Exploring the Possible Role of Cannabinoids in Managing Post-cardiac Surgery Complications: A Narrative Review of Preclinical Evidence and a Call for Future Research Directions.

ABSTRACT: Open-heart surgery with cardiopulmonary bypass often leads to complications including pain, systemic inflammation, and organ damage. Traditionally managed with opioids, these pain relief methods bring potential long-term risks, prompting the exploration of alternative treatments. The legalization of cannabis in various regions has reignited interest in cannabinoids, such as cannabidiol, known for their anti-inflammatory, analgesic, and neuroprotective properties. Historical and ongoing research acknowledges the endocannabinoid system's crucial role in managing physiological processes, suggesting that cannabinoids could offer therapeutic benefits in postsurgical recovery. Specifically, cannabidiol has shown promise in managing pain, moderating immune responses, and mitigating ischemia/reperfusion injury, underscoring its potential in postoperative care. However, the translation of these findings into clinical practice faces challenges, highlighting the need for extensive research to establish effective, safe cannabinoid-based therapies for patients undergoing open-heart surgery. This narrative review advocates for a balanced approach, considering both the therapeutic potential of cannabinoids and the complexities of their integration into clinical settings.

Cannabinoid treatment for the symptoms of autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 3% of school-age children. The core symptoms are deficits in social communication and restricted and repetitive patterns of behavior. Associated problems in cognition, language, behavior, sleep and mood are prevalent. Currently, no established pharmacological treatment exists for core ASD symptoms. Risperidone and aripiprazole are used to manage associated irritability, but their effectiveness is limited and adverse events are common. AREAS COVERED: This mini-review summarizes existing scientific literature and ongoing clinical trials concerning cannabinoid treatment for ASD. Uncontrolled case series have documented improvements in both core ASD symptoms and related behavioral challenges in children treated with cannabis extracts rich in cannabidiol (CBD). Placebo-controlled studies involving CBD-rich cannabis extracts and/or pure CBD in children with ASD have demonstrated mixed efficacy results. A similar outcome was observed in a placebo-controlled study of pure CBD addressing social avoidance in Fragile X syndrome. Importantly, these studies have shown relatively high safety and tolerability. EXPERT OPINION: While current clinical data suggest the potential of CBD and CBD-rich cannabis extract in managing core and behavioral deficits in ASD, it is prudent to await the results of ongoing placebo-controlled trials before considering CBD treatment for ASD.

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data.

Autism spectrum disorder (ASD) is a heterogenous multifactorial neurodevelopmental condition with a significant genetic susceptibility component. Thus, identifying genetic variations associated with ASD is a complex task. Whole-exome sequencing (WES) is an effective approach for detecting extremely rare protein-coding single-nucleotide variants (SNVs) and short insertions/deletions (INDELs). However, interpreting these variants' functional and clinical consequences requires integrating multifaceted genomic information. We compared the concordance and effectiveness of three bioinformatics tools in detecting ASD candidate variants (SNVs and short INDELs) from WES data of 220 ASD family trios registered in the National Autism Database of Israel. We studied only rare (< 1% population frequency) proband-specific variants. According to the American College of Medical Genetics (ACMG) guidelines, the pathogenicity of variants was evaluated by the InterVar and TAPES tools. In addition, likely gene-disrupting (LGD) variants were detected based on an in-house bioinformatics tool, Psi-Variant, that integrates results from seven in-silico prediction tools. Overall, 372 variants in 311 genes distributed in 168 probands were detected by these tools. The overlap between the tools was 64.1, 22.9, and 23.1% for InterVar-TAPES, InterVar-Psi-Variant, and TAPES-Psi-Variant, respectively. The intersection between InterVar and Psi-Variant (I âˆ© P) was the most effective approach in detecting variants in known ASD genes (PPV = 0.274; OR = 7.09, 95% CI = 3.92-12.22), while the union of InterVar and Psi Variant (I U P) achieved the highest diagnostic yield (20.5%).Our results suggest that integrating different variant interpretation approaches in detecting ASD candidate variants from WES data is superior to each approach alone. The inclusion of additional criteria could further improve the detection of ASD candidate variants.

Mediators of Placebo Response to Cannabinoid Treatment in Children with Autism Spectrum Disorder.

