Neurodevelopmental Disorders Research Articles

Four heterozygous de novo variants in ASXL3 identified with Bainbridge–Ropers syndrome and further dissecting published genotype–phenotype spectrum

Bainbridge–Ropers syndrome (BRPS) is a recently described neurodevelopmental genetic disorder associated with de novo truncating variants in additional sex combs like 3 (ASXL3) on chromosome 18q12.1. Trio-based exome sequencing was conducted on patients admitted to the Children’s Hospital Affiliated to Shandong University and diagnosed with unexplained intellectual disabilities or developmental delay between June 2022 and January 2024. De novo truncation of ASXL3 was identified in four patients, and the pathogenic variants and their de novo status were validated using Sanger sequencing. Comprehensive clinical phenotype–genotype information of all previously reported patients with BRPS was collected and summarized. The common clinical manifestations observed in the four patients included language and intellectual disabilities or psychomotor retardation. Genetic analysis revealed that patient 1 carried a de novo heterozygous variant, c.1667_1668del (p.Thr556Arpfs*3), whereas patient 2 had a novel heterozygous frameshift variant of ASXL3, c.3324del (p.Lys1109Serfs*34). These two variants have not been documented to date. Additionally, patients 3 and 4 exhibited a de novo variant, c.4678C > T (p.Arg1560Ter). Based on the combined assessment of clinical phenotypes and genetic testing results, it was postulated that all four children presented with BRPS syndrome caused by pathogenic variations in ASXL3. The present study complements the range of ASXL3 mutational and phenotypic spectra in the population, highlighting subtle distinctions in clinical manifestations between Chinese patients and other racial groups. The reporting of additional cases will contribute to further elucidating the function of ASXL3 and establishing a solid foundation for clinical diagnosis and treatment.

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder

AbstractEating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981–2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%–100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Exploring ADHD understanding and stigma: Insights from an online survey in Lebanon

Background Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder. Public knowledge of ADHD plays a crucial role in shaping attitudes, reducing stigma, and fostering a supportive environment for individuals with this disease. This study aimed to assess the level of knowledge and stigma of the general Lebanese population regarding ADHD and identify potential factors associated with these variables. Methods An online cross-sectional study was conducted between July and August 2023 among adults from all Lebanese regions. The questionnaire was self-administered, available in Arabic and English, and included a sociodemographic section and the validated tools Knowledge of Attention Deficit Disorders Scale (KADDS) and the ADHD Stigma Questionnaire (ASQ). Results A total of 647 participants were included. Most participants (n = 483 (74.7%)) lacked prior experience with individuals who have ADHD, and only 12.8% reported having good information about the condition. The participants had a mean knowledge score of 20.49 ±3.23 and a mean ADHD stigma score of 75.71 ±20.58. A significantly higher knowledge score was associated with a university level of education (B = 0.14, p < 0.001), older age (B = 0.14, p = 0.001), using the internet (B = 0.13, p = 0.001) and lecture (B = 0.09, p = 0.015) as a source of ADHD information, having a high monthly income (B = 0.13, p = 0.001), being female (B = 0.08, p = 0.030) and having a health coverage (B = 0.08, p = 0.025). Conversely, a lower knowledge was significantly associated with obtaining ADHD information from television (B = -0.13, p = 0.001) and family (B = -0.08, p = 0.043). A significantly lower score was associated with ever being diagnosed with ADHD (B = -0.18, p < 0.001), having an intermediate monthly income (B = -0.10, p = 0.005), and consuming alcohol (B = -0.11, p = 0.004), while a higher score was significantly associated with a higher KADDS total score (B = 0.12, p = 0.002) and being employed (B = 0.07, p = 0.044). Conclusion The present study addressed a gap in the existing literature by examining ADHD knowledge and stigma in the Lebanese population. Surprisingly, a positive correlation between higher ADHD knowledge and increased stigma challenges common assumptions, suggesting a complex relationship between knowledge, misconceptions, and societal attitudes. The findings emphasize the need for targeted education and advocacy to improve knowledge and alleviate misconceptions and stigma within the general population.

