Phrase parsing in a second language as indexed by the closure positive shift: The impact of language experience and acoustic cue salience.

Despite the importance of prosodic processing in utterance parsing, a majority of studies investigating boundary localization in a second language focus on word segmentation. The goal of the present study was to investigate the parsing of phrase boundaries in first and second languages from different prosodic typologies (stress-timed vs. syllable-timed). Fifty English-French bilingual adults who varied in native language (French or English) and second language proficiency listened to English and French utterances with different prosodic structures while event-related brain potentials were recorded. The utterances were built around target words presented either in phrase-final position (bearing phrase-final lengthening) or in penultimate position. Each participant listened to both English and French stimuli, providing data in their native language (used as reference) and their second language. Target words in phrase-final position elicited closure positive shifts across listeners in both languages, regardless of the language-specific acoustic cues associated with phrase-final lengthening (shorter phrase-final lengthening in English compared to French). Interestingly, directional effects were observed, where learning to parse English as a second language in a native-like manner seemed to require a higher proficiency level than learning to parse French as a second language. This pattern of results supports the idea that L2 listeners need to learn to recognize L2-specific phrase-final lengthening regardless of the apparent similarity across languages and that some language combinations might present greater challenges than others.

Predicting Death or Disability after Surgery in the Older Adult.

BACKGROUND: Older patients are vulnerable to developing new or worsening disability after surgery. Despite this, patient or surgical characteristics predisposing to postoperative disability are poorly defined. The aim of the study was to develop and validate a model, subsequently transformed to point-score form, to predict 6-month death or disability in older patients after surgery. METHODS: The authors built a prospective, single-center registry to develop and validate the prediction model. The registry included patients 70 yr of age or older undergoing elective and nonelective, cardiac and noncardiac surgery between May 25, 2017, and February 11, 2021, and combined clinical data from the electronic medical record, hospital administrative data (International Classification of Diseases, Tenth Revision, Australian Modification codes) and World Health Organization (Geneva, Switzerland) Disability Assessment Schedule data collected directly from the patients. Death or disability was defined as being dead or having a World Health Organization Disability Assessment Schedule score 16% or greater. Included patients were randomly divided into model development (70%) and internal validation (30%) cohorts. Once constructed, the logistic regression and point-score models were assessed using the internal validation cohort and an external validation cohort comprising data from a separate randomized trial. RESULTS: Of 2,176 patients who completed the World Health Organization Disability Assessment Schedule immediately before surgery, 927 (43%) patients were disabled, and 413 (19%) had significant disability. By 6 months after surgery, 1,640 patients (75%) had data available for the primary outcome analysis. Of these patients, 195 (12%) patients had died, and 691 (42%) were dead or disabled. The developed point-score model included the preoperative World Health Organization Disability Assessment Schedule score, patient age, dementia, and chronic kidney disease. The point score model retained good discrimination in the internal (area under the curve, 0.74; 95% CI, 0.69 to 0.79) and external (area under the curve, 0.77; 95% CI, 0.74 to 0.80) validation data sets. CONCLUSIONS: The authors developed and validated a point score model to predict death or disability in older patients after surgery.

Subcellular Delivery of Hydrogen Sulfide Using Small Molecule Donors Impacts Organelle Stress.

Hydrogen sulfide (H2S) is an endogenously produced gaseous signaling molecule with important roles in regulating organelle function and stress. Because of its high reactivity, targeted delivery of H2S using small molecule H2S donors has garnered significant interest to minimize off-target effects. Although mitochondrially targeted H2S donors, such as AP39, have been reported previously and exhibit significantly higher potency than nontargeted donors, the expansion of targeted H2S delivery to other subcellular organelles remains largely absent. To fill this key unmet need, we report a library of organelle-targeted H2S donors that localize H2S delivery to specific subcellular organelles, including the Golgi apparatus, lysosome, endoplasmic reticulum, and mitochondria. We measured H2S production in vitro from each donor, confirmed the localization of H2S delivery using organelle-specific H2S responsive fluorescent probes, and demonstrated enhanced potency of these targeted H2S donors in providing protection against organelle-specific stress. We anticipate this class of targeted H2S donors will enable future studies of subcellular roles of H2S and the pathways by which H2S alleviates subcellular organelle stress.

The Role of Low-frequency Neural Oscillations in Speech Processing: Revisiting Delta Entrainment.

