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Papers of the Week

  • 1) J Neurosci. 2015 Apr 8;35(14):5837-50. doi: 10.1523/JNEUROSCI.5182-14.2015.

    Idiosyncratic brain activation patterns are associated with poor social comprehension in autism.

    Byrge L(1), Dubois J(2), Tyszka JM(3), Adolphs R(3), Kennedy DP(4).
    
    Author information: 
    (1)Department of Psychological and Brain Sciences, Indiana University,
    Bloomington, Indiana 47405, and lbyrge@indiana.edu jcrdubois@gmail.com.
    (2)Division of Humanities and Social Sciences, California Institute of
    Technology, Pasadena, California 91125 lbyrge@indiana.edu jcrdubois@gmail.com.
    (3)Division of Humanities and Social Sciences, California Institute of
    Technology, Pasadena, California 91125. (4)Department of Psychological and Brain 
    Sciences, Indiana University, Bloomington, Indiana 47405, and.
    
    Autism spectrum disorder (ASD) features profound social deficits but neuroimaging
    studies have failed to find any consistent neural signature. Here we connect
    these two facts by showing that idiosyncratic patterns of brain activation are
    associated with social comprehension deficits. Human participants with ASD (N =
    17) and controls (N = 20) freely watched a television situation comedy (sitcom)
    depicting seminaturalistic social interactions ("The Office", NBC Universal) in
    the scanner. Intersubject correlations in the pattern of evoked brain activation 
    were reduced in the ASD group-but this effect was driven entirely by five ASD
    subjects whose idiosyncratic responses were also internally unreliable. The
    idiosyncrasy of these five ASD subjects was not explained by detailed
    neuropsychological profile, eye movements, or data quality; however, they were
    specifically impaired in understanding the social motivations of characters in
    the sitcom. Brain activation patterns in the remaining ASD subjects were
    indistinguishable from those of control subjects using multiple multivariate
    approaches. Our findings link neurofunctional abnormalities evoked by
    seminaturalistic stimuli with a specific impairment in social comprehension, and 
    highlight the need to conceive of ASD as a heterogeneous classification.
    
    Copyright © 2015 the authors 0270-6474/15/355837-14$15.00/0.
    
    PMID: 25855192  [PubMed - in process]
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  • 2) Front Hum Neurosci. 2015 Mar 26;9:159. doi: 10.3389/fnhum.2015.00159. eCollection 2015.

    The first 1000 days of the autistic brain: a systematic review of diffusion imaging studies.

    Conti E(1), Calderoni S(2), Marchi V(1), Muratori F(1), Cioni G(1), Guzzetta
    A(1).
    
    Author information: 
    (1)Department of Developmental Neuroscience, Stella Maris Scientific Institute,
    IRCCS Stella Maris Foundation Pisa, Italy ; Department of Clinical and
    Experimental Medicine, University of Pisa Pisa, Italy. (2)Department of
    Developmental Neuroscience, Stella Maris Scientific Institute, IRCCS Stella Maris
    Foundation Pisa, Italy.
    
    There is overwhelming evidence that autism spectrum disorder (ASD) is related to 
    altered brain connectivity. While these alterations are starting to be well
    characterized in subjects where the clinical picture is fully expressed, less is 
    known on their earlier developmental course. In the present study we
    systematically reviewed current knowledge on structural connectivity in ASD
    infants and toddlers. We searched PubMed and Medline databases for all English
    language papers, published from year 2000, exploring structural connectivity in
    populations of infants and toddlers whose mean age was below 30 months. Of the
    264 papers extracted, four were found to be eligible and were reviewed. Three of 
    the four selected studies reported higher fractional anisotropy values in
    subjects with ASD compared to controls within commissural fibers, projections
    fibers, and association fibers, suggesting brain hyper-connectivity in the
    earliest phases of the disorder. Similar conclusions emerged from the other
    diffusion parameters assessed. These findings are reversed to what is generally
    found in studies exploring older patient groups and suggest a developmental
    course characterized by a shift toward hypo-connectivity starting at a time
    between two and four years of age.
    
    PMID: 25859207  [PubMed]
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  • 3) Nat Neurosci. 2015 Apr 13. doi: 10.1038/nn.3996. [Epub ahead of print]

    A coding-independent function of an alternative Ube3a transcript during neuronal development.

    Valluy J(1), Bicker S(1), Aksoy-Aksel A(1), Lackinger M(1), Sumer S(1), Fiore
    R(1), Wüst T(2), Seffer D(3), Metge F(4), Dieterich C(4), Wöhr M(3), Schwarting
    R(3), Schratt G(1).
    
