Correction: Elucidation of the RamA Regulon in Klebsiella pneumoniae Reveals a Role in LPS Regulation.

[This corrects the article DOI: 10.1371/journal.ppat.1004627.].

Children's Judgments and Reasoning About Same-Sex Romantic Relationships.

Children's (5-, 7- to 8-, and 10- to 11-year-olds), and adolescents' (13- to 14-year-olds) judgments and reasoning about same-sex romantic relationships were examined (N = 128). Participants' beliefs about the acceptability and legal regulation of these relationships were assessed, along with their judgments and beliefs about excluding someone because of his or her sexual orientation and the origins of same-sex attraction. Older participants evaluated same-sex romantic relationships more positively and used more references to personal choice and justice/discrimination reasoning to support their judgments. Younger participants were less critical of a law prohibiting same-sex relationships and were more likely to believe it was not acceptable to violate this law. Beliefs about origins of same-sex attraction showed age-specific patterns in their associations with evaluations.

Clinical phenotype of the recurrent 1q21.1 copy-number variant.

PURPOSE: To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. METHODS: Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging. RESULTS: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers. CONCLUSIONS: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.

16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort.

Chromosome 16p11.2 deletions and duplications are among the most frequent genetic etiologies of autism spectrum disorder (ASD) and other neurodevelopmental disorders, but detailed descriptions of their neurologic phenotypes have not yet been completed. We utilized standardized examination and history methods to characterize a neurologic phenotype in 136 carriers of 16p11.2 deletion and 110 carriers of 16p11.2 duplication-the largest cohort to date of uniformly and comprehensively characterized individuals with the same 16p copy number variants (CNVs). The 16p11.2 deletion neurologic phenotype is characterized by highly prevalent speech articulation abnormalities, limb and trunk hypotonia with hyporeflexia, abnormalities of agility, sacral dimples, seizures/epilepsy, large head size/macrocephaly, and Chiari I/cerebellar tonsillar ectopia. Speech articulation abnormalities, hypotonia, abnormal agility, sacral dimples, and seizures/epilepsy are also seen in duplication carriers, along with more prominent hyperreflexia; less, though still prevalent, hyporeflexia; highly prevalent action tremor; small head size/microcephaly; and cerebral white matter/corpus callosum abnormalities and ventricular enlargement. The neurologic phenotypes of these reciprocal 16p11.2 CNVs include both shared and distinct features. Reciprocal phenotypic characteristics of predominant hypo- versus hyperreflexia and macro- versus microcephaly may reflect opposite neurobiological abnormalities with converging effects causing the functional impairments shared between 16p11.2 deletion and duplication carriers (i.e., abnormal motor agility and articulation). While the phenotypes exhibit overlap with other genetically-caused neurodevelopmental disorders, clinicians should be aware of the more striking features-such as the speech and motor impairments, growth abnormalities, tremor, and sacral dimples-when evaluating individuals with developmental delay, intellectual disability, ASD, and/or language disorders. © 2016 Wiley Periodicals, Inc.

Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy.

The association between autism spectrum disorder (ASD) and epilepsy has been described for decades, and yet we still lack the full understanding of this relationship both clinically and at the pathophysiologic level. This review evaluates the available data in the literature pertaining to the clinical characteristics of patients with autism spectrum disorder who develop epilepsy and, conversely, patients with epilepsy who develop autism spectrum disorder. Many studies demonstrate an increased risk of epilepsy in individuals with ASD, but rates vary widely. This variability is likely secondary to the different study methods employed, including the study population and definitions of the disorders. Established risk factors for an increased risk of epilepsy in patients with ASD include intellectual disability and female gender. There is some evidence of an increased risk of epilepsy associated with other factors such as ASD etiology (syndromic), severity of autistic features, developmental regression, and family history. No one epilepsy syndrome or seizure type has been associated, although focal or localization-related seizures are often reported. The age at seizure onset can vary from infancy to adulthood with some evidence of a bimodal age distribution. The severity and intractability of epilepsy in populations with ASD have not been well studied, and there is very little investigation of the role that epilepsy plays in the autism behavioral phenotype. There is evidence of abnormal EEGs (especially epileptiform abnormalities) in children with ASD even in the absence of clinical seizures, but very little is known about this phenomenon and what it means. The development of autism spectrum disorder in patients with epilepsy is less well studied, but there is evidence that the ASD risk is greater in those with epilepsy than in the general population. One of the risk factors is intellectual disability, and there is some evidence that the presence of a particular seizure type, infantile spasms, may increase risk, but some of the data are conflicting. We believe that one of the reasons that so little is known about this phenomenon is the lack of cross talk between researchers and clinicians alike in the two fields. We conclude that large systematic studies that employ strict ascertainment of samples using standardized definitions of both disorders, validated data collection tools, and appropriate longitudinal follow-up are needed to better shed light on certain clinical aspects of the comorbidity of ASD and epilepsy. Ideally, we could provide the optimal diagnostic and treatment services to these patients in a multidisciplinary setting with both epilepsy and neurobehavioral specialists. This article is part of a Special Issue entitled "Autism and Epilepsy".

