Search

Purpose: This longitudinal study assessed continuity and stability of productive language (vocabulary and grammar) and discourse features (turn-taking; asking and responding to questions) during mother–child play. Method: Parent–child language use in 119 Spanish-speaking, Mexican immigrant mothers and their children at two ages ( M = 2.5 and 3.6 years) was evaluated from transcriptions of interactions. Results: Child productive language significantly increased over the year, whereas mothers showed commensurate increases in vocabulary diversity but very little change in grammatical complexity. Mother–child discourse was characterized by discontinuity: Mothers decreased their turn length and asked fewer questions while children increased on both measures. Rates of responding to questions remained high for both mothers and children even as children increased and mothers decreased over time. Mothers and children showed significant rank-order stability in productive language and measures of discourse. Mothers' rate of asking questions and children's responses to questions during the first interaction predicted children's receptive vocabulary a year later. Conclusions: As children become more sophisticated communicators, language input remains important, with discourse features growing in relevance. Children's early opportunities to respond to parents' questions in the context of play benefit their language skills. This work extends the evidence base from monolingual English-speaking families and is interpreted in the context of prior research on parenting practices in U.S. families of Mexican origin.

Children learning two languages (Dual Language Learners; DLLs) represent a rapidly growing population in the United States. DLLs are disproportionately more likely to live in families of low socioeconomic status (SES), which places many of them at risk for poor dual-language outcomes. To date, most studies on SES and dual language development have relied on static measures of vocabulary and syntactic skills, without examining the language learning processes – children’s ability to acquire new language items. The current study used a newly developed language measure, the Quick Interactive Language Screener: English and Spanish (QUILS:ES), to assess 3- through 5-year-old Spanish-English DLLs’ language learning processes. We also examined the association between SES (as measured by primary caregivers’ education) and language learning processes, and further explored mechanisms underlying the association. DLLs from higher-SES families showed better language learning skills than those from lower-SES families. The size of the gap did not vary by child age. Home literacy environment (i.e., access to books, book-reading frequency) and children’s existing knowledge (i.e., vocabulary and syntactic knowledge) mediated the SES effect. Together, these findings highlight the need to better prepare DLLs from low-SES families for learning from a dual-language environment. Supporting DLLs’ language environment and knowledge through learning materials and language and literacy activities in both languages is crucial for ameliorating the SES gap in language learning processes.

Infants from low-socioeconomic status (SES) households hear a projected 30 million fewer words than their higher-SES peers. In a recent study, Hirsh-Pasek et al. (Psychological Science, 2015; 26: 1071) found that in a low-income sample, fluency and connectedness in exchanges between caregivers and toddlers predicted child language a year later over and above quantity of talk (Hirsh-Pasek et al., Psychological Science, 2015; 26: 1071). Here, we expand upon this study by examining fluency and connectedness in two higher-SES samples. Using data from the NICHD Study of Early Child Care and Youth Development, we sampled 20 toddlers who had low, average, and high language outcomes at 36 months from each of 2 groups based on income-to-needs ratio (INR; middle and high) and applied new coding to the mother-toddler interaction at 24 months. In the high-INR group, the quality of mother-toddler interaction at 24 months accounted for more variability in language outcomes a year later than did quantity of talk, quality of talk, or sensitive parenting. These results could not be accounted for by child language ability at 24 months. These effects were not found in the middle-INR sample. Our findings suggest that when the quality of interaction, fluency and connectedness, predicts language outcomes, it is a robust relation, but it may not be universal.

This research examined the classification accuracy of the Quick Interactive Language Screener (QUILS) for identifying preschool-aged children (3;0 to 6;9) with developmental language disorder (DLD). We present data from two independent samples that varied in prevalence and diagnostic reference standard.Study 1 included a clinical sample of children (54 with DLD; 13 without) who completed the QUILS and a standardized assessment of expressive grammar (Syntax subtest from the Diagnostic Evaluation of Language Variation-Norm Referenced; Structured Photographic Expressive Language Test-Preschool 2nd Edition; or Structured Photographic Expressive Language Test-3 rd Edition). Study 2 included a community sample of children (25 with DLD; 101 without) who completed the QUILS and the Auditory Comprehension subtest of the Preschool Language Scales-5th Edition (PLS-5; Zimmerman et al., 2011). Discriminant analyses were conducted to compare classification accuracy (i.e., sensitivity and specificity) using the normreferenced cut score (25th percentile) with empirically derived cut scores.In Study 1, the QUILS led to low fail rates (i.e., high specificity) in children without impairment and statistically significant group differences as a function of children's clinical status; however, only 65% of children with DLD were accurately identified using the norm-referenced cutoff. In Study 2, 76% of children with DLD were accurately identified at the 25th percentile cutoff and accuracy improved to 84% when an empirically derived cutoff (32nd percentile) was applied.Findings support the clinical application of the QUILS as a component of the screening process for identifying the presence or absence of DLD in community samples of preschool-aged children.