Studies that use measures of cerebro-acoustic coherence have shown that theta oscillations (3-10 Hz) entrain to syllable-size modulations in the energy envelope of speech. This entrainment creates sensory windows in processing acoustic cues. Recent reports submit that delta oscillations (<3 Hz) can be entrained by nonsensory content units like phrases and serve to process meaning-though such views face fundamental problems. Other studies suggest that delta underlies a sensory chunking linked to the processing of sequential attributes of speech sounds. This chunking associated with the "focus of attention" is commonly manifested by the temporal grouping of items in sequence recall. Similar grouping in speech may entrain delta. We investigate this view by examining how low-frequency oscillations entrain to three types of stimuli (tones, nonsense syllables, and utterances) having similar timing, pitch, and energy contours. Entrainment was indexed by "intertrial phase coherence" in the EEGs of 18 listeners. The results show that theta oscillations at central sites entrain to syllable-size elements in speech and tones. However, delta oscillations at frontotemporal sites specifically entrain to temporal groups in both meaningful utterances and meaningless syllables, which indicates that delta may support but does not directly bear on a processing of content. The findings overall suggest that, although theta entrainment relates to a processing of acoustic attributes, delta entrainment links to a sensory chunking that relates to a processing of properties of articulated sounds. The results also show that measures of intertrial phase coherence can be better suited than cerebro-acoustic coherence in revealing delta entrainment.

Development of Acid-Mediated H2S/COS Donors That Respond to a Specific pH Window.

Hydrogen sulfide (H2S) is a biologically relevant molecule, and recent efforts have focused on developing small molecular donors that deliver H2S on demand. Acid-activated donors have garnered significant interest due to the potential application of such systems in myocardial ischemia injury or for suppressing tumor growth. In this work, we report a new strategy for tuning H2S delivery to a specific pH window. Specifically, we utilize self-immolative thiocarbamates with an imine-derived triggering group. After imine hydrolysis, the self-immolative decomposition releases carbonyl sulfide (COS), which is quickly hydrolyzed to H2S by carbonic anhydrase. Although acid-mediated hydrolysis results in imine cleavage, environments that are too acidic result in protonation of the aniline intermediate and results in inhibition of COS/H2S release. Taken together, this mechanism enables access to donor motifs that are only activated within specific pH windows. Here, we demonstrate the design, preparation, and pH evaluation of a series of imine-based COS/H2S donor motifs, which we anticipate that will have utility in investigating H2S in acidic microenvironments.

Adaptive and selective production of syllable duration and fundamental frequency as word segmentation cues by French-English bilinguals.

Despite the significant impact of prosody on L2 speakers' intelligibility, few studies have examined the production of prosodic cues associated with word segmentation in non-native or non-dominant languages. Here, 62 French-English bilingual adults, who varied in L1 (French or English) and language dominance, produced sentences built around syllable strings that can be produced either as one bisyllabic word or two monosyllabic words. Each participant produced both English and French utterances, providing both native productions (used as reference) and L2 productions. Acoustic analyses of the mean fundamental frequency (F0) and duration of both syllables of the ambiguous string revealed that speakers' relative language dominance affected the speakers' prosodic cue production over and above L1. Speakers also produced different prosodic patterns in English and French, suggesting that the production of prosodic cues associated with word-segmentation is both adaptive (modified by language experience) and selective (specific to each language).

Do CH-Anion and Anion-π Interactions Alter the Mechanism of 2:1 Host-Guest Complexation in Arylethynyl Monourea Anion Receptors?

Selective tuning of arylethynyl urea scaffolds for anionic guests requires an understanding of preferred binding motifs of the host-guest interaction. To investigate the binding preference of receptors without a pre-organized binding pocket, two electron-deficient phenylacetylene receptors with a single urea moiety have been prepared and were found to bind halides as 2:1 host-guest complexes that feature key CH-anion or anion-π interactions. These supporting interactions also appear to influence the mechanism of the 2:1 binding event.

Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P.

Extensive alternative pre-mRNA splicing of the mu opioid receptor gene, OPRM1, has demonstrated an array of splice variants in mice, rats and humans. Three classes of splice variants have been identified: full-length seven transmembrane (TM) domain variants with C-terminal splicing, truncated 6TM variants and single TM variants. The current studies isolates and characterizes an additional three full-length C-terminal splice variants generated from the mouse OPRM1 gene: mMOR-1A, mMOR-1O, and mMOR-1P. Using RT-qPCR, we demonstrated differential expression of these variants' mRNAs among selected brain regions, supporting region-specific alternative splicing. When expressed in Chinese Hamster Ovary cells, all the variants displayed high mu binding affinity and selectivity with subtle differences in the affinities toward some agonists. [³5S]γGTP binding assays revealed marked differences in agonist-induced G protein activation in both potency and efficacy among the variants. Together with the previous studies of mu agonist-induced phosphorylation and internalization in several carboxyl terminal splice variants, the current studies further suggest the existence of biased signaling of various agonists within each individual variant and/or among different variants.

