Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Acute acalculous cholecystitis following extended administration of nirmatrelvir/ritonavir for persistent SARS-CoV-2 infection.

Immunocompromised patients with hematologic malignancies, particularly those treated with anti-CD20 antibodies such as rituximab and obinutuzumab, are known to be at risk of prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prolonged administration or combination therapy with antiviral medications reportedly yields favorable outcomes in these patients. However, knowledge regarding the adverse events associated with such therapeutic approaches is limited. Herein, we report a case of acute acalculous cholecystitis (AAC) following extended administration of nirmatrelvir/ritonavir (NMV/r) in a 68-year-old Japanese man with persistent SARS-CoV-2 infection. The patient had received obinutuzumab and bendamustine for follicular lymphoma and was diagnosed with coronavirus disease 2019 (COVID-19) approximately one year after treatment initiation with these drugs. Subsequently, he was admitted to a different hospital, where he received antiviral drugs, monoclonal antibodies, and steroids. Despite these interventions, the patient relapsed and was subsequently transferred to our hospital due to persistent SARS-CoV-2 infection. Remdesivir administration was ineffective, leading to the initiation of extended NMV/r therapy. One week later, he exhibited elevated gamma-glutamyl transpeptidase (GGT) levels, and one month later, he developed AAC. Cholecystitis was successfully resolved via percutaneous transhepatic gallbladder drainage and administration of antibiotics. We speculate that extended NMV/r administration, in addition to COVID-19, may have contributed to the elevated GGT and AAC. During treatment of persistent SARS-CoV-2 infection with extended NMV/r therapy, patients should be carefully monitored for the appearance of findings suggestive of biliary stasis and the development of AAC.

Angiopoietin-like 4 Is a Critical Regulator of Fibroblasts during Pulmonary Fibrosis Development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial pneumonia caused by the excessive production and deposition of extracellular matrix components, including type I collagen. Activated fibroblasts, called α-SMA (α-smooth muscle actin)-expressing myofibroblasts, are the major source of type I collagen in pulmonary fibrosis (PF), but the mechanisms underlying disease progression have not been fully elucidated. Here, we obtained lung fibroblasts from patients with IPF from both nonfibrotic and fibrotic areas as determined by a lung computed tomography scan and compared gene expression between these areas by DNA microarray. We found that ANGPTL4 (angiopoietin-like 4) was highly expressed only in fibroblasts from the fibrotic area. ANGPTL4 was selectively expressed in the fibroblastic area of IPF lungs, where the myofibroblast marker α-SMA was also expressed. ANGPTL4 also regulates the gene expression of fibrosis-related markers, cell migration, and proliferation. In addition, ANGPTL4 expression in a murine model of PF induced by treatment with bleomycin was significantly induced in the lungs from the acute to the chronic phase. Single-cell transcriptome analysis during the course of bleomycin-induced PF revealed that Angptl4 was predominantly expressed in the activated fibroblasts and myofibroblasts. Moreover, the administration of recombinant ANGPTL4 to the bleomycin-induced fibrosis model significantly increased collagen deposition and exacerbated the PF. In contrast, the pathogenesis of PF in Angptl4-deficient mice was improved. These results indicate that ANGPTL4 is critical for the progression of PF and might be an early diagnostic marker and therapeutic target for IPF.

Association Between Smoking and Hypertension in Pregnancy Among Japanese Women: A Meta-analysis of Birth Cohort Studies in the Japan Birth Cohort Consortium (JBiCC) and JECS.

BACKGROUND: Recent literature suggest the effect of maternal smoking on risk of hypertensive disorders in pregnancy (HDP) and preeclampsia may differ by ethnicity; however, studies on Asians are limited. METHODS: We investigated the association of maternal smoking with HDP and preeclampsia using a common analysis protocol to analyze the association in six birth cohorts participating in a Japanese consortium of birth cohorts (JBiCC). Results were compared with-published results from cohorts not included in this consortium, and, where possible, we produced a meta-analysis including these studies. RESULTS: Meta-analysis of four cohort studies including 28,219 participants produced an odds ratio (OR) of 1.24 (95% confidence interval [CI], 0.88-1.87) for the effect of smoking beyond early pregnancy compared to women who did not smoke during pregnancy. These results combined with those from the Japan Environment and Children's Study (JECS) yielded an OR of 1.19 (95% CI, 1.00-1.43, P = 0.056). Meta-analysis results for categories of smoking volume were insignificant, but when combined with JECS yielded an OR of 0.86 (95% CI, 0.65-1.12) for smoking 1-4 cigarettes, 1.25 (95% CI, 0.98-1.60) for smoking 5-9 cigarettes, and 1.27 (95% CI, 1.04-1.54) for smoking 10 or more cigarettes per day. All effects were insignificant for preeclampsia. CONCLUSION: Our results suggest that the protective effects of smoking longer and smoking more on HDP and preeclampsia repeatedly observed among Europeans and North Americans likely do not hold for the Japanese.