Safety and effectiveness of methylphenidate ER multi-unit pellet system in ADHD patients: An open label study

Background: Attention deficit hyperactive disorder (ADHD) is a neurodevelopmental disorder occurring in children and adults. Pharmacotherapy remains the cornerstone of ADHD treatment. Stimulants such as methylphenidate are effective and have been one of the best studied and most frequently used treatment for ADHD. However, different delivery mechanisms and devices may potentially impact patient experience and real-life outcomes.Aim: This study evaluated the effectiveness of Multiple-Unit Pellet System Delivered Extended-Release Methylphenidate (Contramyl XR) on symptom control and reported outcomes in ADHD patients, in a real-world setting.Setting: A phase IV, open label, flexible dose, prospective, observational study conducted at six sites covering five provinces of South Africa.Methods: About 119 participants with ADHD (both newly diagnosed [treatment-naïve] and methylphenidate-treated [switch-over] patients) were enrolled and initiated either on Contramyl XR or switched over from methylphenidate to Contramyl XR. Primary efficacy was assessed by Weiss Functional Impairment Rating Scale (WFIRS) over 12 weeks.Results: In all, 117 participants completed the study (treatment-naïve patients: 46% [n = 55] and switch-over patients: 54% [n = 64]). Mean change from baseline in total WFIRS (95% confidence interval) was –17.7 (–21.1, –14.3; p 0.001) at week 4 and –29.3 (–33.5, –25.2; p 0.001) at week 12. At week 12, there was significant improvement in WFIRS scores, with treatment satisfaction reported by treatment-naïve patients. Switch-over patients also demonstrated comparable effectiveness.Conclusion: Contramyl XR was found to be clinically effective either as de novo or as switch therapy. It was well tolerated, and all patients chose to continue with the treatment option.Contribution: Despite distinct and different delivery mechanism of Contramyl XR, this study provides evidence for using it as an alternate treatment option versus reference methylphenidate, in both treatment-naïve and switch-over ADHD patients. Study participants willingness to continue Contramyl XR therapy post study, further strengthens the confidence on the effectiveness of Contramyl XR in managing ADHD patients.

Ligand distances as key predictors of pathogenicity and function in NMDA receptors

Abstract Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by electrophysiological readouts that show whether they can enhance or reduce the function of the receptor. This includes new functional data from 33 variants reported here, for the first time. By mapping these variants onto the NMDAR protein structures, we found that pathogenic/benign variants and variants that increase/decrease the channel function were distributed unevenly on the protein structure, with spatial proximity to ligands bound to the agonist and antagonist binding sites being a key predictive feature for both variant pathogenicity and molecular functional consequences. Leveraging distances from ligands, we developed two machine-learning based predictors for NMDA variants: a pathogenicity predictor which outperforms currently available predictors and the first molecular function (increase/decrease) predictor. Our findings can have direct application to patient care by improving diagnostic yield for genetic neurodevelopmental disorders and by guiding personalized treatment informed by the knowledge of the molecular disease mechanism.

The Power of Delphi and Advocacy: Consensus in SCN8A-Related Epilepsy and Neurodevelopmental Disorders

[Box: see text]

A Vaccine Clinic for Individuals With Neurodevelopmental Disabilities

A Vaccine Clinic for Individuals With Neurodevelopmental Disabilities

Intravenous Dextrose for the Treatment of Neonatal Hypoglycaemia: A Systematic Review

