Bi-allelic variants in INTS11 are associated with a complex neurological disorder.

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.

Early childhood development and its association with maternal parity.

BACKGROUND: Maternal parity, which is usually measured as the number of children born to a mother, has a substantial impact on the social and environmental factors around children and their development. This paper estimates the Early Childhood Development Index (ECDI) of 3- and 4-year-old children in Bangladesh and examines the relationship between maternal parity and early childhood development. METHODS: The study analysed nationally representative data from the Bangladesh Multiple Indicator Cluster Survey 2019. The dataset had 9453 children aged from 36 to 59 months. The ECDI was computed following the UNICEF's approach involving psychometric computation of four domains of development: physical, literacy-numeracy, learning and social-emotional. Since the dataset has a hierarchical structure, we used multilevel logistic regression. RESULTS: A quarter (25%) of the children were not on track in their early childhood development. Seventy-one percent were not developmentally on track in the literacy-numeracy domain, 27% were not in the social-emotional and smaller percentages were not in learning (9%) and physical (1%) domains. There was a significant negative association between maternal parity and ECDI (adjusted odds ratio [AOR] 0.95; 95% CI: 0.91-0.99). Attendance at early childhood education programmes was significantly associated with early childhood development (AOR 1.73; 95% CI: 1.47-2.03). Also, female children, those who were not stunted, located in rural areas, received parental stimulation activities, lived in relatively wealthy households or had mothers who had received secondary or further education were more likely than others to be on track of early childhood development. CONCLUSIONS: Early childhood development is negatively correlated with maternal parity. The literacy-numeracy domain constitutes the major developmental delay. Programmes for parental awareness should be widely expanded.

A New Perspective of Attention Deficit Hyperactivity Disorder Associated With Delayed Language Development: An Egyptian Sample.

OBJECTIVE: The current study aimed to get an easy objective method to detect attention deficit hyperactivity disorder (ADHD) by investigating the simple inflammatory blood ratios platelet/lymphocyte ratio (PRL), neutrophil/lymphocyte ratio (NLR) & the monocyte/lymphocyte ratio (MLR), for the sake of receiving early management to such cases and overcoming language affection as a comorbid symptom. METHODS: This study was conducted on two groups: Group 1 (SG) consisted of 70 ADHD children who had delayed language development (DLD), freshly diagnosed, according to DSM-V criteria, and those patients were not on medical treatment. Group 2 healthy group (HG) consisted of 44 healthy control normal children that were both physically and mentally free of the same socio-demographic characters of the first group. RESULTS: The PLR, NLR and MLR, were significantly higher in the ADHD group than the healthy control group (HG) group, although the simple blood indices were average. CONCLUSION: Inflammation has a role as a comorbid cause of ADHD. Simple blood inflammatory mediators may be used as comorbid factors in ADHD. This study explained that the language abilities must be taken in consideration when assessing children with ADHD. The screening tools for inflammatory markers are important when dealing with ADHD children with/ without delayed language development (DLD). Also, working memory assessment is mandatory in ADHD with DLD to assign a special program in language therapy for each child.

Development of receptive vocabulary and verbal intelligence in Japanese children with unilateral hearing loss.