Sex differences in neurodevelopmental trajectories in children with different levels of autistic traits.

AIM: Little is known about early manifestations of autism spectrum disorders (ASD) in females, including those who may be overlooked by the current diagnostic criteria. We longitudinally explored sex differences in the trajectories of cognitive and motor functions and adaptive behaviors in children with different levels of autistic traits. METHODS: The participants were 824 children from the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), Japan, who were classified into three autistic trait groups-low, moderate, and high-based on the Social Responsiveness Scale-Second Edition. Cognitive and motor functions were measured at seven time-points from 0.5 to 3.5 years of age using the Mullen Scales of Early Learning. Adaptive behaviors were measured at five time-points from 2.7 to 9 years of age using the Vineland Adaptive Behavior Scales-Second Edition. Trajectories were depicted using latent growth curve modeling. RESULTS: Sex-specific trajectories were observed in the high-autistic-trait group, with only males showing a temporary decline in expressive language around the age of 2 years and a slight improvement thereafter. They also showed a slight improvement around 3 years in the adaptive behavior communication domain but a gradual downward trend later. Females in the high-autistic-trait group showed no distinct manifestation before the age of 3 years but showed a downward trend after 3.5 years in the adaptive behavior communication domain. CONCLUSION: Females and males with higher autistic traits than their same-sex peers, independent of clinical diagnosis, may have different phenotypes in certain neurodevelopmental domains during infancy and early childhood.

[A new method for measuring spinal kyphosis using CT images and a study of its relationship with reflux esophagitis].

[Purpose] This study aimed to examine the validity and reproducibility of a new quantitative method for measuring spinal kyphosis using computed tomography (CT), and to investigate its relationship with reflux esophagitis. [Method] Using a new method to measure the index of kyphosis in CT images (IKCT), 10 examiners evaluated 10 cases of spinal kyphosis. One examiner measured 47 cases twice and 20 cases were examined to assess the validity with the kyphosis index. A case-control study was conducted on 303 cases of reflux esophagitis, of which 241 were mild and 62 severe. [Results] Regarding IKCT reproducibility, the inter-rater intraclass correlation coefficient was 0.977. The intra-rater intraclass correlation coefficient was 0.974. The correlation index with the kyphosis index was 0.731. A greater IKCT value, not contracting serious atrophic gastritis, and severe hiatal hernia were identified as risk factors for severe reflux esophagitis. [Conclusion] IKCT is a simple and useful method for measuring kyphosis. The prevention of kyphosis can help suppress severe reflux esophagitis.

Early temperament as a predictor of language skills at 40 months.

BACKGROUND: Mastering language involves the development of expressive and receptive skills among children. While it has been speculated that early temperament plays a role in the acquisition of language, the actual mechanism has not yet been explored. We investigated whether temperament at 18 months predicted expressive or receptive language skills at 40 months. METHODS: A representative sample of 901 children and their mothers who were enrolled and followed-up longitudinally in the Hamamatsu Birth Cohort for Mothers and Children study was included in the analysis. Child temperament was measured at 18 months using the Japanese version of the Early Childhood Behavior Questionnaire. Expressive and receptive language skills were measured at 40 months using the Mullen Scales of Early Learning. RESULTS: The multiple regression analysis, adjusting for potential confounders, suggested that higher motor activation (fidgeting) at 18 months was associated with lower expressive and receptive language skills at 40 months. Higher perceptual sensitivity was associated with higher expressive and receptive language skills at 40 months. CONCLUSIONS: Specific temperament at 18 months of age predicted the development of the child's expressive and receptive language skills at 40 months.