The cultural value of respeto (respect) is central to Latine parenting. Yet, how respeto manifests in the interactions of Latine parents and their young children remains unexamined. Low-income Mexican immigrant Spanish-speaking mothers and their 2.5-year-old toddlers (N = 128) were video-recorded during play (M(age) = 30.2 months, SD = 0.52), and two culturally informed items of respeto were coded: parent calm authority and child affiliative obedience. Respeto related to standard ratings of mother and child interactions (e.g., maternal sensitivity and child engagement) but also captured unique features of parent–child interactions. Respeto related to mothers’ and toddlers’ language production and discourse during the interaction, and explained unique variance in language variables above standard ratings of mother–child interaction. This is the first effort to document a culturally salient aspect of dyadic interaction in Mexican immigrant mothers and young children and to show that respeto relates to language use during mother– child interactions.

This longitudinal study documents the key role of early joint engagement in the language and early literacy development of Mexican-American children from low-income households. This rapidly growing population often faces challenges as sequential Spanish-English language learners. Videos of 121 mothers and their 2.5-year-old children interacting in Spanish for 15 min were recorded in 2009-2011 in the Dallas-Fort Worth metropolitan area. Researchers reliably rated general dyadic features of joint engagement-symbol-infused joint engagement, shared routines and rituals, and fluency and connectedness-that have been found to facilitate language development in young English-speaking children. The construct respeto, a valued aspect of traditional Latino parenting, was also rated using two culturally specific items-the parent's calm authority and the child's affiliative obedience. In addition, three individual contributions-maternal sensitivity, quality of maternal language input, and quality of child language production-were assessed. General features of joint engagement at 2.5 years predicted expressive and receptive language at 3.6 years and receptive language and early literacy at 7.3 years, accounting for unique variance over and above individual contributions at 2.5 years, with some effects being stronger in girls than boys. The level of culturally specific joint engagement did not alter predictions made by general features of joint engagement. These findings highlight the importance of the quality of early communication for language and literacy success of Mexican-American children from low-income households and demonstrate that culturally specific aspects of early interactions can align well with general features of joint engagement.

Background High-quality, early caregiver-child interaction facilitates language, cognitive, and health outcomes. Children in low socioeconomic status households experience less frequent and lower-quality language interactions on average than their middle to high socioeconomic status peers. Early caregiver-implemented intervention may help to improve outcomes for these children. Objectives This article describes how we used community-based participatory research (CBPR) to develop and implement a community-based, caregiver-implemented early language intervention, including the challenges, solutions, and lessons learned in the process of CBPR. Methods We adopted an ethnographic approach to document and analyze our CBPR experiences in multiple phases of the project, including intervention design, training, implementation, and evaluation. Lessons learned Developing the CBPR partnership, co-designing and implementing the study, and managing systems- level concerns like obtaining funding were central challenges for the researcher-community team. Conclusions The CBPR model enhances early language intervention research by facilitating understanding of families in underserved communities and increasing the cultural relevancy of intervention materials.

Children’s skill levels in language, mathematics, literacy, self-regulation, and social–emotional adjustment at kindergarten entry are believed to play an important role in determining school success through their long-term association with academic and social skills in primary and secondary education. Hence, children’s school readiness is a national priority. To date, there is some evidence that specific individual school readiness skills relate to specific outcomes, but much of that research has not addressed concerns regarding generalization due to the high levels of correlations among the school readiness skills. The interrelationships among school readiness domains and patterns of skill acquisition – during the first three years of primary education in which basic skills are the focus and in the later years of primary or secondary education when higher-order skills are the focus – have not been explored adequately. Using the NICHD Study of Early Child Care and Youth Development dataset (n = 1364), this research conducted growth curve analyses to examine a comprehensive set of readiness indicators in kindergarten and identify which domains were stronger predictors of academic and social trajectories through grade 3 and from grades 3 to 5. Results highlight the importance of examining multiple school readiness domains simultaneously rather than separately, and moving beyond outcomes (skill levels) at a particular grade to consider which kindergarten skills predict gains over time (skill acquisition) both within- and across-domains. Empirical and methodological implications are considered for educational research, policy, and practice.

