Impaired Development Research Articles

Phytochemical composition and insecticidal activity of Acokanthera oblongifolia (Hochst.) Benth & Hook.f. ex B.D.Jacks. extract on life span and biological aspects of Spodoptera littoralis (Biosd.)

Abstract Plant extracts with insecticidal properties are promising alternatives to conventional insecticides, which may pose risks to human health and the environment in pest management. In the current study, the methanolic extract of Acokanthera oblongifolia (Hochst.) Benth & Hook.f. ex B.D.Jacks. was characterized using high-performance liquid and gas-mass spectrometry chromatography. High-performance liquid chromatography analysis identified 14 polyphenols, the highest of which is chlorogenic acid (65637.79 µg/g), followed by naringenin and pyrocatechol at 2022.98 and 1509.11 µg/g, respectively. However, quercetin, gallic acid, ferulic acid, rutin, and kaempferol showed moderate quantities. The gas chromatography–mass spectrometry analysis identified the major polysaccharide, inositol (15.52%), followed by squalene and triterpene (11.02%) out of 35 polysaccharides. The major fatty acids, 11-octadecenoic acid, methyl ester, and methyl 9-cis, 11-trans-octadecadienoate, were 9.06 and 6.30%, respectively. The crude extract and chlorfluazuron 5% EC at LC15 were evaluated for the life table and biological aspects of S. littoralis (Boisd.) neonates after 48 h under laboratory conditions compared to the control. The toxicity of the LC15 at 48 h of chlorfluazuron 5% EC (0.31 mg/L) excelled the extract (178.95 mg/L) on the neonates. Life span tests showed that the larval longevity of the extract and chlorfluazuron colonies were 27.34 and 30 days, respectively. The control colony completed its life span at 38.66 days, whereas the extract colony ended at the pupae stage at 33.67 days. Biological aspects showed that the tested compounds decreased pupation percentages and weight. Pupae malformations caused by the extract (80.56%) outperformed chlorfluazuron (33.33%). The adult emergency decreased by the extract (0.33%), and no emergency was observed in chlorfluazuron colony. Ultimately, A. oblongifolia extract demonstrated significant life table elongations and developmental impairment, which may suggest potential and eco-friendly use for its prospective commercial preparations in controlling S. littoralis alternatively to chlorfluazuron 5% EC.

Systematic Review of Obstetric and Child Outcomes of Prenatal Exposure to Inhalants in the Context of a Use Disorder.

Inhalants are often used for their psychoactive effects, producing feelings of euphoria. Inhalant and solvent use is a serious public health concern, yet little is known about their effects on perinatal, fetal, and child outcomes. The aim of our review is to evaluate the impact of inhalant use by pregnant people on maternal, fetal, neonatal, and early childhood outcomes. A systematic review was conducted on March 1, 2023, in 6 databases using relevant keywords. Bias assessment was performed using JBI Critical Appraisal Tools. Studies were included if they described a prenatal exposure to an inhalant; focused on maternal, fetal, neonatal, or early childhood outcomes; and were published as peer-reviewed reports in English. The search yielded 1101 unique references with 22 studies meeting eligibility criteria and representing 205 pregnancies and 171 infants.The most common symptom of inhalant use reported in pregnant people was altered mentation, followed by renal tubular acidosis (RTA) reported with toluene use. Most common fetal outcomes included fetal growth restriction and preterm delivery (<37 weeks), while neonatal outcomes were withdrawal symptoms, such as jitteriness, trouble feeding, and dystonia. Child outcomes included developmental delays, including cognitive and speech impairments, and postnatal growth restriction, including microcephaly. Perinatal, fetal, and child outcomes associated with inhalant use among pregnant individuals are largely based on case reports and series. Prospective studies are needed to better characterize these outcomes, reduce stigma, increase equitable access to treatment, and identify potential interventions to reduce use and potential harm.

