Cascades in language acquisition: Re-thinking the linear model of development.

The first 5 years of life are characterized by incredible growth across domains of child development. Drawing from over 50 years of seminal research, this chapter contextualizes recent advances in language sciences through the lens of developmental cascades to explore complexities and connections in acquisition. Converging evidence-both classic and contemporary-points to the many ways in which advances in one learning system can pose significant and lasting impacts on the advances in other learning systems. This chapter reviews evidence in developmental literature from multiple domains and disciplines (i.e., cognitive, social, motor, bilingual language learning, and communication sciences and disorders) to examine the phenomenon of developmental cascades in language acquisition.

Classification accuracy of the Quick Interactive Language Screener for preschool children with and without developmental language disorder.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A Longitudinal Study of Language Use During Early Mother-Child Interactions in Spanish-Speaking Families Experiencing Low Income.

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.

The Quality of Mother-Toddler Communication Predicts Language and Early Literacy in Mexican-American Children from Low-Income Households.

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.

Within and Across Language Predictors of Word Learning Processes in Dual Language Learners.

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.

Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial.

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).

Beyond talk: Contributions of quantity and quality of communication to language success across socioeconomic strata.

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.

A Phase 3 Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Intravenously Administered Ravulizumab Compared with Best Supportive Care in Patients with COVID-19 Severe Pneumonia, Acute Lung Injury, or Acute Respiratory Distress Syndrome: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary Objective • To evaluate the effect of ravulizumab, a long-acting complement (C5) inhibitor plus best supportive care (BSC) compared with BSC alone on the survival of patients with COVID-19. Secondary Objectives • Number of days free of mechanical ventilation at Day 29 • Duration of intensive care unit stay at Day 29 • Change from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 29 • Change from baseline in peripheral capillary oxygen saturation/ fraction of inspired oxygen (SpO2 /FiO2) at Day 29 • Duration of hospitalization at Day 29 • Survival (based on all-cause mortality) at Day 60 and Day 90 Safety • Incidence of treatment-emergent adverse events and treatment-emergent serious adverse events. PK/PD/Immunogenicity • Change in serum ravulizumab concentrations over time • Change in serum free and total C5 concentrations over time • Incidence and titer of anti-ALXN1210 antibodies Biomarkers • Change in absolute level of soluble biomarkers in blood associated with complement activation, inflammatory processes, and hypercoagulable states over time Exploratory • Incidence of progression to renal failure requiring dialysis at Day 29 • Time to clinical improvement (based on a modified 6-point ordinal scale) over 29 days • SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores at Day 29 (or discharge), Day 60, and Day 90 • EuroQol 5-dimension 5-level (EQ-5D-5L) scores at Day 29 (or discharge), Day 60, and Day 90 TRIAL DESIGN: This is a multicenter Phase 3, open-label, randomized, controlled, study. The study is being conducted in acute care hospital settings in the United States, United Kingdom, Spain, France, Germany, and Japan. PARTICIPANTS: Male or female patients at least 18 years of age, weighing ≥ 40 kg, admitted to a designated hospital facility for treatment will be screened for eligibility in this study. Key Inclusion criteria • Confirmed diagnosis of SARS-CoV-2 infection (eg, via polymerase chain reaction [PCR] and/or antibody test) presenting as severe COVID-19 requiring hospitalization • Severe pneumonia, acute lung injury, or ARDS confirmed by computed tomography (CT) or X-ray at Screening or within the 3 days prior to Screening, as part of the patient's routine clinical care • Respiratory distress requiring mechanical ventilation, which can be either invasive (requiring endotracheal intubation) or non-invasive (with continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]) Key Exclusion criteria • Patient is not expected to survive for more than 24 hours • Patient is on invasive mechanical ventilation with intubation for more than 48 hours prior to Screening • Severe pre-existing cardiac disease (ie, NYHA Class 3 or Class 4, acute coronary syndrome, or persistent ventricular tachyarrhythmias) • Patient has an unresolved Neisseria meningitidis infection Excluded medications and therapies • Current treatment with a complement inhibitor • Intravenous immunoglobulin (IVIg) within 4 weeks prior to randomization on Day 1 Excluded prior/concurrent clinical study experience • Treatment with investigational therapy in a clinical study within 30 days before randomization, or within 5 half-lives of that investigational therapy, whichever is greater • Exceptions a. Investigational therapies will be allowed if received as part of best supportive care through an expanded access protocol or emergency approval for the treatment of COVID-19. b. Investigational antiviral therapies (such as remdesivir) will be allowed even if received as part of a clinical study. INTERVENTION AND COMPARATOR: The study consists of a Screening Period of up to 3 days, a Primary Evaluation Period of 4 weeks, a final assessment at Day 29, and a Follow-up Period of 8 weeks. For patients randomized to ravulizumab plus BSC, a weight-based dose of ravulizumab (≥40 to < 60 kg/2400 mg, 60 to < 100 kg/2700 mg, ≥ 100 kg/3000 mg) will be administered on Day 1. On Day 5 and Day 10, additional doses of 600 mg (≥40 to <60 kg) or 900 mg (>60 kg) ravulizumab will be administered and on Day 15 patients will receive 900 mg ravulizumab. There is no active or placebo comparator in this open-label clinical trial. The total duration of each patient's participation is anticipated to be approximately 3 months. MAIN OUTCOMES: The primary efficacy outcome of this study is survival (based on all-cause mortality) at Day 29. RANDOMISATION: Patients will be randomized in a 2:1 ratio (ravulizumab plus BSC:BSC alone). Randomization will be stratified by intubated or not intubated on Day 1. Computer-generated randomization lists will be prepared by a third party under the direction of the sponsor. Investigators, or designees, will enrol patients and then obtain randomization codes using an interactive voice/web response system. The block size will be kept concealed so that investigators cannot select patients for a particular treatment assignment. Blinding (masking): This is an open-label study. Numbers to be randomised (sample size): Approximately 270 patients will be randomly assigned in a 2:1 ratio to ravulizumab plus BSC (n=180) or BSC alone (n=90). TRIAL STATUS: Protocol Number: ALXN1210-COV-305 Original Protocol: 09 Apr 2020 Protocol Amendment 1 (Global): 13 Apr 2020 Protocol Amendment 2 (Global): 17 Apr 2020 Protocol Amendment 3 (Global): 09 Jun 2020 Recruitment is currently ongoing. Recruitment was initiated on 11 May 2020. We expect recruitment to be completed by 30 Nov 2020. TRIAL REGISTRATION: Clinicaltrials.gov: Protocol Registry Number: NCT04369469 ; First posted; 30 Apr 2020 EU Clinical Trials Register: EudraCT Number: https://www.clinicaltrialsregister.eu/ctr-search/search?query=ALXN1210-COV-305 , Start date: 07 May 2020 FULL PROTOCOL: The full redacted protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Substrate Plasticity of a Fungal Peptide α-N-Methyltransferase.

