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Purpose Auditory-perceptual assessment, in which trained listeners rate a large number of perceptual features of speech samples, is the gold standard for the differential diagnosis of motor speech disorders. The goal of this study was to investigate the feasibility of applying a similar, formalized auditory-perceptual approach to the assessment of language deficits in connected speech samples from individuals with aphasia. Method Twenty-seven common features of connected speech in aphasia were defined, each of which was rated on a 5-point scale. Three experienced researchers evaluated 24 connected speech samples from the AphasiaBank database, and 12 student clinicians evaluated subsets of 8 speech samples each. We calculated interrater reliability for each group of raters and investigated the validity of the auditory-perceptual approach by comparing feature ratings to related quantitative measures derived from transcripts and clinical measures, and by examining patterns of feature co-occurrence. Results Most features were rated with good-to-excellent interrater reliability by researchers and student clinicians. Most features demonstrated strong concurrent validity with respect to quantitative connected speech measures computed from AphasiaBank transcripts and/or clinical aphasia battery subscores. Factor analysis showed that 4 underlying factors, which we labeled Paraphasia, Logopenia, Agrammatism, and Motor Speech, accounted for 79% of the variance in connected speech profiles. Examination of individual patients' factor scores revealed striking diversity among individuals classified with a given aphasia type. Conclusion Auditory-perceptual rating of connected speech in aphasia shows potential to be a comprehensive, efficient, reliable, and valid approach for characterizing connected speech in aphasia.

Irritability is a common feature of many psychiatric disorders, including both externalizing and internalizing disorders. There is little research, however, examining associations between irritability and these symptom domains, particularly during the important developmental period of adolescence, characterized by sex differences in the prevalence of disorders. We examined the cross-sectional associations between irritability, measured with the Affective Reactivity Index, and symptoms of externalizing and internalizing domains of psychopathology, measured with the Youth Self Report, in a volunteer community sample ( = 183) of 9- to 13-year-old (= 11.39, = 1.07) boys and girls (37% White/Caucasian, 8% Asian, 11% Hispanic, 8% African American, 2% Native American, 2% Pacific Islander, 28% Other, and 3% not reported). A subset of the sample ( = 112) provided data at a 2-year follow-up, used to extend these associations. There were no sex differences in levels of irritability; however, the associations between irritability and symptom domains were moderated by sex. Specifically, in girls, irritability was associated equally with externalizing and internalizing symptoms. In contrast, in boys, irritability was associated more strongly with externalizing symptoms than with internalizing symptoms. Thus, across both sexes, irritability was moderately associated with externalizing symptoms, but the association between irritability and internalizing symptoms was stronger in girls than in boys. At follow-up, sex moderated the association between baseline irritability and later externalizing and internalizing symptoms. These findings indicate that irritability is associated with both externalizing and internalizing symptoms in early adolescence and that irritability is associated with internalizing symptoms more strongly in girls than in boys.

Although histological subtype still underlies tumour classification and treatment, the recognition that lung cancer is, largely, a genetic disease has prompted a push to reconfigure cancer taxonomies according to molecular criteria. In this review, we discuss established (e.g. EGFR, ALK, ROS1, and programmed cell death 1/programmed death-ligand 1), emerging (e.g. MET, RET, and NTRK) and elusive (e.g. TP53, KRAS, and MYC) molecular targets in the treatment of lung cancer. We synthesize a large and rapidly growing body of literature regarding the discovery and therapeutic inhibition of these targets in lung cancer. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

CONTEXT - - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA.
OBJECTIVES - - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making.
DESIGN - - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA.
RESULTS - - The panel is proposing 11 recommendations with strong agreement from the open-comment participants.
RECOMMENDATIONS - - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance.
CONCLUSIONS - - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.

To facilitate fine-scale phenotyping of whole specimens, we describe here a set of tissue fixation-embedding, detergent-clearing and staining protocols that can be used to transform excised organs and whole organisms into optically transparent samples within 1-2 weeks without compromising their cellular architecture or endogenous fluorescence. PACT (passive CLARITY technique) and PARS (perfusion-assisted agent release in situ) use tissue-hydrogel hybrids to stabilize tissue biomolecules during selective lipid extraction, resulting in enhanced clearing efficiency and sample integrity. Furthermore, the macromolecule permeability of PACT- and PARS-processed tissue hybrids supports the diffusion of immunolabels throughout intact tissue, whereas RIMS (refractive index matching solution) grants high-resolution imaging at depth by further reducing light scattering in cleared and uncleared samples alike. These methods are adaptable to difficult-to-image tissues, such as bone (PACT-deCAL), and to magnified single-cell visualization (ePACT). Together, these protocols and solutions enable phenotyping of subcellular components and tracing cellular connectivity in intact biological networks.