Adolescents’ dietary patterns, their drivers and association with double burden of malnutrition in adolescents: a cross-sectional study in Kenya’s urban slums

BackgroundThe double burden of malnutrition (DBM) during adolescence is associated with growth and developmental impairment and risk of non-communicable diseases. There is limited evidence on adolescent’s dietary patterns (DPs), and how they contribute to DBM in urban low income contexts in sub Saharan Africa. This study assessed DPs of adolescents, their drivers and association with DBM in Kenya’s urban slums.MethodsAnthropometric, socio-demographic and dietary-intake data were collected through a cross-sectional survey of 621 adolescents from three major urban slums in Nairobi, Kenya. DPs were derived using principal component analysis. Multinomial-logistic-regression was used to assess the association between the DPs, individual and environmental factors and DBM.ResultsTwo DPs were identified: traditional DP (whole grains/cereals, rice, fruits, legumes/nuts, and water) and transitioning DP (refined cereals (maize/wheat), vegetables, meat, tea/coffee, sweet ultra-processed/deep fried snacks). Adolescents from Mathare (the largest slum) were more likely to adhere to the traditional DP (RRR = 3.43; 95% CI 1.85–6.37). Cultural background (Luo) had a positive association (RRR = 4.28; 95% CI 1.97–9.32), while longer residency in the slum (> 10 years) had a negative association (RRR = 0.47; 95% CI 0.25–0.90) with transitioning DP. The transitioning DP had a positive (non-linear) association with overweight/obesity in girls (RRR = 2.79; 95% CI 1.16–6.71). The DPs were not associated with thinness or stunting.ConclusionThe DPs indicate various stages of nutrition transition of adolescent diets, which are influenced by cultural background, neighbourhood and duration of stay in the slum. Transitioning DP may expose adolescents to the risks of overweight/obesity in the long-term.

Disperse Red 1 azo dye: Consequences of low-dose/low-concentration exposures in mice and zebrafish

Color Index Disperse Red 1 (DR1), an azo dye widely used in the textile industry and released into aquatic environments, is genotoxic in somatic cells, but little is known concerning its effects on the reproductive system or the early stages of embryonic development. We have assessed the effects on the spermatozoa of male mice following oral exposure to the dye, at low doses, for 14 days. Measured endpoints were DNA damage (comet assay), miRNA-34c levels, and sperm number, morphology, and motility. Exposure caused decreased miRNA-34c levels. We have also examined dye effects on zebrafish embryos and larvae, which included developmental impairment, altered glutathione transferase activity, and effects on reactive oxygen species and lipid peroxidation levels.

Language, Motor Ability and Related Deficits in Children at Familial Risk of Schizophrenia or Bipolar Disorder.

It is known that impairments in linguistic ability and motor function tend to co-occur in children, and that children from families with parental mental illness such as schizophrenia tend to perform poorly in both domains, but the exact nature of these links has not yet been fully elucidated. In this study, we leveraged the first wave of the Danish High Risk and Resilience Study (VIA 7), which includes both genetic data and measures covering multiple developmental domains. The VIA 7 cohort comprises 522 7-year-old children born to parents with schizophrenia (N = 202), bipolar disorder (N = 120) or neither (N = 200). We investigated the relationships between linguistic ability and motor function using correlation and regression analyses, focusing on developmental coordination disorder (DCD) and specific language impairment (SLI) and their potential associations with the three risk groups. We found significant correlations between most measures of language and motor function and significant associations of DCD and SLI with language and movement measures, respectively, the largest effect being that of DCD on receptive language, with a significant interaction effect: DCD was associated with poorer performance in children from schizophrenia families compared to bipolar disorder and control families. Both disorders showed higher prevalence among children with familial high risk of mental illness. We did not find significant evidence of genetic overlap between DCD and SLI. Our results suggest strong links between the domains of motor function and linguistic ability. Children of parents with schizophrenia are at high risk of comorbid language and movement disorders.