The current study examined maternal behaviors during incarceration and following release in a sample of corrections-involved mothers who lived with their infants in a Residential Parenting Program (RPP). Using a longitudinal dataset, several factors thought to be associated with behavior were examined including mothers’ length of stay in the program, level of risk and needs, and history of visitation. Maternal outcomes were defined in terms of institutional behavior during participation in the prison nursery program (i.e., misconduct) and field violations during supervision after release into the community. Descriptive and bivariate correlational analyses were conducted to investigate associations between potential explanatory variables and maternal behavioral outcomes. Results are consistent with existing evidence documenting low rates of recidivism following participation in a prison nursery. More importantly, this work begins to move beyond recidivism alone to identify meaningful metrics of success for this highly vulnerable and largely understudied population of incarcerated women.

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

This study investigated the relation between Dual Language Learners' (N = 90) vocabulary and grammar comprehension and word learning processes in preschool (aged 3‐through‐5 years). Of interest was whether: (a) performance in Spanish correlated with performance in English within each domain; and (b) comprehension predicted novel word learning within and across languages. Dual‐language experience was evaluated as a potential moderator. Hierarchical linear modeling revealed stronger predictive associations within each language than across languages. Across languages, results varied by experience and domain. Structural sensitivity theory suggests exposure to two languages heightens awareness of parameters along which languages vary and provides a framework for interpreting complex associations within and across languages. Knowledge from one language may influence learning in both. [ABSTRACT FROM AUTHOR]

The methylation of amide nitrogen atoms can improve the stability, oral availability, and cell permeability of peptide therapeutics. Chemical N-methylation of peptides is challenging. Omphalotin A is a ribosomally synthesized, macrocylic dodecapeptide with nine backbone N-methylations. The fungal natural product is derived from the precursor protein, OphMA, harboring both the core peptide and a SAM-dependent peptide α-N-methyltransferase domain. OphMA forms a homodimer and its α-N-methyltransferase domain installs the methyl groups in trans on the hydrophobic core dodecapeptide and some additional C-terminal residues of the protomers. These post-translational backbone N-methylations occur in a processive manner from the N- to the C-terminus of the peptide substrate. We demonstrate that OphMA can methylate polar, aromatic, and charged residues when these are introduced into the core peptide. Some of these amino acids alter the efficiency and pattern of methylation. Proline, depending on its sequence context, can act as a tunable stop signal. Crystal structures of OphMA variants have allowed rationalization of these observations. Our results hint at the potential to control this fungal α-N-methyltransferase for biotechnological applications., ACS Chemical Biology, 15 (7), ISSN:1554-8929, ISSN:1554-8937

The methylation of amide nitrogen atoms can improve the stability, oral availability, and cell permeability of peptide therapeutics. Chemical N-methylation of peptides is challenging. Omphalotin A is a ribosomally synthesized, macrocylic dodecapeptide with nine backbone N-methylations. The fungal natural product is derived from the precursor protein, OphMA, harboring both the core peptide and a SAM-dependent peptide α-N-methyltransferase domain. OphMA forms a homodimer and its α-N-methyltransferase domain installs the methyl groups in trans on the hydrophobic core dodecapeptide and some additional C-terminal residues of the protomers. These post-translational backbone N-methylations occur in a processive manner from the N- to the C-terminus of the peptide substrate. We demonstrate that OphMA can methylate polar, aromatic, and charged residues when these are introduced into the core peptide. Some of these amino acids alter the efficiency and pattern of methylation. Proline, depending on its sequence context, can act as a tunable stop signal. Crystal structures of OphMA variants have allowed rationalization of these observations. Our results hint at the potential to control this fungal α-N-methyltransferase for biotechnological applications.

