OBJECTIVE:A significant overlap of the risk genes respectively listed for craniosynostosis and autism was recently demonstrated in each case series. The purposes of this article were to review the clinical manifestations systemically in previously reported individual cases with the shared variants and to confirm the pleiotropic associations between genotype and phenotype. METHODS:The risk genes or loci were retrieved from the PubMed database (last searched March 2024) as genetic factors for which genotype-phenotype associations were reported in at least 2 different individuals. Clinical details were reviewed in cases with shared genetic factors between craniosynostosis and autism spectrum disorder. In the genotype-phenotype association of syndromic craniosynostosis genes, both syndromic involvement of autistic traits and nonsyndromic autism cases with nonsyndromic variants in the flanking regions of the syndromic mutations were included. RESULTS:Nonsyndromic craniosynostosis and autism are both underpinned by complex polygenic networks that include multiple risk genes or loci, and a considerable part of the networks might overlap. Although nonsyndromic mild trigonocephaly and autism might be closely associated in carriers of the shared variants, the presence of cases with autism without mild trigonocephaly was confirmed in a PJA1 variant case. As one of the characteristics of epistasis, ethnic specificity has been demonstrated in the interactions between SMAD6 and BMP2 variants. The presence of autism cases without craniosynostosis on a shared genetic basis was also confirmed in syndromic craniosynostosis risk genes and loci, suggesting that the causal relationship from craniosynostosis to autism is unnecessary for the development of autism spectrum disorder. CONCLUSIONS:Regarding the 3 possibilities of the association between craniosynostosis and neurodevelopmental comorbidities proposed by Kapp-Simon's group, only the independent pathway theory can explain the genotype-phenotype findings. There is no causal relationship between craniosynostosis and autism spectrum disorder in the independent pathway theory. Because the mechanical hindrance of brain expansion from poor compliance of the affected cranial vault is less likely in mild craniosynostosis cases, surgical indication of cranioplasty for mild trigonocephaly should never be confused with that of overt craniosynostosis. If there is no cosmetic indication for the metopic ridge in mild trigonocephaly cases with developmental comorbidities, there is no reason for surgical intervention.

Background: Although randomized clinical trials (RCTs) have investigated several treatments for social communication difficulties and repetitive behavior in autism, none has yet shown consistent superiority over placebo. Placebo response in autism RCTs may impede the ability to detect meaningful treatment effects. Objective: We sought to identify individual-level predictors of placebo response in Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B), a 24-week RCT of intranasal oxytocin for social impairment in autistic youth. In our primary analysis, we examined predictors of change in the Aberrant Behavior Checklist-modified Social Withdrawal (ABC-mSW) score at 24 weeks in SOARS-B participants taking placebo. Secondary analyses examined predictors of ABC-mSW change at 12 weeks and of Clinical Global Impressions-Improvement at 24 and 12 weeks. We also examined predictors of response among SOARS-B participants taking oxytocin. Methods: For each analysis, we first used lasso (least absolute shrinkage and selection operator) regression to identify potentially influential predictors from a large group that included demographic factors, rating scale data, and prescribed medications. We then estimated an unpenalized linear regression model for the outcome of interest that included only variables retained by the optimal lasso. We considered variables with statistically significant coefficients to be influential predictors. Results: Higher baseline ABC-mSW score was the only significant predictor of greater ABC-mSW change in the placebo group at 24 and 12 weeks. Conclusions: In SOARS-B, higher baseline severity on a measure of reciprocal social communication predicted greater placebo response. This is consistent with the finding that lower social communication adaptive functioning was associated with greater placebo response in recent RCTs of balovaptan for social impairment in autism. However, it contrasts with findings from a trial of citalopram for repetitive behavior in autism, in which lower baseline severity of a composite of autistic and mood symptoms predicted greater placebo response. This may indicate that different factors contribute to placebo response in different symptom domains.

The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.

The virally encoded 3-chymotrypsin-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a g-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the g-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.