Associations between genotype, phenotype and behaviours measured by the Rett syndrome behaviour questionnaire in Rett syndrome

IntroductionRett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to describe the behavioural and emotional features of RTT. Little is known how RSBQ scores are associated with genetic and clinical characteristics in RTT. This study investigated relationships between genotype, age, walking, hand function, sleep, and RSBQ total and subscale scores in RTT.MethodsThis is a cross-sectional analysis of data collected in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database. Parent caregivers completed the RSBQ and Sleep Disturbance Scale for Children [subscales for disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence (DOES)], and provided information on age, variant type, functional abilities (mobility, hand function), seizure frequency and gastrointestinal problems. Associations between the RSBQ scores and the independent variables were modelled using linear regression.ResultsData were available for 365 individuals with RTT [median (range) age 17.8 (2.9–51.9) years, 2 males]. Compared to adults, 2- to 12-year-old children had higher mean Total, Night-time Behaviour and Fear/Anxiety scores. Compared to individuals with a C-terminal deletion, individuals with the p.Arg255* variant had higher mean Total and Night-time Behaviours scores, whereas the p.Arg294* variant had higher mean Mood scores. Individuals with intermediate mobility and hand function abilities had a higher mean Total score. Total RSBQ and subscale scores were similar across categories for seizures, constipation, and reflux, but were higher with abnormal DIMS and abnormal DOES scores.ConclusionExcept for associations with sleep, the RSBQ measures the behavioural phenotype rather than clinical severity in RTT, as traditionally conceptualised in terms of functional abilities and comorbidities. When designing clinical trials, the RSBQ needs to be complemented by other outcome measures to assess specific core functions and associated comorbidities in RTT.

Screen Time, Nature, and Development: Baseline of the Randomized Controlled Study "Screen-free till 3".

In the first years of life, increased screen media use is presumably associated with health consequences and developmental impairments. "Screen-free till 3" is a prospective Germany-wide randomized intervention study, started in May 2022 with a duration of 3 years. In the intervention group, 2581 pediatric practices received stickers, which were systematically placed in the screening booklet of all children, along with advice to parents to keep children free from screens until the age of 3. A volunteer sample of 17,436 parents received an invitation to take part in the preinterventional questionnaire. The outcomes were parents' internet use (CIUS test), parental screen time in the presence of children, time of screen media in the background, and children's development. Four thousand twenty-one parents answered the questionnaire. 16.7% of mothers and 31.0% of fathers reached the CIUS score of an internet-related disorder. Parents whose children use screen media at an early age had significantly higher CIUS values on average (M = 4.07) than the parents of children who do not yet have any screen time (p < 0.001). Combined developmental characteristics show a negative correlation with parental screen time (p < 0.001). Time spent in nature was positively associated with development (p < 0.001). The evaluation of the survey shows that screen media is to a large extent used on a daily basis. The study confirms the assumption that high screen media use by parents is linked to higher screen media use by children and also has a negative impact on child development. Trial Registration: Number: RKS00032258; https://drks.de/search/en/trial/DRKS00032258.

Toxicological Effects and Mechanisms of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) on Marine Organisms.

2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is a widely used brominated flame retardant belonging to persistent organic pollutants (POPs). After being released into the marine environment, BDE-47 can cause a range of toxic effects on marine organisms through bioaccumulation, biomagnification, and intergenerational transmission. These effects include lethality, impaired motility, photosynthetic toxicity, immune damage, liver toxicity, developmental impairments, and reproductive toxicity. This article reviews the latest research progress on the toxic effects and molecular mechanisms of BDE-47 mentioned above. The primary mechanisms underlying its toxicity include oxidative stress, DNA damage, cellular apoptosis, impaired metabolism, and activation of the MAPK signaling cascade.

Regression of microcephaly as a protective factor of neuropsychomotor development in fetal surgery for occipital encephalocele.

Encephaloceles are neural tube closure defects characterized by herniation of intracranial contents through the skull, with a mortality rate of 33.3%. Approximately 50% of patients who survived have some degree of neuropsychomotor developmental impairment or seizures. This study aimed to analyze the relationship between good neuropsychomotor development (NPMD) in patients undergoing fetal occipital encephalocele correction and the reversal of microcephaly, comparing these outcomes with those observed in patients who underwent postnatal surgery. The 22 participants were categorized into two groups: 10 in the fetal group (FG) and 12 in the postnatal group (PNG). During the study, 1 patient was excluded from the FG and 2 patients were excluded from the PNG, totaling 19 patients in the study. All patients were diagnosed, evaluated, and monitored by the same healthcare service between July 2012 and July 2018. All participants were subjected to a careful developmental assessment using the Bayley Scale of Infant Development, Second Edition (BSID-II), up to 2years and 11months of age. Additionally, CP measurements were taken during the first year of life to monitor their progress. The relationship between microcephaly reversal and NPMD was studied. The CP adjusted for gestational age showed a tendency toward the reversal of progressive microcephaly after correction of encephaloceles in the FG. We found a statistically significant difference in the median BSID-II score between the PNG and FG. Patients in the FG maintained normal CP development in the first year of life, whereas those in the PNG remained microcephalic. The reversal of microcephaly in the FG directly influences good NPMD and can be considered a protective factor.