Do children learn a new word by tracking co-occurrences between words and referents across multiple instances ("cross-situational learning" models), or is word-learning a "one-track" process, where learners maintain a single hypothesis about the possible referent, which may be verified or falsified in future occurrences ("propose-but-verify" models)? Using a novel word-learning task, we ask which learning procedure is utilized by preschool-aged children. We report on findings from three studies comparing the word-learning strategies across different populations of child learners: monolingual English learners, Spanish - English dual language learners, and learners at risk for language-delay. In all three studies, we ask what, if anything, is retained from prior exposures and whether the amount of information retained changes as children get older. The ability to make a good initial hypothesis was a function of various factors, including language ability and experience, but across-the-board, children were no better than chance after a wrong initial hypothesis. This suggests that children do not retain multiple meaning hypotheses across learning instances, lending support to the propose-but-verify models.

Parental attitudes shape play opportunities afforded to children in home, community, and school settings. This study presents evaluation of an intervention designed to enrich parent's conception of play and its relationship with socially valued skills and capacities. On the basis of data from 291 racially and ethnically diverse parents/caregivers of young children (median age between 3 and 6) attending an event in NYC, we find the intervention helped parents conceptualize play in complex ways and altered perceptions of its impact on children's current-but not future-lives. Multivariate analyses reveal the causal pathway for these changes as exposure to multiple play sites, rather than time at the event-a finding with direct implications for exposing parents to developmental science in community settings.

We live in a dynamic world comprised of continuous events. Remembering our past and predicting future events, however, requires that we segment these ongoing streams of information in a consistent manner. How is this segmentation achieved? This research examines whether the boundaries adults perceive in events, such as the Olympic figure skating routine used in these studies, align with the beginnings (sources) and endings (goals) of human goal-directed actions. Study 1 showed that a group of experts, given an explicit task with unlimited time to rewatch the event, identified the same subevents as one another, but with greater agreement as to the timing of goals than sources. In Study 2, experts, novices familiarized with the figure skating sequence, and unfamiliarized novices performed an online event segmentation task, marking boundaries as the video progressed in real time. The online boundaries of all groups corresponded with the sources and goals offered by Study 1's experts, with greater alignment of goals than sources. Additionally, expertise, but not mere perceptual familiarity, boosted the alignment of sources and goals. Finally, Study 3, which presented novices with the video played in reverse, indicated, unexpectedly, that even when spatiotemporal cues were disrupted, viewers' perceived event boundaries still aligned with their perception of the actors' intended sources and goals. This research extends the goal bias to event segmentation, and suggests that our spontaneous sensitivity toward goals may allow us to transform even relatively complex and unfamiliar event streams into structured and meaningful representations. (PsycINFO Database Record

Clinicians are expected to select a therapy based on their appraisal of evidence on benefit-to-risk profiles of therapies. In the management of relapsing-remitting multiple sclerosis (RRMS), evidence is typically expressed in terms of risk (proportion) of event, risk reduction, relative and hazard rate reduction, or relative reduction in the mean number of magnetic resonance imaging lesions. Interpreting treatment effect using these measures from a RRMS clinical trial is fairly reliable; however, this might not be the case when treatment effect is expressed in terms of the number needed to treat (NNT). The objective of this review is to discuss the utility of NNT in RRMS trials. This article presents an overview of the methodological definition and characteristics of NNT as well as the relative merit of NNT use in RRMS controlled clinical trials, where endpoints are typically time-to-event and frequency of recurrent events. The authors caution against using NNT in multiple sclerosis, a clinically heterogeneous disease that can change course and severity unpredictably. The authors also caution against the use of NNT to interpret results in comparative trials where the absolute risk difference is not statistically significant, computing NNT using the time-to-event endpoint at intermediate time points, computing NNT using the annualized relapse rate, and comparing NNT across trials.

Children from low-income backgrounds consistently perform below their more advantaged peers on standardized measures of language ability, setting long-term trajectories that translate into gaps in academic achievement. Our primary goals in this review are to describe how and why this is so, in order to focus attention on ways to enrich early language experiences across socioeconomic strata. We first review the literature on the relation between socioeconomic status (SES) and language ability across domains in early childhood. We then identify three potential pathways by which SES might influence language development—child characteristics, parent–child interaction, and availability of learning resources—recognizing the complicated interaction between the child's own language learning skill and his/her environmental support. Finally, we review interventions that target these three pathways with an eye toward best practice. Future research should focus on the diversity of contexts in which children acquire language and adopt methods of language measurement that are sensitive to cultural variation.

