Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically-defined entry points for mechanistic investigation. The 3q29 deletion (3q29Del) is one such variant, conferring a 40-100-fold increased risk for schizophrenia, as well as high risk for autism and intellectual disability. However, the mechanisms leading to neurodevelopmental disability remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in individuals with 3q29Del (N = 24) and neurotypical controls (N = 1608) using structural MRI. Given prior radiology reports of posterior fossa abnormalities in 3q29Del, we focused our investigation on the cerebellum and its tissue-types and lobules. Additionally, we compared the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del and controls and examined the association between neuroanatomical findings and quantitative traits to probe gene-brain-behavior relationships. 3q29Del participants had smaller cerebellar cortex volumes than controls, before and after correction for intracranial volume (ICV). An anterior-posterior gradient emerged in finer grained lobule-based and voxel-wise analyses. 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction and displayed elevated rates of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Cerebellar white matter and subregional gray matter volumes were associated with visual-perception and visual-motor integration skills as well as IQ, while cystic/cyst-like malformations yielded no behavioral link. In summary, we find that abnormal development of cerebellar structures may represent neuroimaging-based biomarkers of cognitive and sensorimotor function in 3q29Del, adding to the growing evidence identifying cerebellar pathology as an intersection point between syndromic and idiopathic forms of neurodevelopmental disabilities.

Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Development of attention from birth to 5 months in infants at risk for autism spectrum disorder.

Social-communication skills emerge within the context of rich social interactions, facilitated by an infant's capacity to attend to people and objects in the environment. Disruption in this early neurobehavioral process may decrease the frequency and quality of social interactions and learning opportunities, potentially leading to downstream deleterious effects on social development. This study examined early attention in infant siblings of children with autism spectrum disorder (ASD) who are at risk for social and communication delays. Visual and auditory attention was mapped from age 1 week to 5 months in infants at familial risk for ASD (high risk; N = 41) and low-risk typically developing infants (low risk; N = 39). At 12 months, a subset of participants (N = 40) was administered assessments of social communication and nonverbal cognitive skills. Results revealed that high-risk infants performed lower on attention tasks at 2 and 3 months of age compared to low-risk infants. A significant association between overall attention at 3 months and developmental outcome at 12 months was observed for both groups. These results provide evidence for early vulnerabilities in visual attention for infants at risk for ASD during a period of important neurodevelopmental transition (between 2 and 3 months) when attention has significant implications for social communication and cognitive development.

Screening for Autism Spectrum Disorder: Profiles of Children Who Are Missed.

OBJECTIVE: To characterize children presenting with concerns for autism spectrum disorder (ASD) missed by parent-report screeners and to examine benefits of a combined screening approach with the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) and the Ages and Stages Questionnaire, Third Edition (ASQ-3). METHODS: Participants included were 154 children aged 16 to 42 months presenting for an evaluation at an autism center. Caregivers completed the M-CHAT-R, ASQ-3, and a demographic questionnaire. Children participated in an autism diagnostic evaluation consisting of the Mullen Scales of Early Learning (Mullen) and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). RESULTS: A total of 124 children (81%) were diagnosed with ASD. The M-CHAT-R identified 85% (n = 105) of these children. Children with ASD missed by the M-CHAT-R had significantly higher scores on the Mullen and significantly lower scores on the ADOS-2. Of the ASQ-3 domains, the majority (n = 102, 82%) of children with ASD failed the communication domain; missed cases showed similar patterns of higher Mullen scores and lower ADOS-2 scores. When adopting a combined screening approach, using a failed screen from either the M-CHAT-R or ASQ-3 communication domain, 93% of children were identified. Parent-reported concerns on an open-ended questionnaire revealed ASD red flags for many missed cases. CONCLUSION: Children with ASD missed by screeners had higher scores on developmental testing and lower scores on the ADOS-2; however, children still performed below average on developmental tests. Our findings suggest that a combined screening approach was most effective for identifying children with ASD from a sample group referred for an ASD evaluation.

