Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response.

OBJECTIVES: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. METHODS: Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults. RESULTS: Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching Cmax values with adults. CONCLUSIONS: The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposure-response for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.

Morphological Decomposition in Japanese De-adjectival Nominals: Masked and Overt Priming Evidence.

Whether morpheme-based processing extends to relatively unproductive derived words remains a matter of debate. Although whole-word storage and access has been proposed for some derived words, such as Japanese de-adjectival nominals with the unproductive (-mi) suffix (e.g., Hagiwara et al. in Language 75:739-763, 1999), Clahsen and Ikemoto (Ment Lex 7:147-182, 2012) found masked priming from de-adjectival nominals with productive (-sa) and unproductive (-mi) suffixes to their adjectivally-inflected base morpheme. Using masked and unmasked priming, we examine whether adjectivally-inflected base morpheme primes facilitate the processing of Japanese de-adjectival nominal targets with a productive or unproductive affix, including an orthographic-overlap condition and semantic relatedness measure that Clahsen and Ikemoto (2012) did not include. Our results replicate and extend Clahsen and Ikemoto (2012), revealing significant, statistically-equivalent morphological priming effects for -sa and -mi affixed targets, independent of orthographic and semantic relatednesss, suggesting that the processing of derived words with the unproductive -mi affix makes recourse to morpheme-level representations.

Electrophysiological evidence for the morpheme-based combinatoric processing of English compounds.

The extent to which the processing of compounds (e.g., "catfish") makes recourse to morphological-level representations remains a matter of debate. Moreover, positing a morpheme-level route to complex word recognition entails not only access to morphological constituents, but also combinatoric processes operating on the constituent representations; however, the neurophysiological mechanisms subserving decomposition, and in particular morpheme combination, have yet to be fully elucidated. The current study presents electrophysiological evidence for the morpheme-based processing of both lexicalized (e.g., "teacup") and novel (e.g., "tombnote") visually presented English compounds; these brain responses appear prior to and are dissociable from the eventual overt lexical decision response. The electrophysiological results reveal increased negativities for conditions with compound structure, including effects shared by lexicalized and novel compounds, as well as effects unique to each compound type, which may be related to aspects of morpheme combination. These findings support models positing across-the-board morphological decomposition, counter to models proposing that putatively complex words are primarily or solely processed as undecomposed representations, and motivate further electrophysiological research toward a more precise characterization of the nature and neurophysiological instantiation of complex word recognition.

Cross-sector sponsorship of research in eosinophilic esophagitis: a collaborative model for rational drug development in rare diseases.

Like many rare diseases, eosinophilic esophagitis (EoE) is a poorly understood disorder, and assessment tools to accurately determine disease activity, remission, and natural history have long been inadequate. Clinical outcome end points able to assess the effectiveness of candidate therapeutic agents in clinical trials have been a particular deficiency and are urgently needed. With no approved therapy available to patients and with the prevalence of EoE on the increase, collaborative approaches to drug development are becoming ever more important. We describe a collaborative effort mobilized across institutions, including both the public and private sectors, that was initiated within the past 18 months expressly to address the need for further clinical research into the cause and treatment of EoE. Collaborators include the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition; the International Gastrointestinal Eosinophilic Researchers; and the US Food and Drug Administration. This effort has resulted in the elucidation of several parameters essential for effective EoE registration trials, including the need for clinically meaningful end points that measure changes in clinical symptoms in addition to the assessment of intraepithelial mucosal eosinophilia. The development and use of biomarkers, particularly in early-phase drug development, have become an important focus for investigations that might reduce clinical reliance on serial invasive monitoring. The concerted efforts described here to develop rational therapeutics and drug development paradigms in EoE also appear to provide a model for effective collaboration in the context of drug development for rare diseases and perhaps more generally for public health initiatives.

Phonological Well-Formedness Constraints in Mandarin Phonotactics: Evidence From Lexical Decision.

This article investigates the role of phonological well-formedness constraints in Mandarin speakers' phonotactic grammar and how they affect online speech processing. Mandarin non-words can be categorized into systematic gaps and accidental gaps, depending on whether they violate principled phonotactic constraints based on the Obligatory Contour Principle (OCP). Non-word acceptability judgment experiments have shown that systematic gaps received lower wordlikeness ratings than accidental gaps. Using a lexical decision task, this study found that systematic gaps were rejected significantly faster than accidental gaps, even after lexical statistics were taken into account. These findings thus provide converging evidence for the essential status of the OCP-based phonotactic constraints in Mandarin speakers' phonological knowledge.

