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.).

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.

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.

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.

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.

Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy.

OBJECTIVE: The increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti-JC virus (JCV) antibodies. We analyzed whether anti-JCV antibody levels, measured as index, may further define PML risk in seropositive patients. METHODS: The association between serum or plasma anti-JCV antibody levels and PML risk was examined in anti-JCV antibody-positive multiple sclerosis (MS) patients from natalizumab clinical studies and postmarketing sources. For PML and non-PML patients, the probabilities of having an index below and above a range of anti-JCV antibody index thresholds were calculated using all available data and applied to the PML risk stratification algorithm. Longitudinal stability of anti-JCV antibody index was also evaluated. RESULTS: Anti-JCV antibody index data were available for serum/plasma samples collected >6 months prior to PML diagnosis from 71 natalizumab-treated PML patients and 2,522 non-PML anti-JCV antibody-positive patients. In patients with no prior immunosuppressant use, anti-JCV antibody index distribution was significantly higher in PML patients than in non-PML patients (p < 0.0001). Among patients who were anti-JCV antibody negative at baseline in the AFFIRM and STRATIFY-1 trials, 97% remained consistently negative or below an index threshold of 1.5 over 18 months. Retrospective analyses of pre-PML samples collected longitudinally from PML patients displayed sustained higher anti-JCV antibody index over time. INTERPRETATION: Anti-JCV antibody levels in serum/plasma, measured as index, may differentiate PML risk in anti-JCV antibody-positive MS patients with no prior immunosuppressant use. Continued evaluation of anti-JCV antibody index and PML risk is warranted.

The Contribution of Early Communication Quality to Low-Income Children's Language Success.

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.

Mice lacking NKCC1 are protected from development of bacteremia and hypothermic sepsis secondary to bacterial pneumonia.

The contribution of the Na(+)-K(+)-Cl(-) transporter (NKCC1) to fluid in ion transport and fluid secretion in the lung and in other secretory epithelia has been well established. Far less is known concerning the role of this cotransporter in the physiological response of the pulmonary system during acute inflammation. Here we show that mice lacking this transporter are protected against hypothermic sepsis and bacteremia developing as a result of Klebsiella pneumoniae infection in the lung. In contrast, this protection was not observed in NKCC1(-/-) mice with K. pneumoniae-induced peritonitis. Although overall recruitment of cells to the lungs was not altered, the number of cells present in the airways was increased in the NKCC1(-/-) animals. Despite this robust inflammatory response, the increase in vascular permeability observed in this acute inflammatory model was attenuated in the NKCC1(-/-) animals. Our studies suggest that NKCC1 plays a unique and untoward unrecognized role in acute inflammatory responses in the lung and that specific inhibition of this NKCC isoform could be beneficial in treatment of sepsis.

Event-related potentials to intact and disrupted actions in children and adults.

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.

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.

Anti-JC virus antibodies: implications for PML risk stratification.

OBJECTIVE: 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). METHODS: 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 from >800 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. RESULTS: 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 (p < 0.0001). INTERPRETATION: 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.

Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis.

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.

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).

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.

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.

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.

Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) 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. INTERPRETATION: Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.