Longitudinal association between smartphone ownership and depression among schoolchildren under COVID-19 pandemic.

Under the COVID-19 pandemic, concerns regarding prolonged screen time and mental health effects in children have increased. We examined the association of depression with smartphone ownership in school children at four time points: September 2019, July 2020, December 2020, and March 2021. The analysis revealed an interaction between group and time, indicating that depressive symptoms among smartphone owners were significantly more severe than in the other group. These results were clearer for fourth-year students, pointing that smartphone possession at younger ages may be a risk factor for mental health in the new lifestyle caused by the COVID-19 pandemic.

Elevated risk of attention deficit hyperactivity disorder (ADHD) in Japanese children with higher genetic susceptibility to ADHD with a birth weight under 2000 g.

BACKGROUND: Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. METHODS: We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as <2000 g, 2000-2499 g, and ≥2500 g. Polygenic risk score for ADHD was generated using the summary data of a large-scale genome-wide association study. The Rating Scale IV (ADHD-RS) assessed ADHD traits (inattention and hyperactivity/impulsivity) based on parental reports. Following previous studies, sex, birth order of the child, gestational age at birth, mother's age at delivery, educational attainment, pre-pregnancy body mass index, pre-pregnancy or during pregnancy smoking status, alcohol consumption during pregnancy, father's age, education, and annual family income were considered as covariates. Multivariable negative binomial regression was applied to evaluate the association between birth weight and ADHD traits, while adjusting for potential covariates. The interaction term between birth weight categories and binary polygenic risk was added to the model. RESULTS: Birth weight of 2000-2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight < 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07-2.27) and hyperactivity (RR 1.87, 95% CI 1.14-3.06). CONCLUSIONS: Birth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology.

Factors associated with viral clearance periods from patients with COVID-19: A retrospective observational cohort study.

INTRODUCTION: Knowledge is limited on the virologic course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, particularly the time taken for viral clearance and the optimal time to discontinue isolation. This study aims to identify the clinical and demographic factors influencing the time taken for viral clearance in patients with COVID-19 to determine the optimal isolation period. METHODS: This two-center retrospective observational cohort study was conducted between March 1 and June 31, 2020. Patients with COVID-19, which was confirmed by real-time reverse transcription polymerase chain reaction, were included. Data were extracted from medical records. The positive duration, which was defined as the period from the day of symptom onset to the negative conversion day, was assessed using a generalized linear model. RESULTS: We included 63 patients. The mean positive duration was 20 days. The positive duration was significantly shorter for patients younger than 30 years of age and those between 30 and 60 years of age than for patients older than 60 years of age. We observed a more scattered distribution of the positive duration in older patients than in younger patients. CONCLUSIONS: Younger patients who recovered from COVID-19 took less time to clear SARS-CoV-2 than older patients; thus, a classification of the isolation periods based on age could be considered. A uniform viral clearance period for older patients may be difficult to determine because of biases such as underlying medical conditions. Further surveillance measures are recommended to determine the viral clearance time and the optimal isolation period.

Spinal epidural abscess caused by non-typhoidal Salmonella: A case report and literature review.

Non-typhoidal Salmonellae are Gram negative bacilli commonly causing self-limiting gastroenteritis, representing a public health issue particularly in tropical countries. Further, the epidemiology of invasive infection by non-typhoidal Salmonella species is poorly understood. Herein, we presented a case of an unusual Salmonella enterica subsp. enterica serovar Altona epidural abscess that cause osteomyelitis and psoas abscess in a 52-year-old Japanese man. To ensure adequate antibiotics penetration into the epidural space, the patient was treated with antibiotics in doses similar to those administered for meningitis. We also reviewed the literature on patients who developed non-typhoidal Salmonella epidural abscesses, and we found 10 other previously reported cases. Salmonella Enteritidis was the pathogen most commonly identified, similar to gastroenteritis. More surveillance of non-typhoidal Salmonella serovars, especially in cases of severe infection, and investigation of antibiotic penetration rate into the epidural space are warranted to decide the best treatment course.

Neurodevelopmental Trajectory During Infancy and Diagnosis of Autism Spectrum Disorder as an Outcome at 32 Months of Age.