ASD encompasses a wide variety of heterogeneous patients, making diagnosis and treatment of ASD and co-occurring disorders challenging. Children with ASD can have severe, maladaptive behaviors that prompt outpatient referral. They can have difficulty processing sensory input, coping with daily stressors and traumatic experiences, predisposing them to anxiety, OCD, depression, and PTSD. The goals of this Clinical Perspectives is to provide clinicians with the knowledge needed to accurately diagnose and treat patients with ASD and comorbidities and review the literature so that a safe treatment plan can be developed encompassing pharmacological, therapeutic, and behavioral intervention that is supported by current research review. Presenters will review the current literature regarding comorbidities that can be seen in individuals with ASD. Alice Mao, MD, will examine treatment options for the management of aggression and emotional dysregulation in ASD. Janice Forster, MD, will explore atypical sensory processing in children with ASD, including the neurological underpinnings and potential of sensory integration therapy. Roma Vasa, MD, will discuss the evaluation and treatment of OCD in ASD. Olivia Hindera, BS, will outline the diagnostic criteria for PTSD within this population and evidence-based treatments. Bryan King, MD, MBA, a world renowned expert in ASD, will be the discussant for the presentation. Participants will learn how to identify and manage common comorbid disorders in children with ASD, including assessment tools and pharmacological interventions supported by a review of the literature. Case examples will be included in each presentation to demonstrate diagnostic and treatment challenges. Comorbidities in ASD can be difficult to distinguish from the primary diagnosis of ASD, causing them to be often overlooked. Clinicians should be able to recognize the signs and symptoms of co-occurring disorders in order to provide optimal patient care.

Importance Autism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD. Observations The estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child's first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child's behavior and semistructured caregiver interview focused on the individual's development and behaviors using standardized measures, such as the Autism Diagnostic Observation Schedule-Second Edition and the Autism Diagnostic Interview. These diagnostic measures have sensitivity of 91% and 80% and specificity of 76% and 72%, respectively. Compared with people without ASD, individuals with ASD have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% with co-occurring intellectual disability vs 0.8%). Intensive behavioral interventions, such as the Early Start Denver Model, are beneficial in children 5 years or younger for improvement in language, play, and social communication (small to medium effect size based on standardized mean difference). Pharmacotherapy is indicated for co-occurring psychiatric conditions, such as emotion dysregulation or attention-deficit/hyperactivity disorder. Risperidone and aripiprazole can improve irritability and aggression (standardized mean difference of 1.1, consistent with a large effect size) compared with placebo. Psychostimulants are effective for attention-deficit/hyperactivity disorder (standardized mean difference of 0.6, consistent with a moderate effect size) compared with placebo. These medications are associated with adverse effects including, most commonly, changes in appetite, weight, and sleep. Conclusions and Relevance ASD affects approximately 2.3% of children aged 8 years and approximately 2.2% of adults in the US. First-line therapy consists of behavioral interventions, while co-occurring psychiatric conditions, such as anxiety or aggression, may be treated with specific behavioral therapy or medication.

Importance:Autism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD.Observations:The estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child's first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child's behavior and semistructured caregiver interview focused on the individual's development and behaviors using standardized measures, such as the Autism Diagnostic Observation Schedule-Second Edition and the Autism Diagnostic Interview. These diagnostic measures have sensitivity of 91% and 80% and specificity of 76% and 72%, respectively. Compared with people without ASD, individuals with ASD have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% with co-occurring intellectual disability vs 0.8%). Intensive behavioral interventions, such as the Early Start Denver Model, are beneficial in children 5 years or younger for improvement in language, play, and social communication (small to medium effect size based on standardized mean difference). Pharmacotherapy is indicated for co-occurring psychiatric conditions, such as emotion dysregulation or attention-deficit/hyperactivity disorder. Risperidone and aripiprazole can improve irritability and aggression (standardized mean difference of 1.1, consistent with a large effect size) compared with placebo. Psychostimulants are effective for attention-deficit/hyperactivity disorder (standardized mean difference of 0.6, consistent with a moderate effect size) compared with placebo. These medications are associated with adverse effects including, most commonly, changes in appetite, weight, and sleep.Conclusions and Relevance:ASD affects approximately 2.3% of children aged 8 years and approximately 2.2% of adults in the US. First-line therapy consists of behavioral interventions, while co-occurring psychiatric conditions, such as anxiety or aggression, may be treated with specific behavioral therapy or medication.