The placebo response has a substantial impact on treatment outcome. However, data regarding mediators of the placebo response in children with autism spectrum disorder (ASD) are sparse. This retrospective study investigated possible mediators of the placebo response among participants of a placebo-controlled trial of cannabinoid treatment for behavioral problems in children with ASD (CBA trial, age 5-21 years). We used a specifically designed questionnaire to explore possible mediators of the placebo response in 88 participants of the CBA trial who received a placebo and had valid outcome scores. The parents of 67 participants completed the questionnaire. The placebo response was positively associated with the child's comprehension of the treatment purpose (p = 0.037). There was also a trend for participants who had a relative aggravation of symptoms before treatment onset to improve following placebo treatment (p = 0.053). No other domains, including parental expectations, previous positive experience with similar treatments (behavioral conditioning), parental locus of control, quality of the patient-physician relationships, and adherence to study medications were associated with placebo-response. This finding suggests that efforts to explain the treatment purpose to children with disabilities may enhance treatment efficacy in clinical practice and decrease differences in the placebo response between study arms. Contrary to our hypothesis, parental expectations regarding cannabinoid treatment were not associated with the placebo response.

The NO Answer for Autism Spectrum Disorder.

Autism spectrum disorders (ASDs) include a wide range of neurodevelopmental disorders. Several reports showed that mutations in different high-risk ASD genes lead to ASD. However, the underlying molecular mechanisms have not been deciphered. Recently, they reported a dramatic increase in nitric oxide (NO) levels in ASD mouse models. Here, they conducted a multidisciplinary study to investigate the role of NO in ASD. High levels of nitrosative stress biomarkers are found in both the Shank3 and Cntnap2 ASD mouse models. Pharmacological intervention with a neuronal NO synthase (nNOS) inhibitor in both models led to a reversal of the molecular, synaptic, and behavioral ASD-associated phenotypes. Importantly, treating iPSC-derived cortical neurons from patients with SHANK3 mutation with the nNOS inhibitor showed similar therapeutic effects. Clinically, they found a significant increase in nitrosative stress biomarkers in the plasma of low-functioning ASD patients. Bioinformatics of the SNO-proteome revealed that the complement system is enriched in ASD. This novel work reveals, for the first time, that NO plays a significant role in ASD. Their important findings will open novel directions to examine NO in diverse mutations on the spectrum as well as in other neurodevelopmental disorders. Finally, it suggests a novel strategy for effectively treating ASD.

Machine Learning-Based Blood RNA Signature for Diagnosis of Autism Spectrum Disorder.

Early diagnosis of autism spectrum disorder (ASD) is crucial for providing appropriate treatments and parental guidance from an early age. Yet, ASD diagnosis is a lengthy process, in part due to the lack of reliable biomarkers. We recently applied RNA-sequencing of peripheral blood samples from 73 American and Israeli children with ASD and 26 neurotypically developing (NT) children to identify 10 genes with dysregulated blood expression levels in children with ASD. Machine learning (ML) analyzes data by computerized analytical model building and may be applied to building diagnostic tools based on the optimization of large datasets. Here, we present several ML-generated models, based on RNA expression datasets collected during our recently published RNA-seq study, as tentative tools for ASD diagnosis. Using the random forest classifier, two of our proposed models yield an accuracy of 82% in distinguishing children with ASD and NT children. Our proof-of-concept study requires refinement and independent validation by studies with far larger cohorts of children with ASD and NT children and should thus be perceived as starting point for building more accurate ML-based tools. Eventually, such tools may potentially provide an unbiased means to support the early diagnosis of ASD.

Risk-Taking Behaviors in Children with ADHD Compared to Children with Primary Headaches.

The study examined the engagement in risk-taking behaviors and their onset in children with attention-deficit/hyperactivity disorder (ADHD) compared with children with primary headaches. Whether ADHD is associated with higher engagement in risk-taking behavior compared with other neurodevelopmental disorders (and not only typical development) has yet to be demonstrated. A sample of 189 children, 10 to 18 years old, undergoing neurological surveillance for ADHD (N = 144) or primary headaches (N = 45) participated in the study. The children and their parents reported the children's engagement in various risk-taking behaviors. The ADHD group reported a higher level of general risk-taking behavior relative to the headache group. The differences remained significant even after controlling for demographic and clinical variables. No differences in the age of onset of risk-taking behaviors were found. It is concluded that risk-taking behavior is more common in children with ADHD under active neurological surveillance than in children followed for primary headaches.