PurposeThis article reports preliminary outcomes from a service-learning (SL) experience for graduate students in the Speech-Language Pathology program with incarcerated mothers who reside with their infants at a residential parenting program. We present an ecological model to serve as a framework for interpreting the impact of the experience on student learning and maternal perceptions.MethodGraduate speech-language pathology students (totaln= 30) participated in an SL project, called thePartnership for Healthy Parenting. With faculty guidance, students implemented parent education and child development workshops designed to foster secure attachment relationships, enhance the quality of mother–child interactions, and promote communication and language development. Students completed self-report scales measuring civic attitudes and self-efficacy before participating; they also provided written reflections about their experience that were analyzed qualitatively. Mothers completed voluntary feedback surveys after each workshop.ResultsStudent reflections revealed a variety of perceived positive learning outcomes related to personal attitudes and beliefs about their role as a clinician, family-centered practices in early intervention, and knowledge about the population of interest. Feedback surveys administered to mothers who attended the workshops indicated satisfaction relating to the value of the services provided.ConclusionsSL programs may benefit students, faculty, communities, higher education institutions, and the relationships among all these stakeholders. Results, limitations, and implications for strengthening university–community collaborations in the field of communication disorders are discussed.

Infants must learn to carve events at their joints to best understand who is doing what to whom or whether an object or agent has reached its intended goal. Recent behavioral research demonstrates that infants do not see the world as a movie devoid of meaning, but rather as a series of sub-events that include agents moving in different manners along paths from sources to goals. This research uses behavioral and electrophysiological methods to investigate infants' (10-14 months) attention to disruptions within relatively unfamiliar human action that does not rely on goal-objects to signal attainment (i.e., Olympic figure skating). Infants' visual (Study 1, N = 48) and neurophysiological (Study 2, N = 21) responses to pauses at starting points, endpoints, and within-action locations were recorded. Both measures revealed differential responses to pauses at endpoints relative to pauses elsewhere in the action (i.e., starting point; within-action). Eye-tracking data indicated that infants' visual attention was greater for events containing pauses at endpoints relative to events with pauses at starting points or within-actions. ERP activity reflecting perceptual processes in early-latency windows (200 ms) and memory updating processes in long-latency windows (700-1000 ms) showed differential activation to disruptions at the end of a figure-skating action compared to other locations. Mid-latency windows (250-750 ms), in contrast, showed enhanced activation at frontal regions across conditions, suggesting electrophysiological resources may have been recruited to encode disruptions within unfamiliar dynamic human action. Combined, results hint at broad sensitivity to endpoints as a mechanism that supports infants' proclivity for carving continuous and complex event streams into meaningful units. Findings have potential implications for language development as these units are mapped onto budding linguistic representations. We discuss empirical and methodological contributions for action perception and address potential merits and pitfalls of applying behavioral techniques in conjunction with brain-based measures to study infant development.

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNβ) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible. In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects. To explore how soon after natalizumab initiation clinical effects become apparent, annualized relapse rates per 3-month period and time to first relapse were analyzed in the phase III AFFIRM study (natalizumab vs. placebo) and in the multinational Tysabri® Observational Program (TOP). In AFFIRM, natalizumab reduced the annualized relapse rate within 3 months of treatment initiation compared with placebo in the overall population (0.30 vs. 0.71; p

The present article investigates spatial- and social-cognitive processes in toddlers' mapping of concepts to real-world events. In 2 studies we explore how event segmentation might lay the groundwork for extracting actions from the event stream and conceptually mapping novel verbs to these actions. In Study 1, toddlers demonstrated the ability to segment a novel multiaction event by selecting a single action for behavioral reenactment when prompted. In Study 2, a single action embedded in the event sequence was specified as the referent for a novel verb through cues to support intentional inference. As in Study 1, toddlers spontaneously segmented the sequence. In addition, they mapped a novel label to the embedded action specified by the novel label and intentional cues. These data are consistent with current thinking that suggests a convergence of spatial and social cognition in verb learning. In the present research, toddlers built upon event segmentation skills and used intentional inference when mapping verbs to actions embedded in the motion stream.

This article is a revision of the previous edition article by Z. Chen, R. Siegler, volume 20, pp. 13714–13719, © 2001, Elsevier Ltd.