Introduction: Hypoglycaemic neonates are usually admitted to neonatal intensive care for intravenous (IV) dextrose infusion if increased feeding and dextrose gel fail to restore normoglycaemia. However, the effectiveness of this intervention is uncertain. This review aimed to assess the evidence for the risks and benefits of IV dextrose for treatment of neonatal hypoglycaemia. Methods: Four databases and three clinical trial registries were searched from inception to October 5, 2023. Randomised controlled trials (RCTs), non-randomised studies of interventions, cohort studies, and before and after studies were considered for inclusion without language or publication date restrictions. Risk of bias was assessed using Cochrane’s Risk of Bias 2 tool or Risk of Bias in Non-Randomized Studies of Interventions tool. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. Meta-analysis was planned but not carried out due to insufficient data. Results: Across 6 studies (two RCTs and four cohort), 711 participants were included. Evidence from one cohort study suggests IV dextrose treatment may not be associated with neurodevelopmental impairment at ≥18 months of age (no effect numbers, p > 0.2; very low certainty evidence; 60 infants). Evidence from one RCT suggests IV dextrose treatment may reduce the likelihood of repeated hypoglycaemia (risk ratio [RR]: 0.67 [95% CI: 0.20, 2.18], p = 0.5; low certainty evidence; 80 infants) compared to treatment with oral sucrose bolus. However, the risk of a hyperglycaemic episode may be increased (RR: 2.33 [95% CI: 0.65, 8.39], p = 0.19; 80 infants). Conclusion: More evidence is needed to clarify the benefits and risks of IV dextrose for treatment of neonatal hypoglycaemia.

Emerging role of microglia in the developing dopaminergic system: perturbation by early life stress

Early life stress correlates with a higher prevalence of neurological disorders, including autism, attention-deficit/hyperactivity disorder, schizophrenia, depression, and Parkinson's disease. These conditions, primarily involving abnormal development and damage of the dopaminergic system, pose significant public health challenges. Microglia, as the primary immune cells in the brain, are crucial in regulating neuronal circuit development and survival. From the embryonic stage to adulthood, microglia exhibit stage-specific gene expression profiles, transcriptome characteristics, and functional phenotypes, enhancing the susceptibility to early life stress. However, the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood. This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia, leading to dopaminergic system disorders, along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions. Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support (e.g., insulin-like growth factor-1) and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning. Furthermore, blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission. Furthermore, inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons, inhibiting dopamine synthesis, reuptake, and receptor activity. Enhanced microglial phagocytosis inhibits dopamine axon extension. These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia. Indirectly, early life stress may influence microglial function through various pathways, such as astrocytic activation, the hypothalamic–pituitary–adrenal axis, the gut–brain axis, and maternal immune signaling. Finally, various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed. These strategies include classical antidepressants and antipsychotics, antibiotics and anti-inflammatory agents, and herbal-derived medicine. Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.

Mutations in mitochondrial ATAD3 gene and disease, lessons from in vivo models

Pathogenic variants in the ATAD3 gene cluster have been associated with different neurodevelopmental disorders showing clinical symptoms like global developmental delay, muscular hypotonia, cardiomyopathy, congenital cataracts, and cerebellar atrophy. ATAD3A encodes for a mitochondrial ATPase whose function is unclear and has been considered one of the five most common nuclear genes associated with mitochondrial diseases in childhood. However, the mechanism causing ATAD3-associated disorders is still unknown. In vivo models have been used to identify ATAD3 function. Here we summarize the features of mouse models with ATAD3 loss of function and Drosophila models overexpressing pathogenic ATAD3 variants. We discuss how these models have contributed to our understanding of ATAD3 function and the pathomechanism of the ATAD3-associated disease.

KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain

Heterozygous mutations in the histone lysine acetyltransferase geneKAT6B(MYST4/MORF/QKF) underlie neurodevelopmental disorders, but the mechanistic roles of KAT6B remain poorly understood. Here, we show that loss of KAT6B in embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, and neurite outgrowth. Mechanistically, loss of KAT6B resulted in reduced acetylation at histone H3 lysine 9 and reduced expression of key nervous system development genes in NSPCs and the developing cortex, including the SOX gene family, in particularSox2, which is a key driver of neural progenitor proliferation, multipotency and brain development. In the fetal cortex, KAT6B occupied theSox2locus. Loss of KAT6B caused a reduction inSox2promoter activity in NSPCs.Sox2overexpression partially rescued the proliferative defect ofKat6b−/−NSPCs. Collectively, these results elucidate molecular requirements for KAT6B in brain development and identify key KAT6B targets in neural precursor cells and the developing brain.