Electrophysiological Signatures of Perceiving Alternated Tone in Mandarin Chinese: Mismatch Negativity to Underlying Tone Conflict.

Although phonological alternation is prevalent in languages, the process of perceiving phonologically alternated sounds is poorly understood, especially at the neurolinguistic level. We examined the process of perceiving Mandarin 3rd tone sandhi (T3 + T3 → T2 + T3) with a mismatch negativity (MMN) experiment. Our design has two independent variables (whether the deviant undergoes tone sandhi; whether the standard and the deviant have matched underlying tone). These two independent variables modulated ERP responses in both the first and the second syllables. Notably, despite the apparent segmental conflict between the standard and the deviant in all conditions, MMN is only observed when neither the standard nor the deviant undergoes tone sandhi, suggesting that discovering the underlying representation of an alternated sound could interfere with the generation of MMN. A tentative model with three hypothesized underlying processing mechanisms is proposed to explain the observed latency and amplitude differences across conditions. The results are also discussed in light of the potential electrophysiological signatures involved in the process of perceiving alternated sounds.

Examining variability in the processing of agreement in novice learners: Evidence from event-related potentials.

The present study examines both properties of the language and properties of the learner to better understand variability at the earliest stages of second language (L2) acquisition. We used event-related potentials, an oral production task, and a battery of individual differences measures to examine the processing of number and gender agreement in two groups of low-proficiency English-speaking learners of Spanish who were tested in multiple sessions. The results showed an advantage for number, the feature also instantiated in the native language, as both groups showed a native-like P600 response to subject-verb and noun-adjective number violations across sessions. The more advanced group showed larger effects for number and marginal sensitivity to gender violations. These results suggest that native-like processing of shared features is possible even for novice learners, contrary to proposals suggesting that all morphosyntactic dependencies are initially processed in a non-native manner. Working memory (WM) was a predictor of P600 effects for number and also for gender (where the effect was marginal), suggesting that similar abilities may capture variability in the processing of both shared and unique features despite differences in overall sensitivity. Furthermore, whereas WM predicted performance on online tasks (P600 effects/oral production), verbal aptitude predicted performance on tasks examining morphosyntactic accuracy (grammaticality judgment task/oral production). Our results show that the linguistic properties of the L2, the individual characteristics of the learner, and the nature of the task at hand all play an important role in capturing the variability often observed in the L2 processing of agreement. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Role of Surface and Underlying Forms When Processing Tonal Alternations in Mandarin Chinese: A Mismatch Negativity Study.

Phonological alternation (sound change depending on the phonological environment) poses challenges to spoken word recognition models. Mandarin Chinese T3 sandhi is such a phenomenon in which a tone 3 (T3) changes into a tone 2 (T2) when followed by another T3. In a mismatch negativity (MMN) study examining Mandarin Chinese T3 sandhi, participants passively listened to either a T2 word [tʂu2 je4] /tʂu2 je4/, a T3 word [tʂu3 je4] /tʂu3 je4/, a sandhi word [tʂu2 jen3] /tʂu3 jen3/, or a mix of T3 and sandhi word standards. The deviant in each condition was a T2 word [tʂu2]. Results showed an MMN only in the T2 and T3 conditions but not in the Sandhi or Mix conditions. All conditions also yielded omission MMNs. This pattern cannot be explained based on the surface forms of standards and deviants; rather these data suggest an underspecified or underlying T3 stored linguistic representation used in spoken word processing.

Context-Sensitivity and Individual Differences in the Derivation of Scalar Implicature.