Imaging mass spectrometry (IMS) has become a valuable tool for the production of molecular maps in samples ranging from solid inorganic materials to biologicals such as cells and tissues. The unique features of IMS are its ability to map a wide variety of different types of molecules, its superb molecular specificity, and its potential for discovery since no target-specific reagents are needed. IMS has made significant contributions in biology and medicine and promises to be a next generation tool in anatomic pathology.

Institutional rearing of young children has been demonstrated to increase risk for a broad range of psychiatric disorders and other impairments. This has led many countries to consider or to invest in foster care. However, no study to date has explored potential differences in psychiatric symptoms in children placed in different types of foster care. We assessed internalizing disorders, externalizing disorders, and attention deficit hyperactivity disorder (ADHD) in 54-month-old children living with foster families. We compared one group of children living in high-quality foster families who had benefited from specialized training and support to another group of children placed with government-sponsored foster care in Bucharest, Romania. After controlling for duration of time spent in foster care, there was a main group effect in predicting ADHD (p = .021) and a marginal group × gender interaction effect. No effects were noted for signs of externalizing disorders. There was, however, a significant group × gender interaction effect of signs of internalizing disorders (p = .007), with the girls in high-quality foster care having less severe symptomatology than did their counterparts in the government-sponsored group. Governments must invest in quality interventions for their most vulnerable citizens to prevent serious and potentially lasting problems.
© 2014 Michigan Association for Infant Mental Health.

Current frameworks for understanding the link between early adverse childhood experiences and later negative life outcomes, including psychopathology, focus on the mediating negative impact on brain and biological systems in the developing child resulting broadly from stress and trauma. Although this approach is useful, we argue that the framework could be functionally extended by distinguishing the effects of two different types of abnormal input, both deviations from the expectable environment in early childhood. Specifically, we review the consequences of inadequate input (eg, neglect/deprivation) and harmful input (eg, abuse/trauma) on brain and biological development. We then review evidence on the differential links between each type of abnormal input to four selected domains of psychopathology (indiscriminate social behavior, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and conduct problems), and consider potential mechanisms for inadequate and harmful input to lead to these outcomes. We conclude that the careful consideration of the type of deviation from the expected environment, while acknowledging the practical difficulties in assessing this, is likely to lead to clearer understanding of the mechanism of risk for psychopathology, and that tailored approaches to prevention and intervention may be informed by considering the unique consequences of inadequate and harmful input when experienced in early childhood.

IMPORTANCE - Mental disorders predict future occurrences of both the same disorder (homotypic continuity) and other disorders (heterotypic continuity). Heterotypic continuity is inconsistent with a view of mental disorders as fixed entities. In contrast, hierarchical-dimensional conceptualizations of psychopathology, in which each form of psychopathology is hypothesized to have both unique and broadly shared etiologies and mechanisms, predict both homotypic and heterotypic continuity.
OBJECTIVE - To test predictions derived from a hierarchical-dimensional model of psychopathology that (1) heterotypic continuity is widespread, even controlling for homotypic continuity, and that (2) the relative magnitudes of heterotypic continuities recapitulate the relative magnitudes of cross-sectional correlations among diagnoses at baseline.
DESIGN, SETTING, AND PARTICIPANTS - Ten prevalent diagnoses were assessed in the same person twice (ie, in 2 waves separated by 3 years). We used a representative sample of adults in the United States (i.e., 28,958 participants 18-64 years of age in the National Epidemiologic Study of Alcohol and Related Conditions who were assessed in both waves).
MAIN OUTCOMES AND MEASURES - Diagnoses from reliable and valid structured interviews.
RESULTS - Adjusting for sex and age, we found that bivariate associations of all pairs of diagnoses from wave 1 to wave 2 exceeded chance levels (P < .05) for all homotypic (median tetrachoric correlation of ρ = 0.54 [range, 0.41-0.79]) and for nearly all heterotypic continuities (median tetrachoric correlation of ρ = 0.28 [range, 0.07-0.50]). Significant heterotypic continuity was widespread even when all wave 1 diagnoses (including the same diagnosis) were simultaneous predictors of each wave 2 diagnosis. The rank correlation between age- and sex-adjusted tetrachoric correlation for cross-sectional associations among wave 1 diagnoses and for heterotypic associations from wave 1 to wave 2 diagnoses was ρ = 0.86 (P < .001).
CONCLUSIONS AND RELEVANCE - For these prevalent mental disorders, heterotypic continuity was nearly universal and not an artifact of failure to control for homotypic continuity. Furthermore, the relative magnitudes of heterotypic continuity closely mirrored the relative magnitudes of cross-sectional associations among these disorders, consistent with the hypothesis that both sets of associations reflect the same factors. Mental disorders are not fixed and independent entities. Rather, each diagnosis is robustly related to other diagnoses in a correlational structure that is manifested both concurrently and in patterns of heterotypic continuity across time.