Arachidonic acid-derived dihydroxy fatty acids in neonatal cord blood relate symptoms of autism spectrum disorders and social adaptive functioning: Hamamatsu Birth Cohort for Mothers and Children (HBC Study).

AIM: Autism spectrum disorder (ASD) is associated with abnormal lipid metabolism, such as a high total ratio of omega-6 to omega-3 in polyunsaturated fatty acids (PUFAs). PUFAs are metabolized to epoxy fatty acids by cytochrome P450 (CYP); then, dihydroxy fatty acid is produced by soluble epoxide hydrolase. This study examined the association between PUFA metabolites in the cord blood and ASD symptoms and adaptive functioning in children. METHODS: This prospective cohort study utilized cord blood to quantify PUFA metabolites of the CYP pathway. The Autism Diagnostic Observation Schedule (ADOS-2) and Vineland Adaptive Behaviors Scales, Second Edition (VABS-II) were used to assess subsequent ASD symptoms and adaptive functioning in children at 6 years. The analysis included 200 children and their mothers. RESULTS: Arachidonic acid-derived diols, 11,12-diHETrE was found to impact ASD symptom severity on the ADOS-2-calibrated severity scores and impairment in the socialization domain as assessed by the VABS-II (P = 0.0003; P = 0.004, respectively). High levels of 11,12-diHETrE impact social affect in ASD symptoms (P = 0.002), while low levels of 8,9-diHETrE impact repetitive/restrictive behavior (P = 0.003). Notably, there was specificity in the association between diHETrE and ASD symptoms, especially in girls. CONCLUSION: These findings suggest that the dynamics of diHETrE during the fetal period is important in the developmental trajectory of children after birth. Given that the role of diol metabolites in neurodevelopment in vivo is completely uncharacterized, the results of this study provide important insight into the role of diHETrE and ASD pathophysiology.

Camouflaging in Autistic Adults is Modulated by Autistic and Neurotypical Characteristics of Interaction Partners.

Many autistic people reportedly engage in camouflaging to navigate everyday social interactions; however, the function of this behavior remains largely unknown. We hypothesized that autistic people camouflage more toward neurotypical others than toward autistic others, employing it as a strategy to "fit in" within the neurotypical-majority community. This study aimed to empirically investigate this hypothesis for the first time. Autistic and neurotypical participants took part in a web-based survey. Data from 48 autistic and 137 neurotypical participants were analyzed. Camouflaging toward autistic and neurotypical others was separately measured using the modified Camouflaging Autistic Traits Questionnaire (CAT-Q). For each CAT-Q item, a sentence describing a hypothetical interaction partner with autistic or neurotypical characteristics was added, creating respective sentence conditions. The interaction effect of the participants' characteristics and sentence conditions was analyzed using a multilevel regression analysis, accounting for differing individual baselines. The analysis revealed an interaction effect between participants' characteristics and sentence conditions. The autistic group showed significantly more camouflaging in the autistic sentence condition than in the neurotypical sentence condition. Conversely, the neurotypical group did not differ significantly in camouflaging levels in the sentence conditions. Contrary to our hypothesis, autistic people demonstrated more camouflaging toward autistic others than toward neurotypical others. This finding questions the assumption that autistic people camouflage to assimilate into a neurotypical-majority society. Instead, it could be conceptualized as a more general social strategy used by autistic people aiming to improve their relationships with others.

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.

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.

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.

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.

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.

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.

[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.

Adverse childhood experiences: impacts on adult mental health and social withdrawal.

Background: Adverse childhood experiences (ACEs) have been found to negatively impact adult mental health outcomes. Numerous studies have highlighted on ACEs in family and community settings. However, few have examined the impact of ACEs in school settings, despite the potential influence on social participation. Hikikomori, characterized by severe social withdrawal, was first studied in Japan and has gained recognition in recent years. The present study aims to present the concept of ACEs specific to schools and investigate the impact of both school ACEs and traditional ACEs on adult mental health and Hikikomori. Methods: A total of 4,000 Japanese adults, aged 20-34, were recruited through an Internet survey form. All data were obtained in October 2021. Participants answered questions regarding their ACEs in the family (10 items), school ACEs (five teacher-related items and two bullying-related items), depressive/anxiety symptoms, and Hikikomori (remaining at home for more than 6 months). Results: A significant association with depressive/anxiety symptoms was shown in both ACEs and school ACEs. An increase of one point in the ACE scores was associated with a 24% increase in the risk of depressive/anxiety symptoms. School ACE scores also demonstrated a significant association with depressive/anxiety symptoms, with an increase of one point associated with a 44% increase in the risk of these symptoms. As for Hikikomori, a significant association was shown in the school ACEs only: a 29% increased risk of Hikikomori for every one-point increase in school ACE scores. Both school ACE scores for teacher-related and bullying-related factors revealed a significant association with Hikikomori; the rates of increased risk were 23 and 37%, respectively. Conclusion: These results suggest that school ACEs, rather than ACEs in the family, are associated with the risk of Hikikomori. School ACEs are important for social adaptation, and reducing traumatic experiences in school settings may have the potential to prevent problems in later life, specifically in terms of social participation.