Abstract 4144597: Cardiovascular Health Among Youth with Neurodevelopmental Disability: Analysis of National Survey of Children's Health (NSCH) – 2021

Introduction: The National Survey of Children's Health (NSCH) provides data for key measures of child health and well-being. The aim of this study is to characterize the cardiovascular health (CVH) status of youth with neurodevelopmental disabilities (NDD) compared to those without neurodevelopmental disabilities (non-NDD). Hypothesis: Youth with NDD are more likely to have poor CVH status compared to non-NDD youth. Methods: We compared the odds of poor CVH status in youth with NDD vs non-NDD, using 2021 NSCH data, according to a modified AHA Life’s Essential 8 (LE8) scoring system. Participants were identified as having NDD based on the Diagnostic and Statistical Manual of Mental Disorders and diagnosis of an intellectual, communication, autism spectrum, attention-deficit/hyperactivity, specific learning, or neurodevelopmental motor disorder, including Tic disorder. The CVH status of each youth was scored according to a modified LE8 score- range 0 to 100 points, with higher scores indicating good health. Individual scores were generated for sleep (sleep duration), smoking (smoking/exposure), diabetes mellitus (yes/no), obesity (BMI percentile), heart condition (yes/no), and dyslipidemia (yes/no). A composite CVH score was generated using scores for sleep, smoking, diabetes mellitus, and obesity. Logistic regression was used to analyze the relationship between NDD and CVH status. Propensity score techniques were applied to address the potential selection bias between NDD and non-NDD. Results: 12,134 youth, 3 to 17 years of age, were identified as having NDD and 44,960 without. Compared to those with NDD, non-NDD participants were less likely to have age-inappropriate sleep duration (63.4 vs. 55.3, p <0.0001 ), smoking/exposure (94.5 vs. 90.7, p<0.0001 ), diabetes mellitus (95.2 vs. 90.2, p <0.0001 ), obesity (80.0 vs. 73.2, p <0.0001 ), a heart condition (95.4 vs. 93.8, p=0.021 ), or dyslipidemia (98.1 vs. 95, p<0.0001 ). Overall CVH status was (93.9 vs. 91.0, p<0.0001 ) among non-NDD vs NDD participants. NDD participants had a greater odds of having a heart condition (OR=1.91, 95% CI: 1.51-2.42) and poor CVH status (OR=1.53, 95% CI: 1.45-1.62). Propensity score matching showed similar results. Conclusions: Neurodevelopmental disability is associated with poorer CVH status in youth. Efforts to improve CVH status in youth should include greater focus on youth with NDD.

Hospital Dental Admissions and Caries Experience Among Children With Neurodevelopmental Disabilities: A Population‐Based Record Linkage Cohort Study

ABSTRACTBackgroundWithin Aotearoa | New Zealand, rates of largely preventable severe caries and dental hospitalisations among children are increasing and inequalities exist. However, little population‐based empirical evidence exists describing this oral health burden among children with neurodevelopmental disabilities (NDDs). This study aimed to estimate and compare the rates of dental hospital admissions in a near‐national population of children aged ≤ 14 years with attention‐deficit hyperactivity disorder, autism, intellectual disability or any NDD after accounting for key confounding variables. Caries status for these children was derived from an oral health screening at 4 years and also examined.MethodsThe cohort were children who had their B4 School Check (B4SC) national health screening assessment undertaken between 1 January 2011 and 31 December 2018 and followed until 1 January 2020 (the study end date). Linked administrative databases, which include NDD indication and dental hospital records, were utilised. Dental hospital admissions were assessed using unadjusted and adjusted Cox proportional hazard regression models treating NDD as a discrete time‐varying covariate. Caries status at 4 years of age was investigated cross‐sectionally and the area under the receiver operating characteristic curve used to assess predictive accuracy.ResultsThe eligible sample included 433 569 children (48.6% female) with a mean age of 9.3 years at the study end date. Overall, 16 359 (3.8%) children had at least one NDD indication and 38 574 (8.9%) had at least one dental hospitalisation. In adjusted analyses, the hazard ratio of dental hospitalisation admissions was 3.40 (95% CI: 3.22–3.60) for children indicated with any NDD compared to their non‐NDD counterparts. At 4 years of age B4SC screening, 465 (17.6%) children out of 2640 indicated with any NDD had visible caries compared to 61 026 (14.3%) from 427 254 children without NDD indication (prevalence ratio = 1.24 [95% CI: 1.14–1.35]). However, the area under the receiver operating characteristic curve for this association was 0.52 (95% CI: 0.51–0.52), suggesting negligible predictive capacity.ConclusionChildren with NDDs in Aotearoa, New Zealand suffer from substantial oral health inequities. Targeted preventive strategies and adaptation to primary oral health services are needed to meet the needs of neurodiverse children and redress this substantial inequity. However, targeting children with NDDs at the B4SC is unlikely to mitigate these oral health inequities.