A survey of seizures and current treatments in 15q duplication syndrome.

OBJECTIVE: Seizures are common in individuals with duplications of chromosome 15q11.2-q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population. METHODS: A detailed electronic survey was conducted through the Dup15q Alliance containing comprehensive questions regarding seizures and their treatments in Dup15q. RESULTS: There were 95 responses from Dup15q families. For the 83 with idic(15), 63% were reported to have seizures, of which 81% had multiple seizure types and 42% had infantile spasms. Other common seizure types were tonic-clonic, atonic, myoclonic, and focal. Only 3 of 12 individuals with int dup(15) had seizures. Broad spectrum antiepileptic drugs (AEDs) were the most effective medications, but carbamazepine and oxcarbazepine were also effective, although typical benzodiazepines were relatively ineffective. There was a 24% response rate (>90% seizure reduction) to the first AED tried. For those with infantile spasms, adrenocorticotropic hormone (ACTH) was more effective than vigabatrin. SIGNIFICANCE: This is the largest study assessing seizures in Duplication 15q syndrome, but because this was a questionnaire-based study with a low return rate, it is susceptible to bias. Seizures are common in idic(15) and typically difficult to control, often presenting with infantile spasms and progressing to a Lennox-Gastaut-type syndrome. Seizures in those with int dup(15) are less common, with a frequency similar to the general autism population. In addition to broad spectrum AED, medications such as carbamazepine and oxcarbazepine are also relatively effective in controlling seizures in this population, suggesting a possible multifocal etiology, which may also explain the high rate of infantile spasms. Our small sample suggests a relative lack of efficacy of vigabatrin and other γ-aminobutyric acid (GABA)ergic medications, such as typical benzodiazepines, which may be attributable to abnormal GABAergic transmission resulting from the duplication of a cluster of GABAß3 receptor genes in the 15q11.2-13 region.

Factors Associated With Underutilization of Genetic Testing in Autism Spectrum Disorders.

BACKGROUND: We sought to identify patient and provider factors associated with low completion of genetic testing, specifically chromosomal microarray (CMA), for autism spectrum disorder (ASD). METHODS: Medical record review was conducted of children newly diagnosed with ASD without prior genetic testing at a single academic medical center from February 2015 through January 2016. RESULTS: Only 41.9% of individuals with ASD completed CMA testing over at least 18 months from diagnosis (n = 140 of 334). Time to CMA completion varied, with a median of 86.5 days (interquartile range 2 to 214.5 days). Provider recommendation of genetic testing at the diagnostic visit and greater number of follow-up visits were associated with CMA completion. On multivariate regression, CMA completion was inversely associated with age (odds ratio [OR] = 0.8 for each year older, 95% confidence interval [CI] 0.7, 0.9; P = 0.001) and directly associated with intellectual disability or global developmental delay (OR = 2.2, 95% CI 1.3, 3.8; P = 0.004), first-degree relative with ASD (OR = 2.5, 95% CI 1.0, 6.0; P = 0.044), and public insurance (OR = 1.7, 95% CI 1.0, 2.9; P = 0.037). Parental concern and cost/insurance coverage were the most frequently documented barriers. CONCLUSIONS: Workflows to support early genetic testing recommendation and ordering soon after diagnosis may increase utilization, incorporating both family and provider perspectives. Genetic counseling highlighting the utility of genetic testing across the life span, phenotypic variability of genetic disorders, and possibility of de novo variants in ASD may also improve utilization.

Optimizing Care for Autistic Patients in Health Care Settings: A Scoping Review and Call to Action.