Autism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD.The estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child's first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child's behavior and semistructured caregiver interview focused on the individual's development and behaviors using standardized measures, such as the Autism Diagnostic Observation Schedule-Second Edition and the Autism Diagnostic Interview. These diagnostic measures have sensitivity of 91% and 80% and specificity of 76% and 72%, respectively. Compared with people without ASD, individuals with ASD have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% with co-occurring intellectual disability vs 0.8%). Intensive behavioral interventions, such as the Early Start Denver Model, are beneficial in children 5 years or younger for improvement in language, play, and social communication (small to medium effect size based on standardized mean difference). Pharmacotherapy is indicated for co-occurring psychiatric conditions, such as emotion dysregulation or attention-deficit/hyperactivity disorder. Risperidone and aripiprazole can improve irritability and aggression (standardized mean difference of 1.1, consistent with a large effect size) compared with placebo. Psychostimulants are effective for attention-deficit/hyperactivity disorder (standardized mean difference of 0.6, consistent with a moderate effect size) compared with placebo. These medications are associated with adverse effects including, most commonly, changes in appetite, weight, and sleep.ASD affects approximately 2.3% of children aged 8 years and approximately 2.2% of adults in the US. First-line therapy consists of behavioral interventions, while co-occurring psychiatric conditions, such as anxiety or aggression, may be treated with specific behavioral therapy or medication.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.

Attention-deficit/hyperactivity disorder (ADHD) symptoms affect 40–60% of autistic children and have been linked to differences in adaptive behavior. It is unclear whether adaptive behavior in autistic youth is directly impacted by co-occurring ADHD symptoms or by another associated feature of both autism and ADHD, such as increased irritability. The current study examined relationships between irritability, ADHD symptoms, and adaptive behavior in 3- to 7-year-old autistic children. Results suggest that, after adjusting for co-occurring ADHD symptoms, higher levels of irritability are associated with differences in social adaptive behavior specifically. Understanding relationships between irritability, ADHD, and adaptive behavior in autistic children is critical because measures of adaptive behavior, such as the Vineland Scales of Adaptive Functioning, are often used as a proxy for global functioning, as well as for developing intervention plans and measuring outcomes as primary endpoints in clinical trials.

ASD encompasses a wide range of behaviors, and thus can pose a diagnostic and treatment puzzle for psychiatrists. Children with ASD often lack the coping skills required to address life’s stresses, leading to mood lability, impulsivity, and self-injury that can be exacerbated by co-occurring anxiety and OCD. This population can have rigid diets, resulting in suboptimal nutrition, and may require significant support from family. The impact on caregivers is often overlooked in discussions of ASD but is an important consideration for clinicians.

In the face of the growing number of adolescents suffering from eating disorders (EDs) and access to psychiatric care limited by the epidemiological and demographic situation, the primary care pediatrician's role in diagnosing and treating EDs is growing. The European Academy of Paediatrics (EAP) decided to summarize knowledge about EDs and formulate recommendations to support European pediatricians and improve care for adolescents with EDs.

The management of children and adolescents with ASD is often complicated by commonly associated behavioral symptoms and mental illness comorbidities including sleep disorders, anxiety, body-focused repetitive behaviors, and irritability.