    Author information: 
    (1)Institute of Physiological Chemistry, Biochemical-Pharmacological Center
    Marburg, Philipps University Marburg, Marburg, Germany. (2)Interdisciplinary
    Center for Neurosciences, SFB488 Junior Group, University Heidelberg, Heidelberg,
    Germany. (3)Behavioral Neuroscience, Experimental and Biological Psychology,
    Philipps-University Marburg, Marburg, Germany. (4)Max Planck Institute for
    Biology of Ageing, Computational RNA Biology Lab, Cologne, Germany.
    
    The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent
    synapse development and plasticity. Ube3a mutations cause Angelman syndrome and
    have been associated with autism spectrum disorders (ASD). However, the
    biological significance of alternative Ube3a transcripts generated in mammalian
    neurons remains unknown. We report here that Ube3a1 RNA, a transcript that
    encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant 
    dendrite growth and promotes spine maturation in rat hippocampal neurons.
    Surprisingly, Ube3a1 RNA function was independent of its coding sequence but
    instead required a unique 3' untranslated region and an intact microRNA pathway. 
    Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134,
    suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA.
    Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo
    is abolished in mice lacking miR-134. Taken together, our results define a
    noncoding function of an alternative Ube3a transcript in dendritic protein
    synthesis, with potential implications for Angelman syndrome and ASD.
    
    PMID: 25867122  [PubMed - as supplied by publisher]
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  • 4) Neuron. 2015 Apr 8. pii: S0896-6273(15)00219-6. doi: 10.1016/j.neuron.2015.03.023. [Epub ahead of print]

    Different Functional Neural Substrates for Good and Poor Language Outcome in Autism.

    Lombardo MV(1), Pierce K(2), Eyler LT(3), Carter Barnes C(2), Ahrens-Barbeau
    C(2), Solso S(2), Campbell K(2), Courchesne E(4).
    
    Author information: 
    (1)Department of Psychology, University of Cyprus, 1 Panepistimiou Avenue,
    Aglantzia, Nicosia 1678, Cyprus; Center for Applied Neuroscience, University of
    Cyprus, 1 Panepistimiou Avenue, Aglantzia, Nicosia 1678, Cyprus; Autism Research 
    Centre, Department of Psychiatry, University of Cambridge, Douglas House, 18B
    Trumpington Road, Cambridge CB2 8AH, UK. Electronic address:
    mvlombardo@gmail.com. (2)Autism Center of Excellence, Department of Neuroscience,
    University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201,
    La Jolla, CA 92093, USA. (3)Autism Center of Excellence, Department of
    Neuroscience, University of California, San Diego, 8110 La Jolla Shores Drive,
    Suite 201, La Jolla, CA 92093, USA; Department of Psychiatry, University of
    California, San Diego, 9500 Gilman Drive, La Jolla, CA 92161, USA; VISN 22 Mental
    Illness Research, Education, and Clinical Center, VA San Diego Healthcare System,
    3350 La Jolla Village Drive, San Diego, CA 92161, USA. (4)Autism Center of
    Excellence, Department of Neuroscience, University of California, San Diego, 8110
    La Jolla Shores Drive, Suite 201, La Jolla, CA 92093, USA. Electronic address:
    ecourchesne@ucsd.edu.
    
    Autism (ASD) is vastly heterogeneous, particularly in early language development.
    While ASD language trajectories in the first years of life are highly unstable,
    by early childhood these trajectories stabilize and are predictive of longer-term
    outcome. Early neural substrates that predict/precede such outcomes are largely
    unknown, but could have considerable translational and clinical impact.
    Pre-diagnosis fMRI response to speech in ASD toddlers with relatively good
    language outcome was highly similar to non-ASD comparison groups and robustly
    recruited language-sensitive superior temporal cortices. In contrast,
    language-sensitive superior temporal cortices were hypoactive in ASD toddlers
    with poor language outcome. Brain-behavioral relationships were atypically
    reversed in ASD, and a multimodal combination of pre-diagnostic clinical
    behavioral measures and speech-related fMRI response showed the most promise as
    an ASD prognosis classifier. Thus, before ASD diagnoses and outcome become
    clinically clear, distinct functional neuroimaging phenotypes are already present
    that can shed insight on an ASD toddler's later outcome. VIDEO ABSTRACT.
    
    Copyright © 2015 Elsevier Inc. All rights reserved.
    
    PMID: 25864635  [PubMed - as supplied by publisher]
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  • 5) JAMA. 2015 Apr 14;313(14):1425-1434. doi: 10.1001/jama.2015.2707.