BACKGROUND: Little is known about the extent to which neurodevelopmental trajectories in infancy predict a later diagnosis of autism spectrum disorder (ASD). METHODS: We investigated the association between the neurodevelopmental trajectory classes identified using a latent class growth analysis and the distal clinical outcome. Participants included 952 infants from the Hamamatsu Birth Cohort for Mothers and Children (HBC study). Neurodevelopment was measured using the Mullen Scales of Early Learning, which contains five subscales (gross motor, fine motor, visual reception, receptive language, and expressive language), at seven time points from 1 to 24 months of age. ASD was diagnosed in 3.1% of the children at 32 months of age. The clinical outcome was included in our analysis model. RESULTS: Five neurodevelopmental classes were identified: high normal (11.5%), normal (49.2%), low normal (21.2%), delayed (14.1%), and markedly delayed (4.0%). The probability of a diagnosis of ASD in the markedly delayed class was highest (32.6%) when compared with the other classes. The probabilities of receiving a diagnosis of ASD in the delayed and low normal classes were 6.4% and 4.0%, respectively, whereas the probabilities in the normal and high normal classes were both 0%. CONCLUSIONS: A diagnosis of ASD may be predicted by the neurodevelopmental trajectories during infancy, which can be evaluated both routinely and objectively in clinical settings. In this representative population, children diagnosed with ASD showed early signs in neurodevelopmental domains during the first 2 years of life.

Reliability and validity of the Japan Ijime Scale and estimated prevalence of bullying among fourth through ninth graders: A large-scale school-based survey.

AIM: The present study aimed at developing a novel scale, the Japan Ijime Scale (JaIS), to measure bullying in Japan with substantial reliability and validity, with which we estimated the prevalence of bullying among children and adolescents of school age. METHODS: The JaIS is a self-report questionnaire and consists of three parts: subscales measuring victimization and witnessing, and an item measuring perpetration. To test the reliability and validity of the two subscales, the authors analyzed responses to the JaIS from 2334 school students (Grades 4-9) in six elementary and three junior high schools in a middle-sized industrial city in central Japan, using exploratory factor analysis, item response theory, and examination of the external validity of the items. The prevalence of bullying victimization, witnessing, and perpetration was estimated. RESULTS: Item response theory models revealed that both the Victimization and Witness subscales have sufficient discrimination power and measurement precision, and the external validity of each scale has been confirmed. Using the JaIS, we found that 35.8% of students had been victims of bullying every 2-3 months (27.6% were solely victims and 8.3% were bully/victims), 32.8% had witnessed some type of bullying act, and 11.8% had perpetrated some type of bullying (3.5% as perpetrators, and 8.3% as bully/victims). CONCLUSION: The JaIS is a reliable and valid measure. Using this scale, we found a high prevalence of bullying victimization in Japanese schools.

Prevalence of pathological and maladaptive Internet use and the association with depression and health-related quality of life in Japanese elementary and junior high school-aged children.

PURPOSE: Pathological Internet use has been predominantly studied in junior high/middle school-aged or older children; data from elementary/primary school-aged children, however, are scarce. The current study aimed to examine the prevalence of problematic Internet use, including pathological and maladaptive Internet use, in elementary and junior high school-aged children and the relationships between problematic Internet use and mental health problems and health-related quality of life. METHODS: The survey was conducted among children who attend national and public elementary and junior high schools in a medium-sized city in Japan; data were received from 3845 elementary school-aged and 4364 junior high school-aged children. RESULTS: Based on the Young's Diagnostic Questionnaire score, the prevalence of pathological and maladaptive Internet use was 3.6% and 9.4% and 7.1% and 15.8% in elementary and junior high school-aged children, respectively. The prevalence of problematic Internet use, including pathological and maladaptive Internet use, consistently increased from the 4th grade to the 8th grade. In addition, the prevalence sharply increased between the 7th grade and the 8th grade. Our study revealed that children with pathological and maladaptive Internet use exhibited more severe depression and decreased health-related quality of life than those with adaptive Internet use. CONCLUSIONS: Our results demonstrated that pathological Internet use is not uncommon even in elementary school-aged children and that those with pathological and maladaptive Internet use have severe mental health problems and decreased health-related quality of life, supporting the importance of providing these children with educational and preventive interventions against problematic Internet use and associated risk factors.

An immunohistochemical, enzymatic, and behavioral study of CD157/BST-1 as a neuroregulator.