Time-course changes in mental distress and their predictors in response to the coronavirus disease 2019 (COVID-19) pandemic: A longitudinal multi-site study of hospital staff.

The coronavirus disease 2019 (COVID-19) pandemic provides a unique opportunity studying individual differences in the trajectory of mental distress to relatively homogeneous stressors by longitudinally examining time-course changes between pandemic waves. For 21 months, we tested the effects of COVID-19 waves on mental health among 545 staffs at 18 hospitals treating COVID-19 patients in Shizuoka Prefecture, Japan. Contrary to increasing new infected cases as waves progressed, initially elevated psychological distress (K6) and fear of COVID-19 (FCV-19S) were decreased among waves (K6: B = -.02, 95% confidence interval [CI] = -.03 to -.01; FCV-19S: B = -.10, 95% CI = -.16 to -.04). This initial increase and subsequent decrease in K6 and FCV-19S were more prominent in individuals with high trait anxiety (K6: B = 1.55, 95% CI = 1.18 to 1.91; FCV-19S: B = 4.27, 95% CI = 2.50 to 6.04) and in occupations other than physicians or nurses. The current study revealed time-course changes in psychological distress and fear regarding COVID-19 in each pandemic wave and across waves, and indicated the usefulness of trait anxiety and occupation as predictors of mental health outcomes.

Autism symptoms, functional impairments, and gaze fixation measured using an eye-tracker in 6-year-old children.

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder clinically characterized by abnormalities in eye contact during social exchanges. We aimed to clarify whether the amount of gaze fixation, measured at the age of 6 years using Gazefinder, which is an established eye-tracking device, is associated with ASD symptoms and functioning. Methods: The current study included 742 participants from the Hamamatsu Birth Cohort Study. Autistic symptoms were evaluated according to the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the functioning of the participating children in real life was assessed using the Japanese version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). The Gazefinder system was used for gaze fixation rates; two areas of interest (eyes and mouth) were defined in a talking movie clip, and eye gaze positions were calculated through corneal reflection techniques. Results: The participants had an average age of 6.06 ± 0.14 years (males: 384; 52%). According to ADOS, 617 (83%) children were assessed as having none/mild ASD and 51 (7%) as severe. The average VABS-II scores were approximately 100 (standard deviation = 12). A higher gaze fixation rate on the eyes was associated with a significantly lower likelihood of the child being assigned to the severe ADOS group after controlling for covariates (odds ratio [OR], 0.02; 95% confidence interval [CI], 0.002-0.38). The gaze fixation rate on the mouth was not associated with ASD symptoms. A higher gaze fixation rate on the mouth was associated with a significantly lower likelihood of the child being assigned to the low score group in VABS-II socialization after controlling for covariates (OR, 0.18; 95% CI, 0.04-0.85). The gaze fixation rate on the eyes was not associated with functioning. Conclusion: We found that children with low gaze fixation rates on the eyes were likely to have more ASD symptoms, and children with low gaze fixation rates on the mouth were likely to demonstrate poorer functioning in socialization. Hence, preschool children could be independently assessed in the general population for clinically relevant endophenotypes predictive of ASD symptoms and functional impairments.

Screen Time at Age 1 Year and Communication and Problem-Solving Developmental Delay at 2 and 4 Years.

Importance: Whether some domains of child development are specifically associated with screen time and whether the association continues with age remain unknown. Objective: To examine the association between screen time exposure among children aged 1 year and 5 domains of developmental delay (communication, gross motor, fine motor, problem-solving, and personal and social skills) at age 2 and 4 years. Design, Participants, and Setting: This cohort study was conducted under the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Pregnant women at 50 obstetric clinics and hospitals in the Miyagi and Iwate prefectures in Japan were recruited into the study between July 2013 and March 2017. The information was collected prospectively, and 7097 mother-child pairs were included in the analysis. Data analysis was performed on March 20, 2023. Exposure: Four categories of screen time exposure were identified for children aged 1 year (<1, 1 to <2, 2 to <4, or ≥4 h/d). Main Outcomes and Measures: Developmental delays in the 5 domains for children aged 2 and 4 years were assessed using the Japanese version of the Ages & Stages Questionnaires, Third Edition. Each domain ranged from 0 to 60 points. Developmental delay was defined if the total score for each domain was less than 2 SDs from its mean score. Results: Of the 7097 children in this study, 3674 were boys (51.8%) and 3423 were girls (48.2%). With regard to screen time exposure per day, 3440 children (48.5%) had less than 1 hour, 2095 (29.5%) had 1 to less than 2 hours, 1272 (17.9%) had 2 to less than 4 hours, and 290 (4.1%) had 4 or more hours. Children's screen time was associated with a higher risk of developmental delay at age 2 years in the communication (odds ratio [OR], 1.61 [95% CI, 1.23-2.10] for 1 to <2 h/d; 2.04 [1.52-2.74] for 2 to <4 h/d; 4.78 [3.24-7.06] for ≥4 vs <1 h/d), fine motor (1.74 [1.09-2.79] for ≥4 vs <1 h/d), problem-solving (1.40 [1.02-1.92] for 2 to <4 h/d; 2.67 [1.72-4.14] for ≥4 vs <1 h/d), and personal and social skills (2.10 [1.39-3.18] for ≥4 vs <1 h/d) domains. Regarding risk of developmental delay at age 4 years, associations were identified in the communication (OR, 1.64 [95% CI, 1.20-2.25] for 2 to <4 h/d; 2.68 [1.68-4.27] for ≥4 vs <1 h/d) and problem-solving (1.91 [1.17-3.14] for ≥4 vs <1 h/d) domains. Conclusions and Relevance: In this study, greater screen time for children aged 1 year was associated with developmental delays in communication and problem-solving at ages 2 and 4 years. These findings suggest that domains of developmental delay should be considered separately in future discussions on screen time and child development.