Grouping by Time and Pitch Facilitates Free but Not Cued Recall for Word Lists in Normally-Hearing Listeners.

Auditory memory is an important everyday skill evaluated more and more frequently in clinical settings as there is recently a greater recognition of the cost of hearing loss to cognitive systems. Testing often involves reading a list of unrelated items aloud; but prosodic variations in pitch and timing across the list can affect the number of items remembered. Here, we ran a series of online studies on normally-hearing participants to provide normative data (with a larger and more diverse population than the typical student sample) on a novel protocol characterizing the effects of suprasegmental properties in speech, namely investigating pitch patterns, fast and slow pacing, and interactions between pitch and time grouping. In addition to free recall, and in line with our desire to work eventually with individuals exhibiting more limited cognitive capacity, we included a cued recall task to help participants recover specifically the words forgotten during the free recall part. We replicated key findings from previous research, demonstrating the benefits of slower pacing and of grouping on free recall. However, only slower pacing led to better performance on cued recall, indicating that grouping effects may decay surprisingly fast (over a matter of one minute) compared to the effect of slowed pacing. These results provide a benchmark for future comparisons of short-term recall performance in hearing-impaired listeners and users of cochlear implants.

A Cell Trappable Methyl Rhodol-Based Fluorescent Probe for Hydrogen Sulfide Detection.

Hydrogen sulfide is a biologically important molecule and developing chemical tools that enable further investigations into the functions of H2 S is essential. Fluorescent turn-on H2 S probes have been developed for use in cellulo and in vivo, but the membrane permeability of these probes can lead to probe leakage and signal attenuation over time. Here we report a cell trappable fluorescent probe for H2 S, CT-MeRhoAz, which is based on a methylrhodolazide scaffold derivatized with an acetoxymethyl ester group. Prior to ester cleavage, the CT-MeRhoAz probe generates a 2500-fold turn-on response to H2 S, which is enhanced to a 3000-fold response for the carboxylic acid form of the probe. Additionally, the probe is highly selective for H2 S over other biologically relevant sulfur, oxygen, and nitrogen-based analytes. Live cell imaging experiments confirmed the biocompatibility of CT-MeRhoAz and also that it is cell trappable, unlike the parent MeRhoAz scaffold.

Reactive sulfur and selenium species in the regulation of bone homeostasis.

Reactive oxygen species (ROS) are important modulators of physiological signaling and play important roles in bone tissue regulation. Both reactive sulfur species (RSS) and reactive selenium species (RSeS) are involved in ROS signaling, and recent work suggests RSS and RSeS involvement in the regulation of bone homeostasis. For example, RSS can promote osteogenic differentiation and decrease osteoclast activity and differentiation, and the antioxidant activity of RSeS play crucial roles in balancing bone remodeling. Here, we outline current research progress on the application of RSS and RSeS in bone disease and regeneration. Focusing on these investigations, we highlight different methods, tools, and sources of RSS and RSeS, and we also highlight future opportunities for delivery of RSS and RSeS in biological environments relating to bone.

Age of Acquisition Modulates Alpha Power During Bilingual Speech Comprehension in Noise.

Research on bilingualism has grown exponentially in recent years. However, the comprehension of speech in noise, given the ubiquity of both bilingualism and noisy environments, has seen only limited focus. Electroencephalogram (EEG) studies in monolinguals show an increase in alpha power when listening to speech in noise, which, in the theoretical context where alpha power indexes attentional control, is thought to reflect an increase in attentional demands. In the current study, English/French bilinguals with similar second language (L2) proficiency and who varied in terms of age of L2 acquisition (AoA) from 0 (simultaneous bilinguals) to 15 years completed a speech perception in noise task. Participants were required to identify the final word of high and low semantically constrained auditory sentences such as "Stir your coffee with a spoon" vs. "Bob could have known about the spoon" in both of their languages and in both noise (multi-talker babble) and quiet during electrophysiological recording. We examined the effects of language, AoA, semantic constraint, and listening condition on participants' induced alpha power during speech comprehension. Our results show an increase in alpha power when participants were listening in their L2, suggesting that listening in an L2 requires additional attentional control compared to the first language, particularly early in processing during word identification. Additionally, despite similar proficiency across participants, our results suggest that under difficult processing demands, AoA modulates the amount of attention required to process the second language.