Improving pediatric idiopathic intracranial hypertension care: a retrospective cohort study.

To describe the clinical course and prognosis of pediatric idiopathic intracranial hypertension (IIH) and examine the preferred management setting. IIH is characterized by increased intracranial pressure and is often associated with headaches and visual complaints. IIH is a preventable cause of vision loss in children. Hence, a rapid diagnosis followed by prompt treatment and follow-up is essential. However, standardization of the management of IIH in the pediatric population is not well established. Computerized medical charts of all 82 pediatric (< 18 years) patients diagnosed with IIH between 2007 and 2018 in the metropolitan area of Jerusalem were reviewed. Comparison was made between children followed in a multidisciplinary clinic in tertiary centers and those followed elsewhere. Detailed demographic and clinical data, as well as data regarding the follow-up setting and clinical course of the disease, were collected and analyzed. Recurrent IIH-related hospital returns were selected as a measurable marker for the uncontrolled disease. Recurrent IIH-related hospital return rate was significantly lower and occurred later among children followed by multidisciplinary teams compared to individual experts. Follow-up in multidisciplinary clinics improve the quality of life, and financial burden and may prevent permanent visual impairment in children with IIH.

Blood RNA Sequencing Indicates Upregulated BATF2 and LY6E and Downregulated ISG15 and MT2A Expression in Children with Autism Spectrum Disorder.

Mutations in over 100 genes are implicated in autism spectrum disorder (ASD). DNA SNPs, CNVs, and epigenomic modifications also contribute to ASD. Transcriptomics analysis of blood samples may offer clues for pathways dysregulated in ASD. To expand and validate published findings of RNA-sequencing (RNA-seq) studies, we performed RNA-seq of whole blood samples from an Israeli discovery cohort of eight children with ASD compared with nine age- and sex-matched neurotypical children. This revealed 10 genes with differential expression. Using quantitative real-time PCR, we compared RNAs from whole blood samples of 73 Israeli and American children with ASD and 26 matched neurotypical children for the 10 dysregulated genes detected by RNA-seq. This revealed higher expression levels of the pro-inflammatory transcripts BATF2 and LY6E and lower expression levels of the anti-inflammatory transcripts ISG15 and MT2A in the ASD compared to neurotypical children. BATF2 was recently reported as upregulated in blood samples of Japanese adults with ASD. Our findings support an involvement of these genes in ASD phenotypes, independent of age and ethnicity. Upregulation of BATF2 and downregulation of ISG15 and MT2A were reported to reduce cancer risk. Implications of the dysregulated genes for pro-inflammatory phenotypes, immunity, and cancer risk in ASD are discussed.

A Placebo-Controlled Trial of Cannabinoid Treatment for Disruptive Behavior in Children and Adolescents with Autism Spectrum Disorder: Effects on Sleep Parameters as Measured by the CSHQ.

Autism spectrum disorder (ASD) is often associated with debilitating sleep disturbances. While anecdotal evidence suggests the positive effect of cannabinoids, randomized studies are lacking. Here, we report the effects of cannabinoid treatment on the sleep of 150 children and adolescents with ASD, as part of a double-blind, placebo-controlled study that assessed the impact of cannabinoid treatment on behavior (NCT02956226). Participants were randomly assigned to one of the following three treatments: (1) whole-plant cannabis extract, containing cannabidiol (CBD) and Δ9-Tetrahydrocannabinol (THC) in a 20:1 ratio, (2) purified CBD and THC extract in the same ratio, and (3) an oral placebo. After 12 weeks of treatment (Period 1) and a 4-week washout period, participants crossed over to a predetermined, second 12-week treatment (Period 2). Sleep disturbances were assessed using the Children's Sleep-Habit Questionnaire (CSHQ). We found that the CBD-rich cannabinoid treatment was not superior to the placebo treatment in all aspects of sleep measured by the CSHQ, including bedtime resistance, sleep-onset delay, and sleep duration. Notably, regardless of the treatment (cannabinoids or placebo), improvements in the CSHQ total score were associated with improvements in the autistic core symptoms, as indicated by the Social Responsiveness Scale total scores (Period 1: r = 0.266, p = 0.008; Period 2: r = 0.309, p = 0.004). While this study failed to demonstrate that sleep improvements were higher with cannabinoids than they were with the placebo treatment, further studies are required.