    Association of Maternal Diabetes With Autism in Offspring.

    Xiang AH(1), Wang X(1), Martinez MP(1), Walthall JC(2), Curry ES(3), Page K(4),
    Buchanan TA(5), Coleman KJ(1), Getahun D(6).
    
    Author information: 
    (1)Department of Research and Evaluation, Kaiser Permanente Southern California, 
    Pasadena. (2)Department of Psychiatry, Kaiser Permanente Southern California,
    Pasadena. (3)Department of Pediatrics, Kaiser Permanente Southern California,
    Pasadena. (4)Division of Endocrinology and Diabetes, Keck School of Medicine,
    University of Southern California, Los Angeles. (5)Division of Endocrinology and 
    Diabetes, Keck School of Medicine, University of Southern California, Los
    Angeles5Department of Medicine, Keck School of Medicine, University of Southern
    California, Los Angeles. (6)Department of Research and Evaluation, Kaiser
    Permanente Southern California, Pasadena6Department of Obstetrics and Gynecology,
    Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey.
    
    Importance: Information about the association of maternal diabetes and autism
    spectrum disorders (ASDs) in offspring is limited, with no report on the
    importance of timing of exposure during gestation.
    Objective: To assess ASD risk associated with intrauterine exposure to
    preexisting type 2 diabetes and gestational diabetes mellitus (GDM) by
    gestational age at GDM diagnosis.
    Design, Setting, and Patients: Retrospective longitudinal cohort study including 
    322 323 singleton children born in 1995-2009 at Kaiser Permanente Southern
    California (KPSC) hospitals. Children were tracked from birth until the first of 
    the following: date of clinical diagnosis of ASD, last date of continuous KPSC
    health plan membership, death due to any cause, or December 31, 2012. Relative
    risks of ASD were estimated by hazard ratios (HRs) using Cox regression models
    adjusted for birth year.
    Exposures: Maternal preexisting type 2 diabetes (n = 6496), GDM diagnosed at 26
    weeks' gestation or earlier (n = 7456) or after 26 weeks' gestation (n = 17 579),
    or no diabetes (n = 290 792) during the index pregnancy.
    Main Outcomes and Measures: Clinical diagnosis of ASD in offspring.
    Results: During follow-up, 3388 children were diagnosed as having ASD (115
    exposed to preexisting type 2 diabetes, 130 exposed to GDM at ≤26 weeks, 180
    exposed to GDM at >26 weeks, and 2963 unexposed). Unadjusted annual ASD
    incidences were 3.26, 3.02, 1.77, and 1.77 per 1000 among children of mothers
    with preexisting type 2 diabetes, GDM diagnosed at 26 weeks or earlier, GDM
    diagnosed after 26 weeks, and no diabetes, respectively. The birth year-adjusted 
    HRs were 1.59 (95% CI, 1.29-1.95) for preexisting type 2 diabetes, 1.63 (95% CI, 
    1.35-1.97) for GDM diagnosed at 26 weeks or earlier, and 0.98 (95% CI, 0.84-1.15)
    for GDM diagnosed after 26 weeks relative to no exposure. After adjustment for
    maternal age, parity, education, household income, race/ethnicity, history of
    comorbidity, and sex of the child, maternal preexisting type 2 diabetes was not
    significantly associated with risk of ASD in offspring (HR, 1.21; 95% CI,
    0.97-1.52), but GDM diagnosed at 26 weeks or earlier remained so (HR, 1.42; 95%
    CI, 1.15-1.74). Antidiabetic medication exposure was not independently associated
    with ASD risk. Adjustment for a mother or older sibling with ASD in the full
    cohort and for maternal smoking, prepregnancy body mass index, and gestational
    weight gain in the subset with available data (n = 68 512) did not affect the
    results.
    Conclusions and Relevance: In this large, multiethnic clinical cohort of
    singleton children born at 28 to 44 weeks' gestation, exposure to maternal GDM
    diagnosed by 26 weeks' gestation was associated with risk of ASD in offspring.
    
    PMID: 25871668  [PubMed - as supplied by publisher]
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  • 6) PLoS One. 2015 Apr 13;10(4):e0123693. doi: 10.1371/journal.pone.0123693.

    Circadian Cycle-Dependent MeCP2 and Brain Chromatin Changes.

    Martínez de Paz A(1), Vicente Sanchez-Mut J(1), Samitier-Martí M(1), Petazzi
    P(1), Sáez M(1), Szczesna K(1), Huertas D(1), Esteller M(2), Ausió J(3).
    