Background: In the phase 3 DEFINE and CONFIRM trials, flushing and gastrointestinal (GI) events were associated with delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) treatment in people with relapsing-remitting multiple sclerosis (MS). To investigate these events, a post hoc analysis of integrated data from these trials was conducted, focusing on the initial treatment period (months 0−3) with the recommended DMF dosage (240 mg twice daily). Methods: Eligibility criteria included age 18 to 55 years, relapsing-remitting MS diagnosis, and Expanded Disability Status Scale score 0 to 5.0. Patients were randomized and received treatment with placebo (n = 771) or DMF (n = 769) for up to 2 years. Adverse events were recorded at scheduled clinic visits every 4 weeks. Results: The incidence of GI and flushing events was highest in the first month of treatment. In months 0 to 3, the incidence of GI events was 17% in the placebo group and 27% in the DMF group and the incidence of flushing and related symptoms was 5% in the placebo group and 37% in the DMF group. Most GI and flushing events were of mild or moderate severity and resolved during the study. The events were temporally associated with the use of diverse symptomatic therapies (efficacy not assessed) and infrequently led to DMF discontinuation. Conclusions: This integrated analysis indicates that in a clinical trial setting, GI and flushing events associated with DMF treatment are generally transient and mild or moderate in severity and uncommonly lead to treatment discontinuation.

The disparity in the amount and quality of language that low-income children hear relative to their more-affluent peers is often referred to as the 30-million-word gap. Here, we expand the literature about this disparity by reporting the relative contributions of the quality of early parent-child communication and the quantity of language input in 60 low-income families. Including both successful and struggling language learners from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development, we noted wide variation in the quality of nonverbal and verbal interactions (symbol-infused joint engagement, routines and rituals, fluent and connected communication) at 24 months, which accounted for 27% of the variance in expressive language 1 year later. These indicators of quality were considerably more potent predictors of later language ability than was the quantity of mothers’ words during the interaction or sensitive parenting. Bridging the word gap requires attention to how caregivers and children establish a communication foundation within low-income families.

The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening (n = 175) were randomized 1:1:2 to continue natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during natalizumab interruption did not exceed pre-natalizumab levels or levels seen in historical control patients.

Compare relapse clinical severity, post-relapse residual disability, and the probability of confirmed complete recovery from relapse between patients who relapsed during natalizumab (n=183/627 [29%]) and placebo (n=176/315 [56%]) treatments in the AFFIRM trial.In this post-hoc analysis, relapse clinical severity and residual disability were defined by change in Expanded Disability Status Scale (EDSS) score occurring between pre-relapse and at-relapse assessment and between pre-relapse and post-relapse assessment, respectively. Patients were considered completely recovered from relapse when their post-relapse EDSS score was less than or equal to their pre-relapse EDSS score, and this was maintained for 12 or 24 weeks.At relapse, an increase in EDSS score of ≥0.5 points occurred in 71% of natalizumab and 84% of placebo patients (P=0.0088); an increase of ≥1.0 point occurred in 49% of natalizumab and 61% of placebo patients (P=0.0349) (mean increase in EDSS at relapse: natalizumab=0.77; placebo=1.09; P=0.0044). After relapse, residual disability of ≥0.5 EDSS points remained in 31% of natalizumab and 45% of placebo patients (P=0.0136) (mean post-relapse residual EDSS increase: natalizumab=0.06; placebo=0.28; P=0.0170). In patients with an increase in EDSS of ≥0.5 or ≥1.0 during relapse, natalizumab increased the probability of 12-week confirmed complete recovery from relapse by 55% (hazard ratio [HR]=1.554; P=0.0161) and 67% (HR=1.673; P=0.0319) compared to placebo, respectively.In AFFIRM, natalizumab treatment decreased the clinical severity of relapses and improved recovery from disability induced by relapses. These beneficial effects would limit the step-wise accumulation of disability.

Objective Determine whether MRI activity 6 months after treatment initiation in the Controlled High-Risk Subjects Avonex ® Multiple Sclerosis Prevention Study (CHAMPS) predicted progression to clinically definite multiple sclerosis (CDMS) over the subsequent 30 months in intramuscular interferon beta-1a (IM IFNβ-1a)-treated patients vs placebo-treated patients. Methods CHAMPS patients were randomized to once-weekly IM IFNβ-1a 30μg or placebo for up to 36 months. MRI was performed every 6 months until CDMS confirmation. Patient groups were defined based on new T2 and/or Gd+ lesions at 6 months. Results Thirteen IM IFNβ-1a patients (6.7%) and 24 placebo patients (12.6%) developed CDMS prior to month 6 and did not undergo the 6-month MRI. At 6 months, 29.7% of IM IFNβ-1a-treated patients vs 40.9% of placebo-treated patients were defined as having high MRI activity levels (≥2 new T2 and/or ≥2 Gd+ lesions). In this subgroup, estimated cumulative probabilities of CDMS were similar between groups (HR=0.88 [0.44–1.77], p =0.7227). A significant treatment response was seen for patients with p =0.0120). Conclusion MRI scans 6 months after IM IFNβ-1a initiation in CIS patients predict early treatment non-response. Standardized scanning and monitoring may facilitate early disease management.