OBJECTIVE: In the past, it was believed that unilateral hearing loss has a minimal impact on the speech and language development in children. However, several studies have suggested that some school-age children with unilateral hearing loss have learning impairments in language. In the present study, we first examined whether preschool-age children with unilateral severe-to-profound hearing loss (UHL) have delays in the development of receptive vocabulary and verbal intelligence. In the follow-up study, we tested the children again after school admission. The objective of the present study was to reveal the development of receptive vocabulary and verbal intelligence from preschool to school years in children with UHL. METHODS: Fifteen Japanese preschool-age children with UHL and a control group of 20 age-matched Japanese children with bilateral normal hearing (NH), who were examined because articulation disorder was suspected, were enrolled in this study. The development of receptive vocabulary and verbal intelligence was evaluated using the Picture Vocabulary Test-Revised (PVT-R) and the Wechsler Intelligence Scale, respectively. The present retrospective study was approved by the Committee for Medical Ethics of Tokushima University Hospital (#3801). RESULTS: The scaled score (SS) of the PVT-R and verbal intelligence quotient (VIQ)/verbal comprehension index (VCI), but not performance intelligence quotient/perceptual reasoning index in children with UHL were significantly lower than those in the control children with NH at preschool-age. The SS of the PVT-R and VIQ/VCI in children with UHL significantly improved after school admission. In the subgroup analysis, the SS of the PVT-R in the lower receptive vocabulary group of children with UHL at preschool-age was significantly increased after school admission, but the SS in the normal and higher receptive vocabulary group of children with UHL at preschool-age were still around the standardized mean of SS after school admission. CONCLUSION: These findings suggest that the development of receptive vocabulary and verbal intelligence was delayed in preschool-age children with UHL and that most of them caught up to exhibit normal language ability after school admission.

Neonatal jaundice and developmental impairment among infants in Kilifi, Kenya.

BACKGROUND: Neonatal jaundice (NNJ) is common in sub-Saharan Africa (SSA), and it is associated with sepsis. Despite the high incidence, little has been documented about developmental impairments associated with NNJ in SSA. In particular, it is not clear if sepsis is associated with greater impairment following NNJ. METHODS: We followed up 169 participants aged 12 months (57 cases and 112 controls) within the Kilifi Health Demographic Surveillance System. The diagnosis of NNJ was based on clinical laboratory measurement of total serum bilirubin on admission, whereas the developmental outcomes were assessed using the Developmental Milestones Checklist and Kilifi Development Inventory. RESULTS: There were significant differences between the cases and controls in all developmental domains. Cases scored lower in language functioning (mean [M] = 6.5, standard deviation [SD] = 4.3 vs. M = 8.9, SD = 4.6; p < .001); psychomotor functioning (Mdn = 23, interquartile range [IQR] = 17-34 vs. Mdn = 31.0, IQR = 22.0-44.0; Mann-Whitney U = 4,122, p = .002); and socio-emotional functioning ([Mdn = 30.0, IQR = 27.0-33.0 vs. Mdn = 34.0, IQR = 30.0-37.0], Mann-Whitney U = 4,289, p < .001). There was no evidence of association between sepsis and psychomotor (rpb = -.2, p = .214), language (rpb = -.1, p = .510), and socio-emotional functioning (rpb = .0, p = .916). Significant and medium to large portions of the variance (34-64%) in the developmental outcomes among children who survived NNJ were associated with home birth, low maternal education, and feeding problems during the first days of life. CONCLUSIONS: NNJ is associated with developmental impairments in the early childhood years; however, NNJ associated with sepsis does not lead to more severe impairment. Prenatal and postnatal care services are needed to reduce the negative impact of NNJ for children from low resourced settings.

Decontextualized talk in caregivers' input to 12-month-old children during structured interaction.

Decontextualized talk is assumed to be used only rarely when children are younger than 30 months. Motivated by Bühler's (1934/1999) linguistic theory that describes different dimensions of (de-)contextualization, we provide evidence that this kind of input can already be found in caregivers' talking to their 12-month-old children. Such early input is characterized by being decontextualized on some dimensions while being grounded in the immediate context on others. In this way, parents may scaffold understanding of talk about the there-and-then. We also examined whether caregivers adapt decontextualized verbal input to individual trajectories in language development. We observed 59 parent-child interactions within a decorated room when children were 12 months old, and assessed the children's linguistic development at 12 and 24 months of age. However, we did not find differences in the input directed toward children with different trajectories in language development.

Hearing screening outcome in neonatal intensive care unit graduates from a tertiary care centre in Singapore.