OBJECTIVE: We conducted a scoping review of interventions designed to improve the health care experiences of autistic individuals and assessed the methodology and outcomes used to evaluate them. METHODS: Literature from January 2005 to October 2020 was searched using PubMed, Excerpta Medica dataBASE (EMBASE), Cumulated Index to Nursing and Allied Health Literature (CINAHL), PsycINFO as well as hand searching. Studies included described an intervention for autistic individuals in inpatient or outpatient settings and evaluated the intervention using standardized methodology. Results were exported to Covidence software. Ten reviewers completed abstract screening, full text review, and then systematic data extraction of the remaining articles. Two reviewers evaluated each article at each stage, with a third reviewer arbitrating differences. RESULTS: A total of 38 studies, including three randomized controlled trials (RCTs) were included. Twenty-six (68%) took place in dental, psychiatric, or procedural settings. Interventions primarily focused on visit preparation and comprehensive care plans or pathways (N = 29, 76%). The most frequent outcome was procedural compliance (N = 15), followed by intervention acceptability (N = 7) and parent satisfaction (N = 6). Two studies involved autistic individuals and caregivers in study design, and no studies assessed racial/ethnic diversity on intervention impact. CONCLUSIONS: Well-designed evaluations of interventions to support autistic individuals in pediatric health care settings are limited. There is a need to conduct large multi-site intervention implementation studies.

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Epistemological development and judgments and reasoning about teaching methods.

Children's, adolescents', and adults' (N = 96 7-8, 10-11, and 13-14-year-olds and university students) epistemological development and its relation to judgments and reasoning about teaching methods was examined. The domain (scientific or moral), nature of the topic (controversial or noncontroversial), and teaching method (direct instruction by lectures versus class discussions) were systematically varied. Epistemological development was assessed in the aesthetics, values, and physical truth domains. All participants took the domain, nature of the topic, and teaching method into consideration in ways that showed age-related variations. Epistemological development in the value domain alone was predictive of preferences for class discussions and a critical perspective on teacher-centered direct instruction, even when age was controlled in the analysis.

Impairment Types and Combinations Among Adolescents and Young Adults with Disabilities: Colorado 2014-2018.

OBJECTIVE: Understanding the types of functional challenges faced by adolescents and young adults with disabilities (AYA-WD) can help payers, clinicians, community-based service providers, and policymakers recognize and meet needs. This paper describes state-level prevalence rates for 1) AYA-WD overall and for 2) impairment types singly and in combinations; and 3) examines how rates may differ between those insured by Medicaid versus commercial insurance. METHODS: This descriptive study uses Colorado's All Payer Claims Dataset 2014-2018 to identify insured 10- to 26-year-olds (Medicaid only: 333,931; commercially only: 392,444). It then applies the previously validated Children with Disabilities Algorithm (CWDA) and its companion, the Diagnosis-to-Impairment-Type Algorithm (DITA), to compare state-level prevalence rates by insurance source for disability overall and for each of five impairment types singly and in combination. RESULTS: Disability prevalence was greater among the Medicaid-insured AYA-WD by +7.6% points (pp)-Medicaid: 11.9% (47,654/333,931), commercial: 4.3% (16,907/392,444). Most AYA-WD had a single impairment, but the prevalence of AYA-WD with two or more impairments was greater among the Medicaid-insured than the commercially insured (+9.9 pp; Medicaid: 33.5% [15,963/47,654], commercial: 23.7% [3992/16, 907]), as was the prevalence of impairment types that were physical (+6.7 pp; Medicaid: 54.7% [26,054/47,654], commercial: 48.0% [8121/16,907]); developmental (+4.1 pp; Medicaid: 35.4% [16,874/47,654], commercial: 31.3% [5290/16,907]); psychiatric (+6.7 pp; Medicaid 21.3% [10,175/47,654], commercial: 14.6% [2470/16,907]), and intellectual (+9.3 pp; Medicaid: 26.2% [12,501/47,654], commercial: 16.9% [2858/16,907]). CONCLUSIONS: CWDA and DITA can be used to understand the rates at which impairment types and combinations occur in a population with childhood-onset disabilities.

Effect of manganese substitution of ferrite nanoparticles on particle grain structure.