The current research used event-related potentials (ERPs) to investigate neurophysiological responses to intact and disrupted actions embedded within an event in children and adults. Responses were recorded as children (24-month-olds) and adults observed a relatively novel event composed of three actions. In one condition pauses were inserted at intact boundaries (i.e., at the endpoint of each action), whereas in the other condition they were inserted at breakpoints that disrupted the action (i.e., in the middle of each action). Evoked responses revealed differences across conditions in both groups; disrupted actions elicited a prolonged negative slow wave from 100 to 700 ms in children, whereas adults demonstrated two distinct negative peaks between 50–150 and 250–350 ms. These findings contribute the first electrophysiological evidence that children readily detect disruptions to ongoing events by the end of the second year, even with limited exposure to the event itself. Furthermore, they suggest that adults rely on two distinct mechanisms when processing novel events. Results are discussed in relation to the role of perceptual and conceptual levels of analysis in the development of action processing.

Background Patients with multiple sclerosis (MS) who are of African descent experience a more aggressive disease course than patients who are of white race/ethnicity. In phase 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]), natalizumab use significantly improved clinical and magnetic resonance imaging outcomes over 2 years in patients with relapsing MS. Because patients of African descent may be less responsive to interferon beta treatment than patients of white race/ethnicity, the efficacy of natalizumab therapy in this population is clinically important. Objective To evaluate the efficacy of natalizumab use in patients of African descent with relapsing MS. Design Post hoc analysis. Setting Academic research. Patients Patients of African descent with relapsing MS who received natalizumab or placebo in the phase 3 AFFIRM study and those who received natalizumab plus intramuscular interferon beta-1a or placebo plus intramuscular interferon beta-1a in the phase 3 SENTINEL study. Main Outcome Measure Efficacy of natalizumab use in patients of African descent with relapsing MS who participated in the AFFIRM or SENTINEL trial. Results Forty-nine patients of African descent participated in AFFIRM (n = 10) or SENTINEL (n = 39). Demographic and baseline disease characteristics were similar between patients treated with natalizumab (n = 21) or placebo (n = 28). Natalizumab therapy significantly reduced the annualized MS relapse rate by 60% (0.21 vs 0.53 in the placebo group,P = .02). Compared with placebo use, natalizumab therapy also significantly reduced the accumulation of lesions observed on magnetic resonance imaging over 2 years: the mean number of gadolinium-enhancing lesions was reduced by 79% (0.19 vs 0.91,P = .03), and the mean number of new or enlarged T2-weighted lesions was reduced by 90% (0.88 vs 8.52,P = .008). Conclusion Natalizumab therapy significantly improved the relapse rate and accumulation of brain lesions in patients of African descent with relapsing MS.

Background. Ambulation impairment is a major component of physical disability in multiple sclerosis (MS) and a major target of rehabilitation programs. Outcome measures commonly used to evaluate walking capacities suffer from several limitations. Objectives. To define and validate a new test that would overcome the limitations of current gait evaluations in MS and ultimately better correlate with the maximum walking distance (MWD). Methods. The authors developed the Timed 100-Meter Walk Test (T100MW), which was compared with the Timed 25-Foot Walk Test (T25FW). For the T100MW, the subject is invited to walk 100 m as fast as he/she can. In MS patients and healthy control volunteers, the authors measured the test–retest and interrater intraclass correlation coefficient. Spearman rank correlations were obtained between the T25FW, the T100MW, the Expanded Disability Status Scale (EDSS), and the MWD. The coefficient of variation, Bland–Altman plots, the coefficient of determination, and the area under the receiver operator characteristic curve were measured. The mean walking speed (MWS) was compared between the 2 tests. Results. A total of 141 MS patients and 104 healthy control volunteers were assessed. Minor differences favoring the T100MW over the T25FW were observed. Interestingly, the authors demonstrated a paradoxically higher MWS on a long (T100MW) rather than on a short distance walk test (T25FW). Conclusion. The T25FW and T100MW displayed subtle differences of reproducibility, variability, and correlation with MWD favoring the T100MW. The maximum walking speed of MS patients may be poorly estimated by the T25FW since MS patients were shown to walk faster over a longer distance.