The association between screen time and genetic risks for neurodevelopmental disorders in children.

Whether longer screen time in infancy increases risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and ADHD has long been debated, but no causal relationship between the two remains has been established. Using ongoing longitudinal cohort data, we found that in children 24 to 40 months of age, the genetic risk of ASD was associated with longer screen time and that of ADHD with an increase in screen time over time. These data suggest that prolonged screen time may not be a cause of the genetic risk for NDD, but an early sign of NDDs.

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.

Interaction of genetic liability for attention deficit hyperactivity disorder (ADHD) and perinatal inflammation contributes to ADHD symptoms in children.

Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8-9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (ß [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (ß [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (ß [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (ß [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; ß [SE], 0.664[0.152]; P < 0.001 for the high-risk group). Conclusion: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8-9 with genetically higher risk for ADHD.

Chorioamnionitis and early pregnancy loss caused by ampicillin-resistant non-typeable Haemophilus influenzae.

Haemophilus influenzae can cause intra-amniotic infection and early pregnancy loss. The mode of transmission and risk factors for H. influenzae uterine cavity infections are unknown. Here, we present the case of chorioamnionitis caused by ampicillin-resistant H. influenzae in a 32-year-old Japanese woman at 16 weeks of gestation. Despite empirical treatment, including ampicillin, as recommended by the current guidelines, she had fetal loss. The antimicrobial regimen was changed to ceftriaxone, and the treatment was completed without complications. Although the prevalence and risk factors for chorioamnionitis caused by ampicillin-resistant H. influenzae are unknown, clinicians need to recognize H. influenzae as a potentially drug-resistant and lethal bacterium for pregnant women.

Socioeconomic and education-based inequality in suspected developmental delays among Nepalese children: a subnational level assessment.

Failure to meet early childhood developmental milestones leads to difficulty in schooling and social functioning. Evidence on the inequality in the burden of developmental delays across population groups, and identification of potential risk factors for suspected developmental delays (SDD) among younger children, are essential for designing appropriate policies and programs. This study explored the level of socioeconomic and maternal education-based inequality in the prevalence of SDD among Nepalese children at subnational level and identified potential risk factors. Individual-level data from the 2019 Nepal Multiple Indicator Cluster Survey was used to estimate the prevalence of SDD among children aged 3-4 years. Regression-based slope index of inequality (SII) and relative index of inequality were used to measure the magnitude of inequality, in terms of household socioeconomic status (SES) and mother's education, in the prevalence of SDD. In addition, a multilevel logistic regression model was used to identify potential risk factors for SDD. The national prevalence of SDD was found to be 34.8%, with relatively higher prevalence among children from rural areas (40.0%) and those from Karnali Province (45.0%) followed by Madhesh province (44.2%), and Sudhurpashchim Province (40.1%). The prevalence of SDD was 32 percentage points higher (SII: -0.32) among children from the poorest households compared to their rich counterparts at the national level. At the subnational level, such inequality was found to be highest in Lumbini Province (SII = -0.47) followed by Karnali Province (SII = -0.37), and Bagmati Province (SII = -0.37). The prevalence of SDD was 36 percentage points higher (SII: -0.36) among children whose mother had no formal education compared to children of higher educated mothers. The magnitude of education-based absolute inequality in SDD was highest in Lumbini Province (SII = -0.44). Multilevel logistic regression model identified lower levels of mother's education, disadvantaged SES and childhood stunting as significant risk factors for SDD. One in each three children in Nepal may experience SDD, with relatively higher prevalence among children from rural areas. Subnational level variation in prevalence, and socioeconomic and education-based inequality in SDD highlight the urgent need for province-specific tailored interventions to promote early childhood development in Nepal.