Statistical analysis plan for the FiO2-C trial: effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcomes of extremely preterm infants—a randomized-controlled parallel group multicentre trial for safety and efficacy

Abstract Background Extremely low gestational age neonates (ELGANs, i.e. those born before 28 weeks postmenstrual age (PMA)) often require supplemental oxygen and frequently experience intermittent hypo- and hyperoxemic episodes. Exposure to episodes with inadequate oxygen concentrations has been shown to be associated with an increased risk of retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI) and death. Closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) reduces number and duration of hypo- and hyperoxemic episodes in ELGANs. Its impacts on clinically important short- and long-term outcomes such as ROP, BPD, NEC, NDI and mortality have not yet been studied. Methods An outcome-assessor-blinded, multicentre, randomized-controlled, parallel-group trial for superiority was designed to study the effects of FiO2-C (provided by standard infant ventilators) in addition to routine manual control (RMC) during respiratory support, compared to RMC only, on short- and long-term clinical outcomes in ELGANs. Two co-primary composite outcomes were defined: (i) death, severe ROP, BPD or NEC, assessed at 36 weeks PMA or, in case of ROP, until complete vascularization of the retina; (ii) death or NDI (defined as language/cognitive delay, motor impairment, severe visual impairment or hearing impairment), assessed at 2 years corrected age. Results Primary outcomes will be compared between the two intervention groups using a Cochran-Mantel-Haenszel test. The factors considered for randomization (centre, sex and gestational age at birth (< 26 weeks and ≥ 26 weeks)) will be used to define strata. Results will be presented as adjusted odds ratios with two-sided 95% and 97.5% confidence intervals and two-sided p values. Conclusions The statistical analyses for the FiO2-C trial were defined in the study protocol and specified in detail in this statistical analysis plan published prior to any statistical analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Trial registration ClinicalTrials.gov NCT03168516. Registered on May 30, 2017.

Genome-wide copy number variation association study in anorexia nervosa

AbstractThis study represents the first large-scale investigation of rare (<1% population frequency) copy number variants (CNVs) in anorexia nervosa (AN). Large, rare CNVs are reported to be causally associated with anthropometric traits, neurodevelopmental disorders, and schizophrenia, yet their role in the genetic basis of AN is unclear. Using genome-wide association study (GWAS) array data from the Anorexia Nervosa Genetics Initiative (ANGI), which included 7414 AN case and 5044 controls, we investigated the association of 67 well-established syndromic CNVs and 178 pleiotropic disease-risk dosage-sensitive CNVs with AN. To identify novel CNV regions (CNVRs) that increase the risk of AN, we conducted genome-wide association studies with a focus on rare CNV-breakpoints (CNV-GWAS). We found no net enrichment of rare CNVs, either deletions or duplications, in AN, and none of the well-established syndromic or pleiotropic CNVs had a significant association with AN status. However, the CNV-GWAS found 21 nominally associated CNVRs that contribute to AN risk, covering protein-coding genes implicated in synaptic function, metabolic/mitochondrial factors, and lipid characteristics, like the CD36 (7q21.11) gene, which transports long-chain fatty acids into cells. CNVRs intersecting genes previously related to neurodevelopmental traits include deletions of NRXN1 intron 5 (2p16.3), IMMP2L (7q31.1), and PTPRD (9p23). Overall, given that our study is well powered to detect the CNV burden level reported for schizophrenia, we can conclude that rare CNVs have a limited role in the etiology of AN, as reported for bipolar disorder. Our nominal associations for the 21 discovered CNVRs are consistent with AN being a metabo-psychiatric trait, as demonstrated by the common genetic architecture of AN, and we provide association results to allow for replication in future research.