Services for people with ankylosing spondylitis in the UK--a survey of rheumatologists and patients.

OBJECTIVE: . To investigate the services offered to patients with AS in the UK in 2010. METHODS: Two thousand non-health-care professional members of the National Ankylosing Spondylitis Society (NASS) were sent a questionnaire asking about their experiences surrounding diagnosis, treatment and access to therapies (response rate 40%). A separate questionnaire was sent to a consultant rheumatologist in every acute NHS trust in the UK, asking about services offered to patients with AS (response rate 68%). RESULTS: Overall, there was a mean diagnostic delay of 8.57 years. Almost one-third (32.2%) of patients were not reviewed in secondary care. Non-attendance was associated with increasing age and longer disease duration. Twenty per cent of patients were taking anti-TNF drugs, but 18.8% of departments reported that their ability to give anti-TNF therapy was restricted (64% reported primary-care trust rationing and 14% lack of staff). Almost all rheumatology departments had access to MRI, but 70.9% still used X-ray radiographs as their first-line investigation. A minority (5.6%) of patients reported they had never seen a physiotherapist, but less than one-third could self-refer for treatment during a flare. CONCLUSION: This is the first study to explore the services available to people with AS in the UK. Almost one-third of patients are not seen in rheumatology departments and therefore may be under-treated. For those who are seen, access to anti-TNF drugs and other therapies remains an issue.

Near native-like stress pattern perception in English-French bilinguals as indexed by the mismatch negativity.

We examined lexical stress processing in English-French bilinguals. Auditory mismatch negativity (MMN) responses were recorded in response to English and French pseudowords, whose primary stress occurred either on a language-consistent "usual" or language-inconsistent "unusual" syllable. In most conditions, the pseudowords elicited two consecutive MMNs, and somewhat surprisingly, these MMNs were not systematically modulated by bilingual experience. This suggests that it is possible to achieve native-like pre-attentive processing of lexical stress, even in a language that one has not learned since birth.

Recognition of vocal socioemotional expressions at varying levels of emotional intensity.

Nonverbal expressions of emotion can vary in intensity, from ambiguous to prototypical exemplars: for instance, facial displays of happiness may range from a faint smile to a full-blown grin. Previous work suggests that the accuracy with which facial expressions are recognized as the intended emotion increases with emotional intensity, although this pattern depends on the displayed emotion. Less is known about the association between emotional intensity and the recognition of vocal emotional expressions (affective prosody), which also convey information about others' socioemotional intent but are perceived and interpreted differently than facial expressions. The current study examined listeners' ability to recognize emotional intent in morphed vocal prosody recordings that varied in emotional intensity from neutral to prototypical exemplars of basic emotions (anger, disgust, fear, happiness, sadness) and social expressions (friendliness, meanness). Results suggest that listeners' accuracy in identifying the intended emotional intent in each recording increased nonlinearly with emotional intensity. This pattern varied by emotion type: for instance, accuracy for anger rose steeply with increasing emotional intensity before plateauing, whereas accuracy for happiness remained unchanged across low-intensity exemplars but increased thereafter. These findings highlight emotion-specific ways in which dynamic changes in emotional intensity inform perceptions of socioemotional intent in emotional prosody. Moreover, these results also point to potential challenges in emotional communication in social interactions that rely primarily on the voice, with many low-intensity expressions having a higher probability of being misinterpreted. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Spoken Word Segmentation in First and Second Language: When ERP and Behavioral Measures Diverge.

Previous studies of word segmentation in a second language have yielded equivocal results. This is not surprising given the differences in the bilingual experience and proficiency of the participants and the varied experimental designs that have been used. The present study tried to account for a number of relevant variables to determine if bilingual listeners are able to use native-like word segmentation strategies. Here, 61 French-English bilingual adults who varied in L1 (French or English) and language dominance took part in an audiovisual integration task while event-related brain potentials (ERPs) were recorded. Participants listened to sentences built around ambiguous syllable strings (which could be disambiguated based on different word segmentation patterns), during which an illustration was presented on screen. Participants were asked to determine if the illustration was related to the heard utterance or not. Each participant listened to both English and French utterances, providing segmentation patterns that included both their native language (used as reference) and their L2. Interestingly, different patterns of results were observed in the event-related potentials (online) and behavioral (offline) results, suggesting that L2 participants showed signs of being able to adapt their segmentation strategies to the specifics of the L2 (online ERP results), but that the extent of the adaptation varied as a function of listeners' language experience (offline behavioral results).