BACKGROUND: Recent rodent and human studies provide evidence in support of the fact that CD157, well known as bone marrow stromal cell antigen-1 (BST-1) and a risk factor in Parkinson's disease, also meaningfully acts in the brain as a neuroregulator and affects social behaviors. It has been shown that social behaviors are impaired in CD157 knockout mice without severe motor dysfunction and that CD157/BST1 gene single nucleotide polymorphisms are associated with autism spectrum disorder in humans. However, it is still necessary to determine how this molecule contributes to the brain's physiological and pathophysiological functions. METHODS: To gain fresh insights about the relationship between the presence of CD157 in the brain and its enzymatic activity, and aberrant social behavior, CD157 knockout mice of various ages were tested. RESULTS: CD157 immunoreactivity colocalized with nestin-positive cells and elements in the ventricular zones in E17 embryos. Brain CD157 mRNA levels were high in neonates but low in adults. Weak but distinct immunoreactivity was detected in several areas in the adult brain, including the amygdala. CD157 has little or no base exchange activity, but some ADP-ribosyl cyclase activity, indicating that CD157 formed cyclic ADP-ribose but much less nicotinic acid adenine dinucleotide phosphate, with both mobilizing Ca2+ from intracellular Ca2+ pools. Social avoidance in CD157 knockout mice was rescued by a single intraperitoneal injection of oxytocin. CONCLUSIONS: CD157 may play a role in the embryonic and adult nervous systems. The functional features of CD157 can be explained in part through the production of cyclic ADP-ribose rather than nicotinic acid adenine dinucleotide phosphate. Further experiments are required to elucidate how the embryonic expression of CD157 in neural stem cells contributes to behaviors in adults or to psychiatric symptoms.

Development of a rating scale for maladaptive symptoms by maltreatment: Perspectives of attachment and dissociation.

Child abuse has been increasing in Japan. Abused children's behavior may often be confused with neurodevelopmental disorders; therefore, specialized tools to identify these cases and specific care for maltreatment are crucial. This study aimed to develop an objective early screening scale for abuse-related maladaptive symptoms. To do this, two surveys were conducted. Survey 1 included 60 children attending public elementary schools, who had been admitted to orphanages due to abuse (maltreated group), and 154 children attending public elementary schools with no reported maltreatment (control group). In this survey, 40 existing scale items related to attachment behavior and dissociative symptoms were evaluated. Childcare staff and homeroom teachers evaluated children's behaviors. Receiver operating characteristic (ROC) curves were drawn to determine optimal cut-off values. In Survey 2, 39 children in the maltreatment group and 186 children in the control group were subjected to confirmatory factor analysis to examine the new scale's reliability and validity. Based on the results of an exploratory factor analysis, a two-factor, 20-item rating scale for maladaptive symptoms due to maltreatment (RS-MSM) was developed. The receiver operating characteristic curve indicated that cutoff values set in Survey 1 were appropriate for screening the general population and children in the clinical range. The results confirmed a two-factor structure with high reliability and convergent validity in the Survey 2 sample. Therefore, the developed RS-MSM scale is valid and will allow for easy screening of maltreated children at school.

Interleukin-23 levels in umbilical cord blood are associated with neurodevelopmental trajectories in infancy.

Our previous study, which aimed to understand the early neurodevelopmental trajectories of children with and without neurodevelopmental disorders, identified five classes of early neurodevelopmental trajectories, categorized as high normal, normal, low normal, delayed, and markedly delayed. This investigation involved measurement using the Mullen Scale of Early Learning in a representative sample of Japanese infants followed up from the age of 0 to 2 years (Nishimura et al., 2016). In the present study, we investigated the potential association between cytokine concentrations in umbilical cord serum with any of the five classes of neurodevelopmental trajectories previously assigned, as follows: high normal (N = 85, 13.0%), normal (N = 322, 49.1%), low normal (N = 137, 20.9%), delayed (N = 87, 13.3%), and markedly delayed (N = 25, 3.8%) in infancy. Decreased interleukin (IL)-23 levels in the cord blood were associated with the markedly delayed class, independent of potential confounders (odds ratio, 0.44; 95%confidence interval: 0.26-0.73). Furthermore, IL-23 levels decreased as the developmental trajectory became more delayed, demonstrating that IL-23 plays an important role in development, and is useful for predicting the developmental trajectory at birth.