Objective: Anxiety disorders are among the most common co-occurring conditions in autism spectrum disorder (ASD). Despite their prevalence and impact, there are no randomized controlled trials (RCTs) aimed at evaluating the efficacy of selective serotonin reuptake inhibitors (SSRIs) for anxiolysis in this population, who may have a different biological basis for anxiety. Methods: Secondary analyses of the STAART double-blind, placebo-controlled RCT of citalopram in children with ASD examined whether citalopram reduced anxiety measured on the parent-reported Child and Adolescent Symptom Inventory-4 (CASI-4) as the primary outcome. An intention-to-treat analysis involving all 149 participants used multiple imputations for missing data and included baseline stratification factors of age group and site, among others. We prespecified as clinically significant a 33% reduction in anxiety in citalopram versus placebo, coinciding with 80% power. We tested whether communicative ability on the Vineland Communication score moderated treatment effect and explored whether initial anxiety was associated with greater adverse events, which could impact on dose titration and achieving optimal dose. Results: Both groups showed substantial reduction in anxiety. Citalopram was associated with a nonsignificant 16.5% greater reduction (observed coefficient = -0.181, bootstrap standard error = 0.126, p = 0.151, confidence interval = -0.428 to 0.066). Anxiety reports were significantly lower in children with reduced communicative ability, but communicative ability did not moderate the treatment effect (interaction p = 0.294). Initial anxiety levels were not associated with increased adverse effects (interaction ps 0.162-0.954). Conclusion: Citalopram did not statistically significantly improve anxiety in children with ASD. Clinicians should be cautious in their use of SSRIs for this indication. There remains a need for well-powered clinical trials testing the efficacy of SSRIs among autistic children with anxiety disorders.

DNMT1 maintains the parental DNA methylation pattern on newly replicated hemimethylated DNA. The failure of this maintenance process causes aberrant DNA methylation that affects transcription and contributes to the development and progression of cancers such as acute myeloid leukemia. Here, we structurally characterized a set of newly discovered DNMT1-selective, reversible, non-nucleoside inhibitors that bear a core 3,5-dicyanopyridine moiety, as exemplified by GSK3735967, to better understand their mechanism of inhibition. All of the dicyanopydridine-containing inhibitors examined intercalate into the hemimethylated DNA between two CpG base pairs through the DNA minor groove, resulting in conformational movement of the DNMT1 active-site loop. In addition, GSK3735967 introduces two new binding sites, where it interacts with and stabilizes the displaced DNMT1 active-site loop and it occupies an open aromatic cage in which trimethylated histone H4 lysine 20 is expected to bind. Our work represents a substantial step in generating potent, selective, and non-nucleoside inhibitors of DNMT1.

While there are no medications that have yet been identified as effective for addressing core features of autistic, there is a general consensus that some adults with autistic may benefit from access to psychopharmacotherapy for a variety of other clinical indications. Psychiatric disorders occur more commonly in autistic than in the non-autistic general population, and some medicines have well-established indications for conditions like irritability specifically in autistic. While it is generally the case that psychosocial therapies should be part of every treatment plan, medication should not be viewed as a last resort. Virtually all of the common classes of psychotropic medication have been explored in autistic, and antidepressant medications are among the most commonly used. Additional studies will be important in informing the practice of psychopharmacotherapy in autistic, particularly with respect to the common practice of combining different classes of medication.

DNA-encoded library (DEL) technology is a powerful platform for hit identification in academia and the pharmaceutical industry. When conducting off-DNA resynthesis hit confirmation after affinity selection, PCR/sequencing, and data analysis, one typically assumes a "one-to-one" relationship between the DNA tag and the chemical structure of the attached small-molecule it encodes. Because library synthesis often yields a mixture, this approximation increases the risk of overlooking positive discoveries and valuable information. To address this issue, we apply a library synthesis "recipe" strategy for on-DNA resynthesis using a cleavable linker, followed by direct affinity selection mass spectrometry (AS-MS) evaluation and identification of binder(s) from the released small-molecule mixture. We validate and showcase this approach employing the receptor-interacting-protein kinase 2 (RIP2) DEL campaign. We also designed and developed two cleavable linkers to enable this method, a photocleavable linker (nitrophenyl-based) and acid-labile linker (tetrahydropyranyl ether). The strategy provides an effective means of hit identification and rapid determination of key active component(s) of the mixture.