Successful Outcome in an Adolescent with Artery of Percheron Occlusion who was Treated with Tissue Plasminogen Activator.

BACKGROUND: Ischemic stroke is relatively rare in children, leading to a low level of suspicion and delayed diagnosis, particularly in cases of posterior circulation occlusion when symptoms are less indicative. Occlusion of the artery of Percheron (AOP) results in nonspecific neurologic symptoms, including drowsiness, aphasia or dysarthria, ophthalmoplegia, ataxia, and dysmetria. Previous reports, mainly in adults, described late diagnosis and severe residual disability. CASE REPORT: We report a case of a 16-year-old male who presented to the pediatric emergency department with altered mental status. There was no history of trauma or intoxication. The main symptoms included confusion, slurred speech, and multiple falls starting 1 h before arrival to the emergency department. No motor deficits or other focal signs were noticed. The patient's consciousness gradually decreased followed by apneic events. Routine laboratory tests, urinary toxic screen, and a computed tomography scan of the head were normal. A magnetic resonance imaging scan of the brain revealed bilateral restrictive changes in the thalamus. A diagnosis of AOP occlusion was made, and the patient was treated with tissue plasminogen activator (6 h after symptom onset). He was extubated on day 4 and discharged on the day 10 of admission without any neuropsychological deficit. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Posterior circulation stroke in the pediatric population is a diagnostic challenge that often results in suboptimal treatment and unfavorable outcomes. Prompt imaging studies in children with nonspecific altered mental status enable timely diagnosis and thrombolytic treatment that may substantially improve the outcome.

Change Blindness in Adolescents With Attention-Deficit/Hyperactivity Disorder: Use of Eye-Tracking.

Objective: This study investigated change detection of central or marginal interest in images using a change-blindness paradigm with eye tracking. Method: Eighty-four drug-naïve adolescents [44 with attention-deficit/hyperactivity disorder (ADHD)/40 controls with typical development] searched for a change in 36 pairs of original and modified images, with an item of central or marginal interest present or absent, presented in rapid alternation. Collected data were detection rate, response time, and gaze fixation duration, latency, and dispersion data. Results: Both groups' change-detection times were similar, with no speed-accuracy trade-off. No between-group differences were found in time to first fixation, fixation duration, or scan paths. Both groups performed better for items of central level of interest. The ADHD group demonstrated greater fixation dispersion in scan paths for central- and marginal-interest items. Conclusion: Results suggest the greater gaze dispersion may lead to greater fatigue in tasks that require longer attention duration.

Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy.

OBJECTIVE: To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP). METHODS: Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause. RESULTS: Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3. CONCLUSIONS: Cryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

Cannabinoid treatment for autism: a proof-of-concept randomized trial.

BACKGROUND: Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD. METHODS: We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). RESULTS: Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. CONCLUSIONS: This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.

Bleeding in Critically Ill Children-Review of Literature, Knowledge Gaps, and Suggestions for Future Investigation.

Clinically significant bleeding complicates up to 20% of admissions to the intensive care unit in adults and is associated with severe physiologic derangements, requirement for significant interventions and worse outcome. There is a paucity of published data on bleeding in critically ill children. In this manuscript, we will provide an overview of the epidemiology and characteristics of bleeding in critically ill children, address the association between bleeding and clinical outcomes, describe the current definitions of bleeding and their respective limitations, and finally provide an overview of current knowledge gaps and suggested areas for future research.

A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures.