Clinical, laboratory and neuroimaging profile of patient's cohort with septo-optic dysplasia treated at a pediatric university hospital

ObjectivesSepto-optic dysplasia (SOD) is a relatively rare clinical condition. However, there has been a significant increase in its incidence over the years. Diagnosis is clinical and made when there are at least 2 components of the classic triad: Optic nerve hypoplasia (ONH), midline malformation, and pituitary dysfunction. This study aims to describe the clinical and complementary exam characteristics of patients with SOD. MethodsA retrospective study of review of medical records of 48 patients cohort (24 female) with SOD followed to 2023. ResultsThe average age at diagnosis was 3.90 ± 3.85 years. Maternal age was ≤ 25 years at the time of delivery in 50% (24/48) of cases. Visual and developmental impairment was observed in 21 (43,7%) and nystagmus in 15 patients. Fourteen of them developed short stature. Regarding the diagnostic criteria for SOD: 92.6% (38/41) had ONH (78.9% bilaterally), 95.3% (41/43) had structural midline abnormalities, 85.7% (24/28) had hypothalamic-pituitary region alterations, and 73% had at least one hormonal deficiency, of which 2/3 had multiple pituitary dysfunctions. The most frequent deficiencies were thyroid-stimulating hormone and growth hormone, and the average age at diagnosis of the first dysfunction was 4.25 ± 3.71 years. ConclusionClinical manifestations that most led to early suspicion were developmental delay, nystagmus and visual impairment. More than 1/3 of the patients had the complete triad and 2/3 developed multiple pituitary deficiencies, with TSH deficiency being the most prevalent followed by GH deficiency. Patients with ONH or midline structural changes should undergo endocrine evaluation.

Mutagenicity of the agriculture pesticide chlorothalonil assessed by somatic mutation and recombination test in Drosophila melanogaster.

Chlorothalonil (CTL) is a pesticide widely used in Brazil, yet its mutagenic potential is not fully determined. Thus, we assessed the mutagenicity of CTL and its bioactivation metabolites using the somatic mutation and recombination test (SMART) in Drosophila melanogaster, by exposing individuals, with basal and high bioactivation capacities (standard and high bioactivation cross offspring, respectively), from third instar larval to early adult fly stages, to CTL-contaminated substrate (0.25, 1, 10 or 20 μM). This substrate served as food and as physical medium. Increased frequency of large single spots in standard cross flies' wings exposed to 0.25 μM indicates that, if CTL is genotoxic, it may affect Drosophila at early life stages. Since the total spot frequency did not change, CTL cannot be considered mutagenic in SMART. The same long-term exposure design was performed to test whether CTL induces oxidative imbalance in flies with basal (wild-type, WT) or high bioactivation (ORR strain) levels. CTL did not alter reactive oxygen species and antioxidant capacity against peroxyl radicals levels in adult flies. However, lipid peroxidation (LPO) levels were increased in WT male flies exposed to 1 μM CTL. SMART and LPO alterations were observed only in flies with basal bioactivation levels, pointing to direct CTL toxicity to DNA and lipids. Survival, emergence and locomotor behavior were not affected, indicating no bias due to lethality, developmental and behavioral impairment. We suggest that, if related to CTL exposure, DNA and lipid damages may be residual damage of earlier life stages of D. melanogaster.