To investigate the influence of manganese substitution on the saturation magnetization of manganese ferrite nanoparticles, samples with various compositions (Mn x Fe3-x O4, x = 0, 0.25, 0.5, 0.75, and 1) were synthesized and characterized. The saturation magnetization of such materials was both calculated using density functional theory and measured via vibrating sample magnetometry. A discrepancy was found; the computational data demonstrated a positive correlation between manganese content and saturation magnetization, while the experimental data exhibited an inverse correlation. X-ray diffraction (XRD) and magnetometry results indicated that the crystallite diameter and the magnetic diameter decrease when adding more manganese, which could explain the loss of magnetization of the particles. For 20 nm nanoparticles, with increasing manganese substitution level, the crystallite size decreases from 10.9 nm to 6.3 nm and the magnetic diameter decreases from 15.1 nm to 3.5 nm. Further high resolution transmission electron microscopy (HRTEM) analysis confirmed the manganese substitution induced defects in the crystal lattice, which encourages us to find ways of eliminating crystalline defects to make more reliable ferrite nanoparticles.

Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.

Background and Objectives: Deletions and duplications at 16p11.2 (BP4 to BP5; 29.5-30.1 Mb) have been associated with several neurodevelopmental and neuropsychiatric disorders including autism spectrum disorder, intellectual disability (ID), and schizophrenia. Seizures have also been reported in individuals with these particular copy number variants, but the epilepsy phenotypes have not been well-delineated. We aimed to systematically characterize the seizure types, epilepsy syndromes, and epilepsy severity in a large cohort of individuals with these 16p11.2 deletions and duplications. Methods: The cohort of ascertained participants with the recurrent 16p11.2 copy number variant was assembled through the multicenter Simons Variation in Individuals Project. Detailed data on individuals identified as having a history of seizures were obtained using a semistructured phone interview and review of medical records, EEG, and MRI studies obtained clinically or as part of the Simons Variation in Individuals Project. Results: Among 129 individuals with the 16p11.2 deletion, 31 (24%) had at least one seizure, including 23 (18%) who met criteria for epilepsy; 42% of them fit the phenotype of classic or atypical Self-limited (Familial) Infantile Epilepsy (Se(F)IE). Among 106 individuals with 16p11.2 duplications, 16 (15%) had at least one seizure, including 11 (10%) who met criteria for epilepsy. The seizure types and epilepsy syndromes were heterogeneous in this group. Most of the individuals in both the deletion and duplication groups had well-controlled seizures with subsequent remission. Pharmacoresistant epilepsy was uncommon. Seizures responded favorably to phenobarbital, carbamazepine, and oxcarbazepine in the deletion group, specifically in the Se(F)IE, and to various antiseizure medications in the duplication group. Discussion: These findings delineate the spectrum of seizures and epilepsies in the recurrent 16p11.2 deletions and duplications and provide potential diagnostic, therapeutic, and prognostic information.

Common neurological co-morbidities in autism spectrum disorders.

PURPOSE OF REVIEW: Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders associated with various co-morbidities. Neurological co-morbidities include motor impairments, epilepsy, and sleep dysfunction. These impairments have been receiving more attention recently, perhaps because of their significant impact on the behavior and cognitive function of children with ASDs. Here, we review the epidemiology, etiology, and clinical approach to these neurological co-morbidities and highlight future research directions. RECENT FINDINGS: Motor impairments include stereotypies, motor delays, and deficits, such as dyspraxia, incoordination, and gait problems. Sleep dysfunction typically presents as difficulty with sleep onset and prolonged awakenings during the night. Recent data suggest that abnormalities in melatonin may affect sleep and may be a potential treatment target. There is no classic epilepsy syndrome associated with ASDs. Intellectual disability, syndromic autism, and female sex are specific risk factors. Recent research has focused on identifying the overlapping pathways between these neurological co-morbidities and the core deficits in ASDs, which may have direct and powerful implications for treatment and prognosis. SUMMARY: Motor impairment, epilepsy, and sleep dysfunction are common neurological co-morbidities in ASDs. Clinicians should be aware that recognition and treatment of these issues may improve the function and outcome of children with ASDs.

The role of epilepsy and epileptiform EEGs in autism spectrum disorders.