    Author information: 
    (1)Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
    Institute (IDIBELL), Barcelona, Catalonia, Spain. (2)Cancer Epigenetics and
    Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL),
    Barcelona, Catalonia, Spain; Department of Physiological Sciences II, School of
    Medicine, University of Barcelona, Barcelona, Catalonia, Spain; Institució
    Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
    (3)Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
    Institute (IDIBELL), Barcelona, Catalonia, Spain; Department of Biochemistry and 
    Microbiology, University of Victoria, Victoria, British Columbia, Canada.
    
    Methyl CpG binding protein 2 (MeCP2) is a chromosomal protein of the brain, very 
    abundant especially in neurons, where it plays an important role in the
    regulation of gene expression. Hence it has the potential to be affected by the
    mammalian circadian cycle. We performed expression analyses of mice brain frontal
    cortices obtained at different time points and we found that the levels of MeCP2 
    are altered circadianly, affecting overall organization of brain chromatin and
    resulting in a circadian-dependent regulation of well-stablished MeCP2 target
    genes. Furthermore, this data suggests that alterations of MeCP2 can be
    responsible for the sleeping disorders arising from pathological stages, such as 
    in autism and Rett syndrome.
    
    PMID: 25875630  [PubMed - as supplied by publisher]
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  • 7) Immunity. 2015 Apr 21;42(4):679-691. doi: 10.1016/j.immuni.2015.03.013.

    Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

    Cronk JC(1), Derecki NC(2), Ji E(3), Xu Y(4), Lampano AE(4), Smirnov I(3), Baker 
    W(3), Norris GT(2), Marin I(2), Coddington N(3), Wolf Y(5), Turner SD(6), Aderem 
    A(7), Klibanov AL(8), Harris TH(2), Jung S(5), Litvak V(9), Kipnis J(10).
    
    Author information: 
    (1)Center for Brain Immunology and Glia, School of Medicine, University of
    Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of
    Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate
    Program in Neuroscience, School of Medicine, University of Virginia,
    Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of
    Medicine, University of Virginia, Charlottesville, VA 22908, USA. (2)Center for
    Brain Immunology and Glia, School of Medicine, University of Virginia,
    Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine,
    University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in
    Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA
    22908, USA. (3)Center for Brain Immunology and Glia, School of Medicine,
    University of Virginia, Charlottesville, VA 22908, USA; Department of
    Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA
    22908, USA. (4)Department of Microbiology and Physiological Systems, University
    of Massachusetts Medical School, Worcester, MA 01655, USA. (5)Department of
    Immunology, Weizmann Institute of Science, Rehovot Israel 76100. (6)Department of
    Public Health Sciences, School of Medicine, University of Virginia,
    Charlottesville, VA 22908, USA. (7)Seattle Biomedical Research Institute,
    Seattle, WA 98109, USA. (8)Cardiovascular Research Center, Cardiovascular
    Division, Department of Internal Medicine, School of Medicine, University of
    Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering,
    School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
    (9)Department of Microbiology and Physiological Systems, University of
    Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address:
    vladimir.litvak@umassmed.edu. (10)Center for Brain Immunology and Glia, School of
    Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of
    Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA
    22908, USA; Graduate Program in Neuroscience, School of Medicine, University of
    Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program,
    School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
    Electronic address: kipnis@virginia.edu.
    
    Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 
    2, are the predominant cause of Rett syndrome, a disease characterized by both
    neurological symptoms and systemic abnormalities. Microglial dysfunction is
    thought to contribute to disease pathogenesis, and here we found microglia become
    activated and subsequently lost with disease progression in Mecp2-null mice.
    Mecp2 was found to be expressed in peripheral macrophage and monocyte
    populations, several of which also became depleted in Mecp2-null mice. RNA-seq
    revealed increased expression of glucocorticoid- and hypoxia-induced transcripts 
    in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was
    found to regulate inflammatory gene transcription in response to TNF stimulation.
    Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of
    otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and 
    macrophage responsiveness to environmental stimuli to promote homeostasis.
    Dysfunction of tissue-resident macrophages might contribute to the systemic
    pathologies observed in Rett syndrome.
    
    Copyright © 2015 Elsevier Inc. All rights reserved.
    
    PMID: 25902482  [PubMed - as supplied by publisher]
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  • 8) J Autism Dev Disord. 2015 Apr 16. [Epub ahead of print]

    Brief Report of Preliminary Outcomes of an Emotion Regulation Intervention for Children with Autism Spectrum Disorder.

    Thomson K(1), Burnham Riosa P, Weiss JA.
    