Postnatal weight loss and neurodevelopmental outcomes at age 3 years in extremely preterm infants: a cohort study

BackgroundPrevious research has suggested a correlation between postnatal maximum weight loss (MWL) and both neonatal mortality and morbidities in extremely preterm infants. However, the relationship between MWL and neurodevelopmental outcomes remains underexplored.MethodsIn a single-center, retrospective cohort study at Okayama Medical Center, we evaluated data from extremely preterm infants admitted to the neonatal intensive care unit from 2010 to 2020. Infants who died within the first 10 days of life were excluded. MWL in the first 10 days was the main exposure, categorized into three groups: >15%, 5–15%, and < 5%. The primary outcome evaluated was the occurrence of death or neurodevelopmental impairment (NDI) at age 3 years, defined as developmental impairments (developmental quotient [DQ] < 85), cerebral palsy, hearing impairments, or visual impairments. Data analysis involved robust Poisson regression, adjusted for perinatal confounders, with a restricted cubic spline function to examine the dose-response relationship. We also conducted a sensitivity analysis using a DQ of < 70 to define developmental impairment.ResultsAmong 135 infants assessed for neurodevelopmental outcomes, 40 were in the > 15% MWL group, 71 in the 5–15% group, and 24 in the < 5% group. Median gestational ages and birth weights were 25.9 weeks and 821 g for > 15% MWL; 26.1 weeks and 818 g for 5–15% MWL; and 26.0 weeks and 734 g for < 5% MWL. Compared with the 5–15% MWL group, the < 5% group exhibited a higher risk of death or NDI at age 3 years (62.8% vs. 80.8%, risk ratio [RR] 1.36, 95% confidence interval [CI] 1.04–1.79) and NDI alone (59.2% vs. 79.2%, RR 1.43, 95% CI 1.06–1.94). Furthermore, higher risks of developmental impairment were also noted in the > 15% (RR 1.32, 95% CI 1.00–1.75) and < 5% (RR 1.46, 95% CI 1.08–1.98) groups. These associations were confirmed by spline analyses. In contrast, the associations between MWL and neurodevelopmental outcomes using a DQ of < 70 were not apparent.ConclusionsMWL within the first 10 days of life may be associated with increased risks of NDI and developmental impairments by age 3 years in extremely preterm infants.

T cell responses and clinical symptoms among infants with congenital cytomegalovirus infection.

BACKGROUNDCongenital cytomegalovirus (cCMV) infection can cause developmental impairment and sensorineural hearing loss (SNHL). To determine the relationship between immune responses to cCMV infection and neurologic sequelae, T cell responses were compared for their connection to clinical symptoms at birth and neurodevelopmental outcomes.METHODSThirty cCMV-infected and 15 uninfected infants were enrolled in a single-center prospective observational case-control study. T cell pp65-specific cytokine responses; CD57, CD28, and PD-1 expression; and memory subsets were compared.RESULTSInfected neonates (73% symptomatic at birth) lacked pp65-specific cytokine-secreting T cells, with elevated frequencies of CD57+, CD28-, and PD-1+CD8+ T cells and effector memory subsets. Though frequencies overlapped between cCMV symptom groups, asymptomatic infants had higher frequencies of CD57+PD-1+CD8+ T cells. Neonates with subsequent developmental delay lacked detectable CMV-specific T cell responses, with patterns resembling those of uninfected infants. Two children with progressive SNHL had high frequencies of PD-1+CD8+ T cells over the first year compared with children without progressive SNHL.CONCLUSIONSimilar to published reports, neonatal viral antigen-specific cytokine-secreting T cell responses were not detected, but overall patterns indicate that globally differentiated memory CD8+ T cell populations were induced by cCMV infection, with higher frequencies of terminally differentiated PD-1+CD8+ T cells potentially associated with asymptomatic infection. In this cohort, a lack of in utero T cell differentiation was associated with developmental delay, and high frequencies of PD-1+CD8+ T cells persisted only in children with progressive SNHL. Further work is needed to define the specificity of these T cells and their mechanistic connection to these outcomes.FUNDINGThis study was funded through an intramural research award at Nationwide Children's Hospital, the Pediatric Infectious Disease Society Fellowship Award funded by Stanley and Susan Plotkin and Sanofi Pasteur, the Abigail Wexner Research Institute at Nationwide Children's Hospital, and the Pichichero Family Foundation Vaccines for Children Initiative Research Award from the Pediatric Infectious Diseases Society Foundation.