Autism is a neurodevelopmental disorder of unknown etiology characterized by social and communication deficits and the presence of restricted interests/repetitive behaviors. Higher rates of epilepsy have long been reported, but prevalence estimates vary from as little as 5% to as much as 46%. This variation is probably the result of sample characteristics that increase epilepsy risk such as sample ascertainment, lower intelligence quotient (IQ), the inclusion of patients with nonidiopathic autism, age, and gender. However, critical review of the literature reveals that the rate in idiopathic cases with normal IQ is still significantly above the population risk suggesting that autism itself is associated with an increased risk of epilepsy. Recently, there has been interest in the occurrence of epileptiform electroencephalograms (EEGs) even in the absence of epilepsy. Rates as high as 60% have been reported and some investigators propose that these abnormalities may play a causal role in the autism phenotype. Although this phenomenon is still not well understood and risk factors have yet to be determined, the treatment implications are increasingly important. We review the recent literature to elucidate possible risk factors for both epilepsy and epileptiform EEGs. We then review existing data and discuss controversies surrounding treatment of EEG abnormalities.

Neurometabolic disorders and dysfunction in autism spectrum disorders.

The cause of autism remains largely unknown because it is likely multifactorial, arising from the interaction of biologic, genetic, and environmental factors. The specific role of metabolic abnormalities also is largely unknown, but current research may provide insight into the pathophysiologic underpinnings of autism, at least in some patients. We review a number of known neurometabolic disorders identified as having an autistic phenotype. We also discuss the possible involvement of mitochondrial disorders and dysfunction as well as a theory regarding an increased vulnerability to oxidative stress, by which various environmental toxins produce metabolic alterations that impair normal cellular function. Finally, we review various strategies for metabolic work-up and treatment. Accurate diagnosis of neurometabolic disorders and a broader understanding of underlying metabolic disturbance even in the absence of known disease have important implications both for individual patients and for research into the etiology of autism.

Evaluation and Management of the Child With Autism Spectrum Disorder.

PURPOSE OF REVIEW: Autism spectrum disorder is a neurodevelopmental disorder defined by deficits in social communication and the presence of restricted and repetitive behaviors and interests. This article provides the tools to diagnose and manage patients with autism spectrum disorder. RECENT FINDINGS: Autism spectrum disorder is a heterogeneous condition with varying presentations, multiple etiologies, and a number of comorbidities that impact the course and management of the disorder. This article defines the core features of social communication deficits, including problems with social reciprocity, decreased nonverbal communication, and difficulties in developing and maintaining relationships. The second domain of repetitive behaviors and restricted interests, which includes the presence of stereotyped behaviors or speech, insistence on sameness and behavioral rigidity, intense or out of the ordinary interests, and unusual responses to sensory stimulation, is also delineated. Comorbidities commonly seen with autism spectrum disorder include medical, neurologic, and psychiatric conditions. Despite intense research efforts, the etiology of autism spectrum disorder remains unknown in most cases, but it is clear that a strong genetic component exists that interacts with various environmental risk factors. Current research is identifying overlapping neurobiological pathways that are involved in pathogenesis. Treatment involves intensive behavioral therapy and educational programming along with traditional ancillary services, such as speech/language, occupational, and physical therapies. Psychopharmacologic treatments are also used to target certain symptoms and comorbid conditions. SUMMARY: Neurologists can play an important role in diagnosing autism spectrum disorder according to clinical criteria through a comprehensive evaluation that includes a thorough medical and developmental history, behavioral and play observations, and a review of standardized cognitive and language evaluations. Neurologists are also responsible for investigating etiologies, recommending and advocating for appropriate behavioral and educational interventions, and identifying and often managing comorbidities.

Psychometric testing of a person-centred care scale the Eden Warmth Survey in a long-term care home in New Zealand.

BACKGROUND: Traditional nursing homes have been viewed as dominated by the medical model. Since the 1990s, the Eden Alternative(TM) has become a significant model in systemic transformations in nursing homes. The purpose of this study was to evaluate the psychometric performance of the 20 items of the Eden Warmth Survey - Residents (EWS-R) in an aged-care home. DESIGN: A resident's satisfaction survey was used to collect a sample of 85 long-term care home residents. METHODS: Psychometric evaluation included item analyses, reliability including internal consistency and stability, criterion-related validity and construct validity. RESULTS: The reduced 13 items demonstrated adequate reliability (α = 0.82) with two factors, Trust and Connectedness with Others and Care Practices, extracted and contributed to 57.9% of the total variance. CONCLUSIONS: The 13-item of EWS-R can be considered as a reliable and predictive scale for assessing quality of life and overall satisfaction on people living in long-term care facilities.