The derivation of scalar implicatures for the quantifier some has been widely studied to investigate the computation of pragmatically enriched meanings. For example, the sentence "I found some books" carries the semantic interpretation that at least one book was found, but its interpretation is often enriched to include the implicature that not all the books were found. The implicature is argued to be more likely to arise when it is relevant for addressing a question under discussion (QUD) in the context, e.g., when "I found some books" is uttered in response to "Did you find all the books?" as opposed to "Did you find any books?". However, most experimental studies have not examined the influence of context on some, instead testing some sentences in isolation. Moreover, no study to our knowledge has examined individual differences in the ability to utilize context in interpreting some, whereas individual variation in deriving implicatures for some sentences in isolation is widely attested, with alternative proposals attributing this variation to individual differences in cognitive resources (e.g., working memory) or personality-based pragmatic abilities (e.g., as assessed by the Autism-Spectrum Quotient). The current study examined how context influences the interpretation of some in a story-sentence matching task, where participants rated some statements ("I cut some steaks") uttered by one character, in response to another character's question (QUD) that established the implicature as relevant ("Did you cut all the steaks?") or irrelevant ("Did you cut any steaks?"). We also examined to what extent individuals' sensitivity to QUD is modulated by individual differences via a battery of measures assessing cognitive resources, personality-based pragmatic abilities, and language abilities (which have been argued to modulate comprehension in other domains). Our results demonstrate that QUD affects the interpretation of some, and reveal that individual differences in sensitivity to QUD are modulated by both cognitive resources and personality-based pragmatic abilities. While previous studies have argued alternatively for cognitive resources or personality-based pragmatic abilities as important for deriving implicatures for some in isolation, we argue that arriving at a context-sensitive interpretation for some depends on both cognitive and personality-based properties of the individual.

Individual differences in the processing of referential dependencies: Evidence from event-related potentials.

The present study examines the processing of referential ambiguity and referential failure using event-related potentials (ERPs). Participants read sentences with pronouns (he, she) which contained either one, two, or no potential gender-matching antecedents. Participants also took tests of working memory (Count Span/Reading Span) and attentional control (Number Stroop). In contexts of referential ambiguity with two potential gender-matching antecedents, two different responder types emerged, with some participants yielding a sustained negativity (Nref) and others a sustained positivity. For individuals who elicited Nref, the size of the effect was related to working memory such that higher Count Span scores were related to a larger Nref. For individuals who elicited a positivity, the effect was marginally related to attentional control such that better performance on the Stroop was related to a less positive, or increasingly negative-going ERP effect. Contexts of referential failure, with no gender-matching antecedents, yielded P600 for all participants, suggesting that participants may treat the failure of the pronoun to agree in gender with the antecedents as a violation despite the absence of an explicit acceptability judgment task.

Using event-related potentials to track morphosyntactic development in second language learners: The processing of number and gender agreement in Spanish.

We used event-related potentials to investigate morphosyntactic development in 78 adult English-speaking learners of Spanish as a second language (L2) across the proficiency spectrum. We examined how development is modulated by the similarity between the native language (L1) and the L2, by comparing number (a feature present in English) and gender agreement (novel feature). We also investigated how development is impacted by structural distance, manipulating the distance between the agreeing elements by probing both within-phrase (fruta muy jugosa "fruit-FEM-SG very juicy-FEM-SG") and across-phrase agreement (fresa es ácida "strawberry-FEM-SG is tart-FEM-SG"). Regression analyses revealed that the learners' overall proficiency, as measured by a standardized test, predicted their accuracy with the target properties in the grammaticality judgment task (GJT), but did not predict P600 magnitude to the violations. However, a relationship emerged between immersion in Spanish-speaking countries and P600 magnitude for gender. Our results also revealed a correlation between accuracy in the GJT and P600 magnitude, suggesting that behavioral sensitivity to the target property predicts neurophysiological sensitivity. Subsequent group analyses revealed that the highest-proficiency learners showed equally robust P600 effects for number and gender. This group also elicited more positive waveforms for within- than across-phrase agreement overall, similar to the native controls. The lowest-proficiency learners showed a P600 for number overall, but no effects for gender. Unlike the highest-proficiency learners, they also showed no sensitivity to structural distance, suggesting that sensitivity to such linguistic factors develops over time. Overall, these results suggest an important role for proficiency in morphosyntactic development, although differences emerged between behavioral and electrophysiological measures. While L2 proficiency predicted behavioral sensitivity to agreement, development with respect to the neurocognitive mechanisms recruited in processing only emerged when comparing the two extremes of the proficiency spectrum. Importantly, while both L1-L2 similarity and hierarchical structure impact development, they do not constrain it.

Drug eluting stents and the critical path initiative: Evolving paradigms for safety evaluation.

Recent discussions between FDA and other stakeholders have focused on the benefits and risks associated with drug eluting stents (DES). A particular topic of focus is DES thrombosis, a rare, but serious, clinical event that may occur months to years after the initial implantation. FDA continues vigilant postmarket surveillance of DES currently on the market and is working with stent manufactures to ensure that new DES platforms in the development pipeline are safe and effective. FDA is also taking steps, under its Critical Path Initiative (CPI) [FDA. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004.http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html], to help address current and future DES safety issues. This article describes some of these activities.:

Fetal rhythm-based language discrimination: a biomagnetometry study.