Background: Validated measures of sustained improvements in neurological function have not been established for multiple sclerosis (MS) clinical studies. Objective: To evaluate sustained Expanded Disability Status Scale (EDSS) change as a potential indicator of neurological improvement and as an outcome measure in MS clinical studies. Methods: Analyses were performed on patients ( n = 620) from the pivotal natalizumab study AFFIRM with baseline EDSS scores ≥2.0. Cumulative probabilities of neurological improvement, defined as a 1.0-point decrease in EDSS score sustained for ≥12 weeks, were estimated by Kaplan–Meier analysis. A Cox proportional hazards model identified associated baseline factors and examined treatment effects. Results: Sustained improvement (as well as sustained worsening) in neurological disability was seen in AFFIRM patients. Sustained EDSS changes correlated well with quality of life measurements (SF36 and VAS). Natalizumab increased the cumulative probability of improvement over 2 years by 69% versus placebo (HR = 1.69; 95% CI 1.16–2.45; p = 0.006). Sensitivity analyses showed consistent benefits of natalizumab with variations in improvement magnitude and duration, and baseline disease activity. Conclusion: These analyses demonstrate that sustained EDSS improvement is an additional measure that is sensitive to treatment effects over 2 years and correlates with quality of life. Further research is warranted to validate its use as an MS study clinical outcome.

A study was undertaken to establish an enzyme-linked immunosorbent assay (ELISA) to detect JC virus (JCV)-specific antibodies in multiple sclerosis (MS) patients, and to evaluate its potential utility for identifying patients at higher or lower risk (ie, risk stratification) of developing progressive multifocal leukoencephalopathy (PML).A 2-step assay for detecting and confirming the presence of anti-JCV antibodies in human serum and plasma was developed and demonstrated to be both sensitive and specific. ELISA cutpoints were statistically established using sera from800 MS patients from natalizumab clinical studies. Subsequently, this assay was used to determine the presence of anti-JCV antibodies in natalizumab-treated PML patients where serum samples were collected 16-180 months prior to the diagnosis of PML.In our evaluation of natalizumab-treated MS patients, 53.6% tested positive for anti-JCV antibodies, with a 95% confidence interval of 49.9 to 57.3%. The false-negative rate of the ELISA was calculated to be approximately 2.5%, with an upper 1-sided confidence limit of 4.4%. Notably, we observed anti-JCV antibodies in all 17 available pre-PML sera samples, which was significantly different from the 53.6% seropositivity observed in the overall MS study population (p0.0001).This 2-step assay provides a means to classify MS patients as having detectable or not detectable levels of anti-JCV antibodies. The finding that all 17 of the pre-PML samples that were available tested seropositive, and none tested seronegative, warrants further research on the clinical utility of the anti-JCV antibody assay as a potential tool for stratifying MS patients for higher or lower risk of developing PML.

Interferon beta (IFNbeta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity.In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b.Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titersor =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6.These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.

Findings from a small clinical study suggested that statins may counteract the therapeutic effects of interferon beta (IFNbeta) in patients with relapsing-remitting multiple sclerosis (RRMS).We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFNbeta-1a in Patients With Relapsing-Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of statins on efficacy of IFNbeta. SENTINEL was a prospective trial of patients with RRMS treated with natalizumab (Tysabri, Biogen Idec, Inc., Cambridge, MA) plus IM IFNbeta-1a (Avonex, Biogen Idec, Inc.) 30 microg compared with placebo plus IM IFNbeta-1a 30 microg. Clinical and MRI outcomes in patients treated with IM IFNbeta-1a only (no-statins group, n = 542) were compared with those of patients taking IM IFNbeta-1a and statins at doses used to treat hyperlipidemia (statins group, n = 40).No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T2-hyperintense lesions (p = 0.802) at 2 years. More patients in the statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the no-statins group. Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes.Statin therapy does not appear to affect clinical effects of IM interferon beta-1a in patients with relapsing-remitting multiple sclerosis or the primary molecular response to interferon beta treatment.

The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity.Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two.383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline.Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.