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.

Keeping the end in mind: Preliminary brain and behavioral evidence for broad attention to endpoints in pre-linguistic infants.

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.

Culture, parenting, and language: Respeto in Latine mother-child interactions.

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.

Community-Based, Caregiver-Implemented Early Language Intervention in High-Risk Families: Lessons Learned.

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.

Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS: In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS: The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS: Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).

Service and Learning at a Residential Parenting Program for Incarcerated Mothers: Speech-Language Pathology Student Outcomes and Maternal Perspectives.

Purpose This 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. Method Graduate speech-language pathology students (total n = 30) participated in an SL project, called the Partnership 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. Results Student 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. Conclusions SL 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.

Fast mapping word meanings across trials: Young children forget all but their first guess.

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.

Playing With Ideas: Evaluating the Impact of the Ultimate Block Party, a Collective Experiential Intervention to Enrich Perceptions of Play.

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.

Number Needed to Treat in Multiple Sclerosis Clinical Trials.

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.

A goal bias in action: The boundaries adults perceive in events align with sites of actor intent.

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

Action Interrupted: Processing of Movement and Breakpoints in Toddlers and Adults.

From early in development, segmenting events unfolding in the world in meaningful ways renders input more manageable and facilitates interpretation and prediction. Yet, little is known about how children process action structure in events comprised of multiple coarse-grained actions. More importantly, little is known about the time-course of action processing in young children or about the specific features that recruit attention. This is particularly true when we consider action that pauses unexpectedly-as actions sometimes do-violating the expectation of a continuous unfolding of motion. We assessed visual preference to intact and disrupted actions embedded within a multi-action event in toddlers and adults. In one condition, pauses were inserted at intact action boundaries whereas in the other condition they disrupted action. Attention in both groups was recruited to the disrupted relative to intact events. Time-course analyses, however, revealed developmental differences in sensitivity to the movement features (e.g., motion, pauses, and transitions) of disrupted events.

Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate.

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.