Prenatal Acetaminophen Exposure and its Associated Risk for Attention Deficit Hyperactivity Disorder

Acetaminophen is one of the most commonly used over-the-counter antipyretic and analgesic drugs on the market and has been relevant in the medical world for almost a hundred years. It has maintained an excellent reputation as a safe therapeutic in several types of patient profiles. However, the number of children diagnosed with neurodevelopmental disorders, namely ADHD, have been on the rise. Recent findings have indicated an association between in utero exposure to acetaminophen and an increased risk of developing neurodevelopmental disorders such as ADHD in offspring. The mechanism by which this potential side effect occurs is difficult to pinpoint. However, it is known that the metabolism of acetaminophen is known to cause oxidative stress, which has been shown to influence the developing fetus. This review highlights the epidemiological data indicating the correlation between prenatal acetaminophen exposure and ADHD and discusses several proposed theories by which this phenomenon may occur. While there is not yet enough clinical evidence to prove that acetaminophen may cause ADHD, there is a strong enough correlation to indicate a warning to pregnant patients of the potential risks. The risks and benefits of treatment should be considered so that the patient may continue with the course of action with the most favorable outcome. This review was mainly based on manuscripts pulled from Google Scholar and PubMed. The purpose of this literature review is to assist clinicians to better understand lesser-known risks in acetaminophen usage in pregnant patients.

What are the Short and Long-Term Impacts of Animal Assisted Interventions on the Therapy Animals?

Abstract Animal assisted interventions (AAIs) are practices used for human wellbeing, whereby interactions with non-human animals are used for therapeutic purposes. AAIs can be offered clinically, to those suffering physical or mental illness; those who have a learning disability or neurodevelopmental disorder; people requiring occupational therapy or enrichment in settings such as prisons and nursing homes, and as an adjunct to formal education in classrooms. Whilst some AAIs are low risk, AAI animals can be placed in emotionally challenging situations, or even situations where they may be at physical risk. At present, there is a paucity of literature examining the welfare of AAI animals, and the practice remains unregulated. This paper therefore discusses the potential welfare issues for animals used in ‘animal assisted interventions’, and suggests how those issues could be addressed.

Choroid plexus extracellular vesicle transport of blood-borne insulin-like growth factor 1 to the hippocampus of the immature brain

Abstract Reduced serum level of insulin-like growth factor 1 (IGF-1), a major regulator of perinatal development, in extremely preterm infants has been shown to be associated with neurodevelopmental impairment. To clarify the mechanism of IGF-1 transport at the blood-cerebrospinal fluid (CSF) barrier of the immature brain, we combined studies of in vivo preterm piglet and rabbit models with an in vitro transwell cell culture model of neonatal primary murine choroid plexus epithelial (ChPE) cells. We identified IGF-1 positive intracellular vesicles in ChPE cells and provided data indicating a directional transport of IGF-1 from the basolateral to the apical media in extracellular vesicles (EVs). Exposure of the ChPE cells to human IGF-1 on the basolateral side increased the secretion of IGF-1 positive EVs in the apical media. Mass spectrometry analysis displayed similarities in protein content between EVs derived from preterm piglet CSF and ChPE derived EVs. Furthermore, exposure of ChPE cells to human IGF-1 caused an enrichment of human IGF-1 and transmembrane p24 trafficking protein 2, proteins important for perinatal development, in apical media derived EVs. Moreover, intraventricular injections of ChPE cell-derived EVs in preterm rabbit pups resulted in an uptake of EVs in the brain, displaying penetration through the ependymal lining and deep into the hippocampus. Finally, exposure of rat hippocampus neurons to ChPE cell derived EVs resulted in internalization of the EVs in hippocampal soma and neurites. In summary, we describe a transport pathway for blood-borne IGF-1 in EVs, through the blood–CSF barrier to the hippocampus in the immature brain.