EFFECTIVENESS OF CSR COMPANION COMMUNICATION RELATIONSHIP TOWARDS PROGRAM SUCCESS RATE (CASE STUDY ON CSR PROGRAM TO REDUCE STUNTING PT PLN INDONESIA POWER UBP JERANJANG WEST LOMBOK)

Stunting represents a developmental impairment in children resulting from malnutrition, recurrent infections, and inadequate psychosocial stimulation. Addressing this issue requires comprehensive strategies and concerted efforts. As part of the initiative to reduce stunting prevalence, PT PLN Indonesia Power UBP Jeranjang has implemented a Corporate Social Responsibility (CSR) program aimed at alleviating stunting through training and supplementary feeding (PMT), in collaboration with CSR facilitators from the company. Effective communication by these facilitators plays a crucial role in the program's success. Therefore, this study aims to investigate the existence of a positive and significant relationship between the effectiveness of CSR facilitator communication at PT PLN Indonesia Power UBP Jeranjang in West Lombok and the success of the CSR program in reducing stunting. The research adopts a quantitative approach. Data were gathered through questionnaire and document analysis. Data analysis employed Spearman Rank correlation and descriptive statistics. The findings indicate a significant positive correlation between CSR facilitator communication effectiveness and program success, with a significance level of 0.002 and a correlation coefficient of 0.383. Therefore, the null hypothesis (H0) is rejected and the alternative hypothesis (Ha) is accepted.

Deciphering Developmental Epileptic Encephalopathies (DEE): Unravelling the Key Signs

&lt;p&gt;&lt;strong&gt;Background:&lt;/strong&gt; Epilepsy, a chronic neurological disorder affecting over 50 million people worldwide, is marked by recurrent seizures and loss of consciousness. It is categorized based on EEG features, etiologies, and comorbidities. Developmental Encephalopathy (DE) involves developmental delays and early-onset seizures without causing developmental regression. In contrast, Epileptic Encephalopathy (EE) features severe epilepsy syndromes where frequent seizures result in developmental delays or regression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This review explores the clinical definitions, epidemiology, and diagnostic criteria for DE, EE, and DEEs. It covers their etiologies, clinical features, diagnostic methods, and treatment strategies, including genetic, structural, metabolic, and immune-related factors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; DE features developmental impairment with epilepsy, while EE involves severe epilepsy causing cognitive and behavioral dysfunction. DEEs are marked by early-onset severe epilepsy and EEG abnormalities that worsen developmental impairments. Essential diagnostic tools include EEG, neuroimaging, and genetic testing. Effective management requires personalized interventions to control seizures and address cognitive deficits.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; DEEs are a complex epilepsy subset with major developmental and cognitive challenges. Early diagnosis and targeted treatments are crucial for improving outcomes. Ongoing research into DEEs' genetic and pathophysiological mechanisms is key to enhancing understanding and management.&lt;/p&gt;

Patients carrying pathogenic SCN8A variants with loss‐ and gain‐of‐function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy

AbstractObjectivePhenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders.

Unveiling the disease progression in developmental and epileptic encephalopathies: Insights from EEG and neuropsychology.