BACKGROUND: We aimed to analyse the outcome of universal newborn hearing screening (UNHS) and high-risk hearing screening in neonatal intensive care unit (NICU) graduates in a tertiary care unit. METHODS: The hearing screen programme comprises a 2-stage automated auditory brainstem response protocol followed by a high-risk hearing screen at 3-6 months. This study is a retrospective study of NICU graduates born between April 2002 and December 2009. Data on hearing screening, audiological assessment, and management were extracted from a computerized data management system (HITRACK). RESULTS: Of 100,225 newborn infants, 2.9% were admitted to the NICU during the study period. The overall incidence of hearing loss (HL) of any type/severity was 35/1,000 infants. Of infants with HL, 92.4% had their first automated auditory brainstem response at/before 1 month of corrected age. The incidence of congenital permanent HL identified by the UNHS was 15.4/1,000. The corrected median age of diagnosis was 4.5 months (1-23.5 months). Of 2,552 NICU graduates who passed the UNHS, 75.5% were retested at 3-6 months of life. Twelve infants with permanent late-onset HL were identified, raising the overall incidence of permanent HL to 19.9/1,000; 1.1/1,000 had auditory neuropathy. Of the 92 infants with HL, 89 (96.7%) had multiple risk factors. CONCLUSIONS: There is a high incidence of HL in NICU graduates; 22.6% were late in onset. An early rescreen in those who pass the UNHS is a beneficial step for this high risk population.

Mild-moderate congenital hearing loss: secular trends in outcomes across four systems of detection.

BACKGROUND: Universal newborn hearing screening (UNHS) targets moderate or greater hearing loss. However, UNHS also frequently detects children with mild loss that results in many receiving early treatment. The benefits of this approach are not yet established. We aimed to (i) compare language and psychosocial outcomes between four hearing loss detection systems for children aged 5-8 years with congenital mild-moderate hearing loss; (ii) determine whether age of detection predicts outcomes; and (iii) compare outcomes between children identified via well-established UNHS and the general population. METHODS: Linear regression adjusted for potential confounding factors was used throughout. Via a quasi-experimental design, language and psychosocial outcomes were compared across four population-based Australian systems of hearing loss detection: opportunistic detection, born 1991-1993, n = 50; universal risk factor referral, born 2003-2005, n = 34; newly established UNHS, born 2003-2005, n = 41; and well-established UNHS, born 2007-2010, n = 21. In pooled analyses, we examined whether age of detection predicted outcomes. Outcomes were similarly compared between the current well-established UNHS system and typically developing children in the Early Language in Victoria Study, born 2003, n = 1217. RESULTS: Age at diagnosis and hearing aid fitting fell steadily across the four systems. For moderate losses, mean expressive language (P for trend .05) and receptive vocabulary (P for trend .06) improved across the four systems, but benefit was not obvious for mild losses. In pooled analyses, diagnosis before age six months predicted better language outcomes for moderate losses. Children with mild-moderate losses exposed to well-established UNHS continue to experience expressive language scores well below children in the general population (adjusted mean difference -8.9 points, 95% CI -14.7 to -3.1). CONCLUSIONS: Treatment arising from UNHS appears to be clearly benefitting children with moderate hearing losses. However, rigorous trials are needed to quantify benefits, versus costs and potential harms, of early aiding of children with mild losses.

Two-Step Screening of the Modified Checklist for Autism in Toddlers in Thai Children with Language Delay and Typically Developing Children.

This study aimed to validate the use of two-step Modified Checklist for Autism in Toddlers (M-CHAT) screening adapted for a Thai population. Our participants included both high-risk children with language delay (N = 109) and low-risk children with typical development (N = 732). Compared with the critical scoring criteria, the total scoring method (failing ≥3 items) yielded the highest sensitivity of 90.7 %; specificity was 99.7 %, positive predictive value 96.1 %, and negative predictive value 99.4 %. The two-step M-CHAT screening is a promising instrument that can be utilized to detect ASD in Thai children in both primary and clinical settings. Moreover, socio-cultural context should be considered when adopting the use and interpretation of the M-CHAT for each country.

The Semantic Associative Ability in Preschoolers with Different Language Onset Time.