Abstract 4135745: Prematurity Predicts Neurodevelopmental Outcomes in Congenital Heart Disease

Background: Neurodevelopmental (ND) impairment is common in both prematurity and congenital heart disease (CHD). Preterm infants with CHD may have a “double hit,” with worse ND impairments than seen in prematurity or CHD alone. We analyzed whether gestational age (GA) at delivery predicted ND outcomes in children with CHD. Methods: We performed a single-institution retrospective study of children who underwent infant heart surgery from 2007-2020 and returned for ND evaluation after discharge. Exclusion criteria were 1) trisomy 21 and 2) PDA ligation alone. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) assessed ND between ages 6-40 months. Patients were stratified into 4 GA groups: very/moderately preterm (≤33 weeks), late-preterm (34-36 weeks), early-term (37-38 weeks) or term/post-term (≥39 weeks). Hierarchical linear regression evaluated potential predictors of Bayley-III composite scores including GA category, demographic, medical, and surgical variables. Results: Among 1350 infants, 513 (38%) had a Bayley-III at median age 28 months [IQR 19, 34]. Of these, 448 (87%) were full-term and 65 (13%) preterm. In univariate analyses, children born preterm vs. full term had lower Bayley-III cognitive, language, and motor scores, explaining from 2.4% (language) to 6.2% (motor) of the variance in Bayley composite scores. In the final models, GA remained a strong independent predictor of motor and cognitive scores. Children with GA ≤33 weeks had the worst outcomes, with age-adjusted cognitive and motor composite scores 11 and 15 points lower, respectively, than those of term infants (Figure). Other significant risk factors included lower primary caregiver education, Black race, longer hospital length of stay, and genetic diagnosis. These models ultimately explained 17-26% of the variance in Bayley scores, with the highest explained variance in the motor domain. Conclusions: Adjusting for other patient and medical factors, preterm infants with CHD have worse cognitive and motor outcomes; risk is highest in those born at ≤33 weeks. Further work is needed to identify potentially modifiable factors to tailor prenatal, postnatal and perioperative care of infants with CHD born prematurely.

Amelioration of propionic acid‐induced autism‐like behaviors in rats by fenofibrate: A focus on reduction of brain galectin‐3 levels

AbstractIntroductionAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions and repetitive behaviors. This study examines the effects of fenofibrate on a propionic acid (PPA)‐induced rat model of ASD, focusing on behavioral changes, inflammatory markers, and histological findings.Materials and MethodsThirty male Wistar rats were divided into three groups: a control group, a group receiving PPA and saline, and a group treated with PPA and fenofibrate for 15 days. Behavioral assessments, including the three‐chamber sociability test, open‐field test, and passive avoidance learning, were conducted. Biochemical analyses measured TNF‐α, NGF, IL‐17, IL‐2, and galectin‐3 levels in brain tissues. Histological evaluations focused on Purkinje neuron counts in the cerebellum and neuronal changes in the CA1 and CA3 regions of the hippocampus, along with glial fibrillary acidic protein (GFAP) levels.ResultsFenofibrate treatment significantly improved behavioral outcomes, reducing autism‐like behaviors compared to the PPA/saline group. Biochemically, the PPA/saline group showed elevated levels of malondialdehyde, TNF‐α, IL‐2, IL‐17, and galectin‐3, which were reduced following fenofibrate treatment. Histologically, the PPA/saline group exhibited fewer, dysmorphic Purkinje neurons and increased glial activity in the CA1 region, both of which were ameliorated by fenofibrate treatment.ConclusionFenofibrate shows promise in mitigating autism‐like behaviors in a rat model of ASD, likely due to its antioxidative and neuroprotective properties, which contribute to preserving neuronal integrity and reducing inflammation.