Developmental and epileptic encephalopathies (DEEs) are neurological disorders characterized by developmental impairment and epilepsy. Our study aims to assess disease progression by comparing clinical findings, electroencephalography (EEG), and neuropsychological data from seizure onset to the last follow-up evaluation. We retrospectively reviewed patients with genetic DEEs who were followed-up at the epilepsy unit of Bambino Gesù Children's Hospital, Rome. We collected information regarding gender, family history, genetic variant, age at onset and at last follow-up, neurological examination, type of seizure, drug resistance, occurrence of status epilepticus, and movement and cognitive and behavioral disorders. We compared EEG background activity, epileptiform abnormalities, and cognitive functions between seizure onset and the last follow-up evaluation using the McNemar-Bowker test (α = 5%). A total of 160 patients (94 female) were included. Genetic analysis revealed a spectrum of pathogenic variants, with SCN1A being the most prevalent (25%). The median age at seizure onset and at the last follow-up was 0.37 (interquartile range [IQR]: 0.09-0.75) and 8.54 years (IQR: 4.32-14.55), respectively. We documented a statistically significant difference in EEG background activity (p = .017) and cognitive impairment (p = .01) from seizure onset to the last follow-up evaluation. No significant differences were detected for epileptiform abnormalities (p = .2). In addition, high prevalence rates were observed for drug resistance (81.9%), movement disorders (60.6%), behavioral and autism spectrum disorders (45%), neurological deficits (31.3%), and occurrence of status epilepticus (23.1%). Our study provides evidence that a clinical progression may appear in genetic DEEs, manifesting as development or worsening of cognitive impairment and disruption of EEG background activity. These results highlight the challenging clinical course and the importance of early intervention and personalized care in the management of patients with DEEs.

Elevated cerebral perfusion in neonatal encephalopathy is associated with neurodevelopmental impairments.

Neonatal encephalopathy (NE) represents a primary cause of neonatal death and neurodevelopmental impairments. In newborns with NE, cerebral hyperperfusion is related to an increased risk of severe adverse outcomes, but less is known about the link between perfusion and mild to moderate developmental impairments or developmental delay. Using arterial spin labelling perfusion MRI, we investigated the link between perfusion in 36 newborns with NE and developmental outcome at 2 years. 53% of the infants demonstrated a normal outcome at 24 months, while two had cerebral palsy with impairments in cognitive, motor, and language domains, and three infants died. The remaining infants showed mild or moderate delays in development in one or two domains. Hyperperfusion across the whole brain was associated with more adverse outcome, including an increased risk of death or severe disability such as cerebral palsy. Among the surviving infants, higher perfusion in the bilateral basal ganglia, thalamus, hippocampus and cerebellum during the neonatal period was related to a poorer cognitive outcome at 2 years. Hyperperfusion in infants with NE was associated with a more adverse outcome and lower cognitive outcome scores. In addition to severe adverse outcomes, altered perfusion is also related to mild to moderate impairment following HIE. Neonates with neonatal encephalopathy (NE) show increased cerebral perfusion globally, which is linked to a more adverse outcome. Higher perfusion in the bilateral basal ganglia, thalamus, hippocampus and cerebellum during the neonatal period was related to a poorer cognitive outcome at 2 years. In addition to severe adverse outcomes altered perfusion is related to mild to moderate impairment following NE. To improve neurodevelopmental outcomes, it is important to improve our understanding of the factors influencing cerebral perfusion in infants with NE.

Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development.

Neonatal Markers of Prematurity as Predictors of Permanent Childhood Hearing Loss and Neurodevelopmental Impairment in Children Admitted to the Neonatal Intensive Care Unit.

Need for admission to the neonatal intensive care unit (NICU) confers an increased risk of hearing loss in the newborn and of later neurodevelopmental impairment. In this retrospective longitudinal case-controlled study, we assess how the degree of prematurity, measured via gestational age, birth weight, and z-scores, in 138 infants admitted to the NICU are associated with permanent childhood hearing loss (PCHI) and 2-year developmental outcomes. Logistic regression analyses, Kruskal-Wallis analysis of variance, and Chi-squared tests were used. Independent of prematurity, PCHI and NICU admission were predictive of poor developmental outcomes. Twenty-one (47%) children with PCHI had a moderate-to-severe developmental delay, compared to three (7%) matched controls. Days in the NICU but not z-scores predicted PCHI. Z-score was not prognostic of moderate or severe developmental impairment in children with PCHI. The odds ratio of moderate-to-severe neurodevelopmental impairment with PCHI was high, at 12.48 [95% CI = 3.37-46.40]. Children with PCHI were significantly more likely to have cerebral palsy than their matched counterparts (30% vs. 2%). These findings challenge the conventional focus on gestational age and birth weight on neurodevelopmental outcomes for children with PCHI and NICU admission. A more nuanced approach to monitoring and intervention is needed.