    Author information: 
    (1)Department of Psychology, York University, Rm. 230, Behavioral Science
    Building, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
    
    Children with autism spectrum disorder (ASD) often present with comorbid
    psychopathology including problems with emotion regulation. The goal of the
    present research was to investigate the feasibility of a multicomponent
    manualized cognitive behavior therapy treatment program for improving emotion
    regulation in youth with ASD 8-12 years of age. Thirteen males and their parents 
    participated in the intervention, reporting high satisfaction with the activities
    and program overall, and attending all sessions. Preliminary outcomes regarding
    emotion regulation and psychopathology, and feasibility of the intervention, are 
    summarized and discussed.
    
    PMID: 25877014  [PubMed - as supplied by publisher]
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  • 9) Neuroimage. 2015 Apr 15. pii: S1053-8119(15)00312-2. doi: 10.1016/j.neuroimage.2015.04.022. [Epub ahead of print]

    Neuroimaging Data Sharing on the Neuroinformatics Database Platform.

    Book GA(1), Stevens M(2), Assaf M(3), Glahn D(2), Pearlson GD(3).
    
    Author information: 
    (1)Olin Neuropsychiatry Research Center, Hartford Hospital, Hartford CT.
    Electronic address: gregory.a.book@gmail.com. (2)Olin Neuropsychiatry Research
    Center, Hartford Hospital, Hartford CT. (3)Olin Neuropsychiatry Research Center, 
    Hartford Hospital, Hartford CT; Yale University, Department of Psychiatry, New
    Haven, CT.
    
    We describe the Neuroinformatics Database (NiDB), an open-source database
    platform for archiving, analysis, and sharing of neuroimaging data. Data from the
    multi-site projects Autism Brain Imaging Data Exchange (ABIDE),
    Bipolar-Schizophrenia Network on Intermediate Phenotypes parts one and two
    (B-SNIP1, B-SNIP2), and Monetary Incentive Delay task (MID) are available for
    download from the public instance of NiDB, with more projects sharing data as it 
    becomes available. As demonstrated by making several large datasets available,
    NiDB is an extensible platform appropriately suited to archive and distribute
    shared neuroimaging data.
    
    Copyright © 2015 Elsevier Inc. All rights reserved.
    
    PMID: 25888923  [PubMed - as supplied by publisher]
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  • 10) J Pediatr. 2015 Apr 14. pii: S0022-3476(15)00254-1. doi: 10.1016/j.jpeds.2015.03.007. [Epub ahead of print]

    Parental Concerns, Provider Response, and Timeliness of Autism Spectrum Disorder Diagnosis.

    Zuckerman KE(1), Lindly OJ(2), Sinche BK(3).
    
    Author information: 
    (1)Division of General Pediatrics, Doernbecher Children's Hospital Oregon Health 
    & Science University, Portland, OR. Electronic address: zuckerma@ohsu.edu.
    (2)Division of General Pediatrics, Doernbecher Children's Hospital Oregon Health 
    & Science University, Portland, OR; School of Public Health, Oregon State
    University, Corvallis, OR. (3)Division of General Pediatrics, Doernbecher
    Children's Hospital Oregon Health & Science University, Portland, OR.
    
    OBJECTIVES: To assess differences between child age at first parental concern and
    age at first parental discussion of concerns with a health care provider among
    children with autism spectrum disorder (ASD) vs those with intellectual
    disability/developmental delay (ID/DD), and to assess whether provider response
    to parental concerns is associated with delays in ASD diagnosis.
    STUDY DESIGN: Using nationally representative data from the 2011 Survey of
    Pathways to Diagnosis and Treatment, we compared child age at parent's first
    developmental concern with age at first discussion of concerns with a provider,
    and categorized provider response as proactive or reassuring/passive, among 1420 
    children with ASD and 2098 children with ID/DD. In the children with ASD, we
    tested the association between provider response type and years of diagnostic
    delay.
    RESULTS: Compared with children with ID/DD, children with ASD were younger when
    parents first had concerns and first discussed those concerns with a provider.
    Compared with parents of children with ID/DD, parents of children with ASD were
    less likely to receive proactive responses to their concerns and more likely to
    receive reassuring/passive responses. Among children with ASD, those with more
    proactive provider responses to concerns had shorter delays in ASD diagnosis
    compared with those with passive/reassuring provider responses.
    CONCLUSION: Although parents of children with ASD have early concerns, delays in 
    diagnosis are common, particularly when providers' responses are reassuring or
    passive, highlighting the need for targeted improvements in primary care.
    
    Copyright © 2015 Elsevier Inc. All rights reserved.
    
    PMID: 25888348  [PubMed - as supplied by publisher]
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