Deficiency of the endoplasmic reticulum transmembrane protein ARV1 leads to epileptic encephalopathy in humans and in mice. ARV1 is highly conserved, but its function in human cells is unknown. Studies of yeast arv1 null mutants indicate that it is involved in a number of biochemical processes including the synthesis of sphingolipids and glycosylphosphatidylinositol (GPI), a glycolipid anchor that is attached to the C-termini of many membrane bound proteins. GPI anchors are post-translational modifications, enabling proteins to travel from the endoplasmic reticulum (ER) through the Golgi and to attach to plasma membranes. We identified a homozygous pathogenic mutation in ARV1, p.Gly189Arg, in two brothers with infantile encephalopathy, and characterized the biochemical defect caused by this mutation. In addition to reduced expression of ARV1 transcript and protein in patients' fibroblasts, complementation tests in yeast showed that the ARV1 p.Gly189Arg mutation leads to deficient maturation of Gas1, a GPI-anchored protein, but does not affect sphingolipid synthesis. Our results suggest, that similar to mutations in other proteins in the GPI-anchoring pathway, including PIGM, PIGA, and PIGQ, ARV1 p.Gly189Arg causes a GPI anchoring defect and leads to early onset epileptic encephalopathy.

Medical Cannabis in Children.

The use of medical cannabis in children is rapidly growing. While robust evidence currently exists only for pure cannabidiol (CBD) to treat specific types of refractory epilepsy, in most cases, artisanal strains of CBD-rich medical cannabis are being used to treat children with various types of refractory epilepsy or irritability associated with autism spectrum disorder (ASD). Other common pediatric disorders that are being considered for cannabis treatment are Tourette syndrome and spasticity. As recreational cannabis use during youth is associated with serious adverse events and medical cannabis use is believed to have a relatively high placebo effect, decisions to use medical cannabis during childhood and adolescence should be made with caution and based on evidence. This review summarizes the current evidence for safety, tolerability, and efficacy of medical cannabis in children with epilepsy and in children with ASD. The main risks associated with use of Δ9-tetrahydrocannabinol (THC) and CBD in the pediatric population are described, as well as the debate regarding the use of whole-plant extract to retain a possible "entourage effect" as opposed to pure cannabinoids that are more standardized and reproducible.

The Role of Parental Monitoring in Mediating the Link Between Adolescent ADHD Symptoms and Risk-Taking Behavior.

Objective: ADHD in adolescents and low level of parental monitoring have been associated with increased risk-taking behavior. The present study examined whether parental knowledge of the child's whereabouts mediates the correlations between adolescent ADHD symptoms and risk-taking behavior. Method: Ninety-two adolescents and their parents completed questionnaires assessing perceptions of parents' monitoring, engagement in risk-taking behaviors, and ADHD symptoms. Results: Greater engagement in risk-taking behavior correlated with higher levels of ADHD symptoms and decreased parental monitoring. Mediation analysis revealed both direct effect of ADHD symptoms on risk-taking behavior and an indirect effect mediated by level of parental knowledge. Conclusion: These findings suggest that parental knowledge is negatively affected by the presence of ADHD symptoms, and may in turn lead to risk-taking behavior. The findings emphasize the need to target parenting and in particular parental knowledge of the child's whereabouts to reduce risk-taking behaviors among youth with ADHD.

Emerging pharmacological therapies in fragile X syndrome and autism.

PURPOSE OF REVIEW: Research on the pathophysiology of syndromic autism spectrum disorder (ASD) has contributed to the uncovering of mechanisms in nonsyndromic ASD. The current review aims to compare recent progress in therapeutics development for ASD with those for fragile X syndrome (FXS), the most frequent monogenic form of ASD. RECENT FINDINGS: Although candidates such as oxytocin, vasopressin, and cannabinoids are being tested as novel therapeutics, it remains difficult to focus on a specific molecular target of drug development for ASD core symptoms. As the pathophysiology of FXS has been well described as having a causal gene, fragile X mental retardation-1, development of therapeutic agents for FXS is focused on specific molecular targets, such as metabotropic glutamate receptor 5 and GABAB receptor. SUMMARY: There is a large unmet medical need in ASD, a heterogeneous and clinically defined behavioral syndrome, owing to its high prevalence in the general population, lifelong cognitive and behavioral deficits, and no established treatment of ASD core symptoms, such as deficits in social communication and restrictive repetitive behaviors. The molecular pathogenesis of nonsyndromic ASD is largely undefined. Lessons from initial attempts at targeted treatment development in FXS, and new designs resulting from these lessons, will inform trials in nonsyndromic ASD for development of therapeutics for its core symptoms.