Fine Motor Skills, a Surrogate of Motor Planning Ability, at Age 2 Predict Social Skills at Age 6.

OBJECTIVES: Motor planning is the cognitive process of planning necessary steps for achieving a purposeful movement and is specifically reflected through object manipulation. This study aimed to investigate whether fine motor skills, a surrogate of the motor planning ability of object manipulation, in early childhood are associated with later social skills, in a general-population birth cohort. METHODS: A total of 913 children, participating in the Hamamatsu Birth Cohort for Mothers and Children, were enrolled. Social skills were measured using the Vineland Adaptive Behavior Scales-II, Socialization domain, at age 6 years. Fine motor skills were measured using the Mullen Scales of Early Learning at 14, 24, and 32 months. The associations between fine motor skills at ages 14, 24, and 32 months and social skills at age 6 years were tested separately through multivariable linear regression after adjusting for covariates, including gross motor and language skills at the contemporaneous age, autistic symptoms at age 6 years, and demographic factors. RESULTS: Fine motor skills at 24 and 32 months were significantly associated with social skills at age 6 years (at 24 months: nonstandardized regression coefficient = 1.38 [95% CI, 0.50-2.26], p = 0.002; at 32 months: 1.47 [0.56-2.38], p = 0.001). CONCLUSION: Fine motor skills in early childhood predicted social skills at age 6 years, indicating an association between the complex motor planning ability of object manipulation and later social skills. Children who demonstrate fine motor delay at as early an age as 2 years should be closely monitored by child professionals.

The Population-Attributable Fractions of Small-for-Gestational-Age Births: Results from the Japan Birth Cohort Consortium.

A fetal growth restriction is related to adverse child outcomes. We investigated risk ratios and population-attributable fractions (PAF) of small-for-gestational-age (SGA) infants in the Japanese population. Among 28,838 infants from five ongoing prospective birth cohort studies under the Japan Birth Cohort Consortium, two-stage individual-participant data meta-analyses were conducted to calculate risk ratios and PAFs for SGA in advanced maternal age, pre-pregnancy underweight, and smoking and alcohol consumption during pregnancy. Risk ratio was calculated using modified Poisson analyses with robust variance and PAF was calculated in each cohort, following common analyses protocols. Then, results from each cohort study were combined by meta-analyses using random-effects models to obtain the overall estimate for the Japanese population. In this meta-analysis, an increased risk (risk ratio, [95% confidence interval of SGA]) was significantly associated with pre-pregnancy underweight (1.72 [1.42-2.09]), gestational weight gain (1.95 [1.61-2.38]), and continued smoking during pregnancy (1.59 [1.01-2.50]). PAF of underweight, inadequate gestational weight gain, and continued smoking during pregnancy was 10.0% [4.6-15.1%], 31.4% [22.1-39.6%], and 3.2% [-4.8-10.5%], respectively. In conclusion, maternal weight status was a major contributor to SGA births in Japan. Improving maternal weight status should be prioritized to prevent fetal growth restriction.

Phase II study of pemetrexed and erlotinib in pretreated nonsquamous, non-small-cell lung cancer patients without an EGFR mutation.

BACKGROUND: Preclinical data indicated that the combination of erlotinib and pemetrexed is synergistic when erlotinib is administered after pemetrexed. PATIENTS AND METHODS: This was a phase II study of pemetrexed and erlotinib in patients with pretreated advanced non-squamous non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR). Chemotherapy consisted of pemetrexed (500 mg/m(2)) on day 1 and erlotinib (150 mg/body) on days 2-15 every 3 weeks. The protocol treatment was repeated until disease progression or intolerable toxicities occurred. RESULTS: Seventeen patients were enrolled between January 2010 and January 2013, and 15 patients were evaluable for both safety and efficacy. The study was terminated due to slow patient accrual. There was 1 complete response. There was a partial response in 3 patients, stable disease in 4 and progressive disease in 7. The response rate was 27% and disease control rate was 53%. The median progression-free survival and overall survival were 2.5 months and 6.7 months, respectively. CONCLUSIONS: Statistical interpretation could not been made due to the early termination of the study. Further studies are needed to clarify the efficacy of this regimen in NSCLC patients without EGFR mutation (UMIN-CTR No. 0000024531).