile 2021.

BACKGROUND: The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco. METHODS: The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures. RESULTS: The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies. CONCLUSIONS: Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.

Hypertensive Disorders during Pregnancy (HDP), Maternal Characteristics, and Birth Outcomes among Japanese Women: A Hokkaido Study.

Hypertension during pregnancy causes a greater risk of adverse birth outcomes worldwide; however, formal evidence of hypertensive disorders during pregnancy (HDP) in Japan is limited. We aimed to understand the association between maternal characteristics, HDP, and birth outcomes. In total, 18,833 mother-infant pairs were enrolled in the Hokkaido study on environment and children's health, Japan, from 2002 to 2013. Medical records were used to identify hypertensive disorders and birth outcomes, namely, small for gestational age (SGA), SGA at full term (term-SGA), preterm birth (PTB), and low birth weight (LBW). The prevalence of HDP was 1.9%. Similarly, the prevalence of SGA, term-SGA, PTB, and LBW were 7.1%, 6.3%, 7.4%, and 10.3%, respectively. The mothers with HDP had increased odds of giving birth to babies with SGA (2.13; 95% Confidence Interval (CI): 1.57, 2.88), PTB (3.48; 95%CI: 2.68, 4.50), LBW (3.57; 95%CI: 2.83, 4.51) than normotensive pregnancy. Elderly pregnancy, low and high body mass index, active and passive smoking exposure, and alcohol consumption were risk factors for different birth outcomes. Therefore, it is crucial for women of reproductive age and their families to be made aware of these risk factors through physician visits, health education, and various community-based health interventions.

Dioxotriazine derivatives as a new class of P2X3 receptor antagonists: Identification of a lead and initial SAR studies.

P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X3 IC50, 16.1 nM; P2X2/3 IC50, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED50, 3.1 mg/kg).

Mediating Factors Between Parental Socioeconomic Status and Small for Gestational Age in Infants: Results from the Hokkaido Study on Environment and Children's Health.

OBJECTIVES: Previous studies indicated a significant association between small for gestational age (SGA) in infants and their parents' socioeconomic status (SES). Thus, this study aimed to examine if parental factors, such as maternal smoking, and the pre-pregnancy body mass index (BMI) could mediate the associations between parental SES and SGA. METHODS: The participants of this study were pregnant women who enrolled in an ongoing birth cohort study, the Hokkaido study, during the first trimester of their pregnancies. A total of 14,593 live singleton births were included in the statistical analysis, of which 1011 (6.9%) were SGA. Two structural equation models were employed to evaluate the associations between parental SES, parental characteristics, and SGA. RESULTS: The effect of low SES on SGA was directly mediated by maternal pre-pregnancy BMI, smoking during the third trimester, and alcohol consumption during the first trimester in the first model, which was based the assumption of independent associations between mediating factors. In the second model, which additionally considered the mediating factors from the first model, smoking during pregnancy mediated decline in parental SES, consequently increased SGA. Moreover, an increase in pregnancy smoking status increased the prevalence of lower maternal pre-pregnancy BMI and its effect on SGA. CONCLUSIONS FOR PRACTICE: In this study, we observed the independent mediating effect of maternal pre-pregnancy BMI, smoking, and alcohol consumption during pregnancy on low SES and, consequently, SGA, with the additional mediating pathway of SES to smoking to low BMI on SGA.

Effects of Repeated 131I-Meta-Iodobenzylguanidine Radiotherapy on Tumor Size and Tumor Metabolic Activity in Patients with Metastatic Neuroendocrine Tumors.

131I-meta-iodobenzylguanidine (131I-MIBG) radiotherapy has shown some survival benefits in metastatic neuroendocrine tumors (NETs). European Association of Nuclear Medicine clinical guidelines for 131I-MIBG radiotherapy suggest a repeated treatment protocol, although none currently exists. The existing single-high-dose 131I-MIBG radiotherapy (444 MBq/kg) has been shown to have some benefits for patients with metastatic NETs. However, this protocol increases adverse effects and requires alternative therapeutic approaches. Therefore, the aim of this study was to evaluate the effects of repeated 131I-MIBG therapy on tumor size and tumor metabolic response in patients with metastatic NETs. Methods: Eleven patients with metastatic NETs (aged 49.2 ± 16.3 y) prospectively received repeated 5,550-MBq doses of 131I-MIBG therapy at 6-mo intervals. In total, 31 treatments were performed. The mean number of treatments was 2.8 ± 0.4, and the cumulative 131I-MIBG dose was 15,640.9 ± 2,245.1 MBq (286.01 MBq/kg). Tumor response was observed by CT and 18F-FDG PET or by 18F-FDG PET/CT before and 3-6 mo after the final 131I-MIBG treatment. Results: On the basis of the CT findings with RECIST, 3 patients showed a partial response and 6 patients showed stable disease. The remaining 2 patients showed progressive disease. Although there were 2 progressive-disease patients, analysis of all patients showed no increase in summed length diameter (median, 228.7 mm [interquartile range (IQR), 37.0-336.0 mm] to 171.0 mm [IQR, 38.0-270.0 mm]; P = 0.563). In tumor region-based analysis with partial-response and stable-disease patients (n = 9), 131I-MIBG therapy significantly reduced tumor diameter (79 lesions; median, 16 mm [IQR, 12-22 mm] to 11 mm [IQR, 6-16 mm]; P < 0.001). Among 5 patients with hypertension, there was a strong trend toward systolic blood pressure reduction (P = 0.058), and diastolic blood pressure was significantly reduced (P = 0.006). Conclusion: Eighty-two percent of metastatic NET patients effectively achieved inhibition of disease progression, with reduced tumor size and reduced metabolic activity, through repeated 131I-MIBG therapy. Therefore, this relatively short-term repeated 131I-MIBG treatment may have potential as one option in the therapeutic protocol for metastatic NETs. Larger prospective studies with control groups are warranted.