Using fetal biomagnetometry, this study measured changes in fetal heart rate to assess discrimination of two rhythmically different languages (English and Japanese). Two-minute passages in English and Japanese were read by the same female bilingual speaker. Twenty-four mother-fetus pairs (mean gestational age=35.5 weeks) participated. Fetal magnetocardiography was recorded while the participants were presented first with passage 1, a passage in English, and then, following an 18 min interval, with passage 2, either a different passage in English (English-English condition: N=12) or in Japanese (English-Japanese condition: N=12). The fetal magnetocardiogram was reconstructed following independent components analysis decomposition. The mean interbeat intervals were calculated for a 30 s baseline interval directly preceding each passage and for the first 30 s of each passage. We then subtracted the mean interbeat interval of the 30 s baseline interval from that of the first 30 s interval, yielding an interbeat interval change value for each passage. A significant interaction between condition and passage indicated that the English-Japanese condition elicited a more robust interbeat interval change for passage 2 (novelty phase) than for passage 1 (familiarity phase), reflecting a faster heart rate during passage 2, whereas the English-English condition did not. This effect indicates that fetuses are sensitive to the change in language from English to Japanese. These findings provide the first evidence for fetal language discrimination as assessed by fetal biomagnetometry and support the hypothesis that rhythm constitutes a prenatally available building block in language acquisition.

Syntactic Constraints and Individual Differences in Native and Non-Native Processing of Wh-Movement.

There is a debate as to whether second language (L2) learners show qualitatively similar processing profiles as native speakers or whether L2 learners are restricted in their ability to use syntactic information during online processing. In the realm of wh-dependency resolution, research has examined whether learners, similar to native speakers, attempt to resolve wh-dependencies in grammatically licensed contexts but avoid positing gaps in illicit contexts such as islands. Also at issue is whether the avoidance of gap filling in islands is due to adherence to syntactic constraints or whether islands simply present processing bottlenecks. One approach has been to examine the relationship between processing abilities and the establishment of wh-dependencies in islands. Grammatical accounts of islands do not predict such a relationship as the parser should simply not predict gaps in illicit contexts. In contrast, a pattern of results showing that individuals with more processing resources are better able to establish wh-dependencies in islands could conceivably be compatible with certain processing accounts. In a self-paced reading experiment which examines the processing of wh-dependencies, we address both questions, examining whether native English speakers and Korean learners of English show qualitatively similar patterns and whether there is a relationship between working memory, as measured by counting span and reading span, and processing in both island and non-island contexts. The results of the self-paced reading experiment suggest that learners can use syntactic information on the same timecourse as native speakers, showing qualitative similarity between the two groups. Results of regression analyses did not reveal a significant relationship between working memory and the establishment of wh-dependencies in islands but we did observe significant relationships between working memory and the processing of licit wh-dependencies. As the contexts in which these relationships emerged differed for learners and native speakers, our results call for further research examining individual differences in dependency resolution in both populations.

The effects of homonymy and polysemy on lexical access: an MEG study.

We examined the neural correlates of semantic ambiguity by measuring changes in MEG recordings during a visual lexical decision task in which the properties of ambiguous words were manipulated. Words that are ambiguous between unrelated meanings (like bark, which can refer to a tree or to a dog) were accessed more slowly than words that have no unrelated meanings (such as cage). In addition, words that have many related senses (e.g., belt, which can be an article of clothing or, closely related in sense, a fan belt used in machinery) were accessed faster than words that have few related senses (e.g., ant). The findings are inconsistent with accounts that posit that both kinds of ambiguity involve separate lexical entries, but instead offer both behavioral and neurophysiological support for separate entry accounts only for homonymy, and a single-entry model of polysemy. The findings also provide neural correlates for a behavioral study of lexical ambiguity that demonstrated that the frequently reported ambiguity advantage in lexical decision tasks is not due to the presence of many unrelated meanings but to the presence of many related senses.

Dissociating morphological and form priming with novel complex word primes: Evidence from masked priming, overt priming, and event-related potentials.