Designing for Clinical Change: Creating an Intervention to Implement New Statin Guidelines in a Primary Care Clinic.

BACKGROUND: Recent clinical practice guidelines from major national organizations, including a joint United States Department of Veterans Affairs (VA) and Department of Defense (DoD) committee, have substantially changed recommendations for the use of the cholesterol-lowering statin medications after years of relative stability. Because statin medications are among the most commonly prescribed treatments in the United States, any change in their use may have significant implications for patients and providers alike. Prior research has shown that effective implementation interventions should be both user centered and specifically chosen to address identified barriers. OBJECTIVE: The objectives of this study were to identify potential determinants of provider uptake of the new statin guidelines and to use that information to tailor a coordinated and streamlined local quality improvement intervention focused on prescribing appropriate statins. METHODS: We employed user-centered design principles to guide the development and testing of a multicomponent guideline implementation intervention to improve statin prescribing. This paper describes the intervention development process whereby semistructured qualitative interviews with providers were conducted to (1) illuminate the knowledge, attitudes, and behaviors of providers and (2) elicit feedback on intervention prototypes developed to align with and support the use of the VA/DoD guidelines. Our aim was to use this information to design a local quality improvement intervention focused on statin prescribing that was tailored to the needs of primary care providers at our facility. Cabana's Clinical Practice Guidelines Framework for Improvement and Nielsen's Usability Heuristics were used to guide the analysis of data obtained in the intervention development process. RESULTS: Semistructured qualitative interviews were conducted with 15 primary care Patient Aligned Care Team professionals (13 physicians and 2 clinical pharmacists) at a single VA medical center. Findings highlight that providers were generally comfortable with the paradigm shift to risk-based guidelines but less clear on the need for the VA/DoD guidelines in specific. Providers preferred a clinical decision support tool that helped them calculate patient risk and guide their care without limiting autonomy. They were less comfortable with risk communication and performance measurement systems that do not account for shared decision making. When possible, we incorporated their recommendations into the intervention. CONCLUSIONS: By combining qualitative methods and user-centered design principles, we could inform the design of a multicomponent guideline implementation intervention to better address the needs and preferences of providers, including clear and direct language, logical decision prompts with an option to dismiss a clinical decision support tool, and logical ordering of feedback information. Additionally, this process allowed us to identify future design considerations for quality improvement interventions.

Maternal morbidity and reproductive outcomes related to fetal surgery.

PURPOSE: The purpose of this manuscript was to examine the maternal morbidity and reproductive outcomes following maternal-fetal surgery with an emphasis on the EXIT procedure. METHODS: The medical records of all women who underwent an ex-utero intrapartum treatment (EXIT) procedure or mid-gestation open maternal fetal surgery (OMFS) at our center from December 2001 to December 2011 were reviewed retrospectively. Future reproductive outcomes were obtained via telephone questionnaire. RESULTS: Thirty-three women underwent maternal-fetal surgery. Twenty-six had EXIT, and seven had OMFS. The questionnaire response was 82% (27/33). Eighty-one percent (17/21) of the EXIT cohort desired future pregnancy. All who attempted (13/13) were successful. The majority (85%) conceived spontaneously and within 2.5 years on average. In the OMFS group, 40% experienced complications. One had uterine dehiscence, and another had uterine rupture requiring urgent delivery at 36 weeks. In subsequent pregnancies, 20% of OMFS cases were complicated by uterine rupture, and 8% of EXIT patients had uterine dehiscence. All had good maternal-fetal outcome. CONCLUSION: Future reproductive capacity and complication rates in subsequent pregnancies following EXIT procedure are similar to those seen in the general population. In contrast, mid-gestation OMFS remains associated with relatively morbid complications. This evidence can help guide in counseling expectant mothers who are faced with the challenge of considering fetal surgery.

Morphological families of self-assembled porphyrin structures and their photosensitization of hydrogen generation.

Varying the solution growth conditions of cooperative binary ionic solids composed of anionic and cationic metalloporphyrins produces a series of families of self-assembled structures that efficiently and durably photosensitize the evolution of hydrogen.