Exposure to Radiofrequency Electromagnetic Field in the High-Frequency Band and Cognitive Function in Children and Adolescents: A Literature Review.

With increasing use of mobile phones, exposure to radiofrequency electromagnetic field (RF-EMF) in the high-frequency band associated with mobile phones has become a public concern, with potentially adverse effects on cognitive function in children and adolescents. However, findings regarding the relation of RF-EMF and cognitive function in children and adolescents have been inconsistent due to a number of study design-related factors, such as types of exposure and outcome measures, age of participants, and the era of study conduction. The present literature review focused on these possible factors that could explain this inconsistency. This review identified 12 eligible studies (participants ages 4 to 17 years) and extracted a total 477 relations. In total, 86% of the extracted relations were not statistically significant; in the remaining 14%, a negative relation between RF-EMF and cognitive performance was detected under limited conditions: when (1) RF-EMF was assessed using objective measurement not subjective measurement (i.e., questionnaire), (2) participants were relatively older (12 years and above) and had greater opportunity of exposure to RF-EMF, and (3) the collection of cognitive function data was conducted after 2012. Given that 86% of the extracted relations in this analysis were not statistically significant, the interpretation should be approached with caution due to the possibility of the 14% of significant relationships, extracted in this review, representing chance findings.

Risk factors for motor coordination problems in preschool-age children.

BACKGROUND: Motor coordination problems (MCP) in children can sometimes be diagnosed as developmental coordination disorder. Early intervention for developmental coordination disorder is necessary because it often continues into adolescence, causing mental and physical complications. Few studies have investigated the prevalence of childhood MCP in the Japanese population, examining the risk factors for MCP. We therefore investigated the prenatal factors associated with MCP in preschool-age children. METHODS: This study was based on a prospective cohort study, the Hokkaido Study on Environment and Children's Health. Mothers of 4,851 children who reached the age of 5 years within the study-period received questionnaires, including the Japanese version of the Developmental Coordination Disorder Questionnaire (DCDQ-J). We examined the risk factors associated with MCP using logistic regression analysis. RESULTS: Of 3,402 returned DCDQ-J questionnaires, 3,369 were answered completely. From the 3,369 children, we categorized having MCP by using two cut-off scores: that of the DCDQ'07 and the cut-off at the 5th percentile of a total DCDQ-J score. Comparing children with and without MCP, we found significant differences in the education level of the mothers, annual household income during pregnancy, maternal alcohol consumption and smoking during pregnancy, and sex and age of the children at the time of completing the DCDQ-J by both categorizations. Adjusted logistic regression analysis revealed that maternal smoking during the first trimester of pregnancy and male sex were significantly associated with MCP. CONCLUSIONS: Our results suggest that maternal smoking during pregnancy is the main factor associated with MCP in preschool-age children.

The elucidation of key factors for oral absorption enhancement of nanocrystal formulations: In vitro-in vivo correlation of nanocrystals.

Nanocrystal formulation is a well-established approach for improving oral absorption of poorly water-soluble drugs. However, it is difficult to predict the in vivo performance of nanocrystal formulations from in vitro dissolution studies. The object of the present study was to investigate the in vitro-in vivo correlation of nanocrystal formulations of different particle sizes. A microsuspension and three nanosuspensions with different particle sizes for model drugs, fenofibrate and megestrol acetate, were prepared. In the comparison between the microsuspension and the nanosuspension having the smallest particle sizes, drug permeation rates from the nanosuspension were about 3-fold higher in the dissolution-permeation study. On the other hand, the solubility enhancement effect due to nanocrystal formation was only up by 1.4-fold, suggesting that nanocrystal formulations dramatically improved not the solubility but the apparent permeability. The oral absorption rate in rats increased with particle size reduction. There were positive and very strong correlations (R2 > 0.95) between the in vitro permeation rate and in vivo maximum absorption rate. We concluded that the enhanced permeability rate due to nanocrystal formation is the main factor for improving oral absorption, and the in vitro dissolution-permeation study could be useful for predicting oral absorption enhancement of nanocrystal formulations.

Prediction Characteristics of Oral Absorption Simulation Software Evaluated Using Structurally Diverse Low-Solubility Drugs.

The purpose of the present study was to characterize current biopharmaceutics modeling and simulation software regarding the prediction of the fraction of a dose absorbed (Fa) in humans. As commercial software products, GastroPlus™ and Simcyp® were used. In addition, the gastrointestinal unified theoretical framework, a simple and publicly accessible model, was used as a benchmark. The Fa prediction characteristics for a total of 96 clinical Fa data of 27 model drugs were systematically evaluated using the default settings of each software product. The molecular weight, dissociation constant, octanol-water partition coefficient, solubility in biorelevant media, dose, and particle size of model drugs were used as input data. Although the same input parameters were used, GastroPlus™, Simcyp®, and the gastrointestinal unified theoretical framework showed different Fa prediction characteristics depending on the rate-limiting steps of oral drug absorption. The results of the present study would be of great help for the overall progression of physiologically based absorption models.