Aim of the study is to verify the semantic associative abilities in children with different language onset times: early, typical, and delayed talkers. The study was conducted on the sample of 74 preschool children who performed a Perceptual Associative Task, in order to evaluate the ability to link concepts by four associative strategies (function, part/whole, contiguity, and superordinate strategies). The results evidenced that the children with delayed language onset performed significantly better than the children with early language production. No difference was found between typical and delayed language groups. Our results showed that the children with early language onset presented weakness in the flexibility of elaboration of the concepts. The typical and delayed language onset groups overlapped performance in the associative abilities. The time of language onset appeared to be a predictive factor in the use of semantic associative strategies; the early talkers might present a slow pattern of conceptual processing, whereas the typical and late talkers may have protective factors.

Neurodevelopment of preterm infants born after in vitro fertilization and spontaneous multiple pregnancy.

BACKGROUND: The aim of this study was to compare perinatal, neonatal characteristics and neurodevelopmental prognosis of preterm infants born after in vitro fertilization (IVF) and spontaneous multiple pregnancy, and to evaluate the factors affecting neurodevelopmental outcome at 24-36 months. METHODS: A total of 125 preterm infants, 65 from spontaneous and 60 from IVF multiple pregnancy were evaluated in terms of neurodevelopmental outcome at the age of 24-36 months. Mean maternal age, chronic maternal disease, birthweight, gestational week, gender, APGAR score, neonatal intensive care unit admission, presence of congenital anomalies, referral to follow up, rehospitalization and socioeconomic status were investigated. Gross Motor Function Classification System and Denver II Developmental Screening Test were carried out. Local ethics committee approved the study (12.10.2010; no: 305). RESULTS: Mean maternal age, chronic maternal illness, pregnancy-related diseases, 5 min APGAR score, rate of cesarean delivery and referral to follow up were significantly higher in the IVF group (P < 0.05). Neurological examination identified increased muscle tone in two children (1.6%); only one infant in the IVF group had cerebral palsy. A total of 26 subjects (20.8%; spontaneous group, n =17, 26.2%; IVF group, n = 9, 15%) had abnormal Denver II findings, mostly in language (8.8%) and personal-social (8.0%) development. CONCLUSION: Morbidity, length of hospitalization and neurodevelopmental outcome of preterm infants born after spontaneous and IVF multiple pregnancy are similar. Delays in language and personal-social development were the most common neurodevelopmental abnormalities. Even within similar socioeconomic status, parents in the IVF group were more compliant with follow up.

Factors affecting the appearance of 'twin language': An original language naturally developing within twin pairs.

OBJECTIVES: The appearance of 'twin language' has been highlighted as a reason for delayed language development in twins. 'Twin language' is a unique language understandable only within the pair, and not by their mother or others. The purpose of this study was to examine and clarify the factors affecting the appearance of 'twin language'. METHODS: A mailed questionnaires survey was conducted in 2733 mothers of twins. Of them, 1395 mothers returned the questionnaires. The core questionnaire asked for data on birth weight, age at first spoken word, whether the twins were as alike as two peas in a pod, household members and non-verbal play. Logistic regression analysis was used in this study. RESULTS: Out of the 1395 pairs included in this analysis, 598 pairs (42.9%) showed the appearance of a 'twin language'. When the 598 pairs were divided by whether the twin pair was exactly alike or not, there were 112 opposite sex pairs, 105 not-alike male pairs, 106 not-alike female pairs, 129 exactly alike male pairs and 140 exactly alike female pairs. Namely, 38.4% of the opposite sex pairs, 40.4% of the not-alike male pairs, 39.3% of the not-alike female pairs, 47.6% of the exactly alike male pairs and 48.4% in the exactly alike female pairs had a twin language. By multivariate logistic regression analysis controlling for twins' age, it was found that 'twin language' was significantly more frequent in exactly alike twin pairs, pairs with non-verbal play, and pairs with fewer older siblings. CONCLUSIONS: These findings suggest that three factors (whether the twin pair is exactly alike or not, older siblings, non-verbal play) affect the appearance of 'twin language'.