Recent research suggests that visually-presented words are initially morphologically segmented whenever the letter-string can be exhaustively assigned to existing morphological representations, but not when an exhaustive parse is unavailable; e.g., priming is observed for both hunter→HUNT and brother →BROTH, but not for brothel→BROTH. Few studies have investigated whether this pattern extends to novel complex words, and the results to date (all from novel suffixed words) are mixed. In the current study, we examine whether novel compounds (drugrack→RACK) yield morphological priming which is dissociable from that in novel pseudoembedded words (slegrack→RACK). Using masked priming, we find significant and comparable priming in reaction times for word-final elements of both novel compounds and novel pseudoembedded words. Using overt priming, however, we find greater priming effects (in both reaction times and N400 amplitudes) for novel compounds compared to novel pseudoembedded words. These results are consistent with models assuming across-the-board activation of putative constituents, while also suggesting that morpheme activation may persevere despite the lack of an exhaustive morpheme-based parse when an exhaustive monomorphemic analysis is also unavailable. These findings highlight the critical role of the lexical status of the pseudoembedded prime in dissociating morphological and orthographic priming.

The realization of scalar inferences: context sensitivity without processing cost.

Scalar inference is the phenomenon whereby the use of a less informative term (e.g., some of) is inferred to mean the negation of a more informative term (e.g., to mean not all of). Default processing accounts assume that the interpretation of some of as meaning not all of is realized easily and automatically (regardless of context), whereas context-driven processing accounts assume that it is realized effortfully and only in certain contexts. In the present study, participants' self-paced reading times were recorded as they read vignettes in which the context did or did not bias the participants to make a scalar inference (to interpret some of as meaning not all of). The reading times suggested that the realization of the inference was influenced by the context, but did not provide evidence for processing cost at the time the inference is realized, contrary to the predictions of context-driven processing accounts. The results raise the question of why inferencing occurs only in certain contexts if it does not involve extra processing effort.

Distinct neural correlates for pragmatic and semantic meaning processing: an event-related potential investigation of scalar implicature processing using picture-sentence verification.

The present study examines the brain-level representation and composition of meaning in scalar quantifiers (e.g., some), which have both a semantic meaning (at least one) and a pragmatic meaning (not all). We adopted a picture-sentence verification design to examine event-related potential (ERP) effects of reading infelicitous quantifiers for which the semantic meaning was correct with respect to the context but the pragmatic meaning was not, compared to quantifiers for which the semantic meaning was inconsistent with the context and no additional pragmatic meaning is available. In the first experiment, only pragmatically inconsistent quantifiers, not semantically inconsistent quantifiers, elicited a sustained posterior negative component. This late negativity contrasts with the N400 effect typically elicited by nouns that are incongruent with their context, suggesting that the recognition of scalar implicature errors elicits a qualitatively different ERP signature than the recognition of lexico-semantic errors. We hypothesize that the sustained negativity reflects cancellation of the pragmatic inference and retrieval of the semantic meaning. In our second experiment, we found that the process of re-interpreting the quantifier was independent from lexico-semantic processing: the N400 elicited by lexico-semantic violations was not modulated by the presence of a pragmatic inconsistency. These findings suggest that inferential pragmatic aspects of meaning are processed using different mechanisms than lexical or combinatorial semantic aspects of meaning, that inferential pragmatic meaning can be realized rapidly, and that the computation of meaning involves continuous negotiation between different aspects of meaning.

Pragmatic inferences modulate N400 during sentence comprehension: evidence from picture-sentence verification.

The present study examines the online realization of pragmatic meaning using event-related potentials (ERPs). Participants read sentences including the English quantifier some, which has both a semantic meaning (at least one) and a pragmatic meaning (not all). Unlike previous ERP studies of this phenomenon, sentences in the current study were evaluated not in terms of their truth with respect to the real world, but in terms of their consistency with a picture presented before the sentence. Sentences (such as "The boy cut some of the steaks in this story") were constructed such that either (1) both the semantic and pragmatic interpretations were true with respect to the preceding picture (when the boy in fact cut some but not all of the steaks); (2) neither interpretation was true (when the boy in fact cut none of the steaks); or (3) the semantic interpretation was true but the pragmatic interpretation false (when the boy in fact cut all of the steaks). ERPs at the object word, which determined whether the sentence was consistent with the story, showed the largest N400 effect for objects that made the sentence false, whereas they showed an intermediate effect for objects that made the sentence false under the pragmatic interpretation but true under the semantic interpretation. The results suggest that this pragmatic aspect of meaning is computed online and integrated into the sentence model rapidly enough to influence comprehension of later words.