Earlier age of second language learning induces more robust speech encoding in the auditory brainstem in adults, independent of amount of language exposure during early childhood.

Learning a second language (L2) at a young age is a driving factor of functional neuroplasticity in the auditory brainstem. To date, it remains unclear whether these effects remain stable until adulthood and to what degree the amount of exposure to the L2 in early childhood might affect their outcome. We compared three groups of adult English-French bilinguals in their ability to categorize English vowels in relation to their frequency following responses (FFR) evoked by the same vowels. At the time of testing, cognitive abilities as well as fluency in both languages were matched between the (1) simultaneous bilinguals (SIM, N = 18); (2) sequential bilinguals with L1-English (N = 14); and (3) sequential bilinguals with L1-French (N = 11). Our results show that the L1-English group show sharper category boundaries in identification of the vowels compared to the L1-French group. Furthermore, the same pattern was reflected in the FFRs (i.e., larger FFR responses in L1-English > SIM > L1-French), while again only the difference between the L1-English and the L1-French group was statistically significant; nonetheless, there was a trend towards larger FFR in SIM compared to L1-French. Our data extends previous literature showing that exposure to a language during the first years of life induces functional neuroplasticity in the auditory brainstem that remains stable until at least young adulthood. Furthermore, the findings suggest that amount of exposure (i.e., 100% vs. 50%) to that language does not differentially shape the robustness of the perceptual abilities or the auditory brainstem encoding of phonetic categories of the language. Statement of significance: Previous studies have indicated that early age of L2 acquisition induces functional neuroplasticity in the auditory brainstem during processing of the L2. This study compared three groups of adult bilinguals who differed in their age of L2 acquisition as well as the amount of exposure to the L2 during early childhood. We demonstrate for the first time that the neuroplastic effect in the brainstem remains stable until young adulthood and that the amount of L2 exposure does not influence behavioral or brainstem plasticity. Our study provides novel insights into low-level auditory plasticity as a function of varying bilingual experience.

Response to lower dose TNF inhibitors in axial spondyloarthritis; a real-world multicentre observational study.

OBJECTIVE: Dose optimization of TNF inhibitors in axial spondyloarthritis (axSpA) is attractive, but it is unclear for which patients this approach might be appropriate. METHODS: Seventy-one patients with axSpA, from six UK centres, were identified who had reduced their dose of TNF inhibitor after being considered to be stable responders. All completed a questionnaire concerning their approach to and experience of dose reduction. Data on patient characteristics, metrology and CRP were retrieved retrospectively from patient records. RESULTS: Over 2 years of observation, 60 (84.5%) remained (REM) on reduced-dose medication and 11 (15.5%) reverted (REV) to the original dose. The overall mean dose reduction was 39% for REM patients and 44% for REV patients. Both groups initially responded in a similar manner to treatment, but the data showed a trend that younger women were more likely to revert. Neither BMI nor smoking was associated with continued low-dose responsiveness. Eight of the 11 REV patients reverted by 6 months. None reached criteria of secondary drug failure, and all regained control after increasing back to the original dose. Most patients in both groups reached the decision to reduce the dose jointly with clinicians. A preference for taking the reduced dose was not associated with low-dose drug survival. CONCLUSION: Many patients with axSpA remain well symptomatically after stepping down the dose of TNF inhibitor, but young women are less likely to do well on a reduced dose. Dose reduction should be one element of the management of patients with axSpA.

Towards a national perioperative clinical quality registry: The diagnostic accuracy of administrative data in identifying major postoperative complications.

Accurately measuring the incidence of major postoperative complications is essential for funding and reimbursement of healthcare providers, for internal and external benchmarking of hospital performance and for valid and reliable public reporting of outcomes. Actual or surrogate outcomes data are typically obtained by one of three methods: clinical quality registries, clinical audit, or administrative data. In 2017 a perioperative registry was developed at the Alfred Hospital and mapped to administrative and clinical data. This study investigated the statistical agreement between administrative data (International Statistical Classification of Diseases and Related Health Problems (10th edition) Australian Modification codes) and clinical audit by anaesthetists in identifying major postoperative complications. The study population included 482 high-risk surgical patients referred to the Alfred Hospital anaesthesia postoperative service over two years. Clinical audit was conducted to determine the presence of major complications and these data were compared to administrative data. The main outcome was statistical agreement between the two methods, as defined by Cohen's kappa statistic. Substantial agreement was observed for five major complications, moderate agreement for three, fair agreement for six and poor agreement for two. Sensitivity and positive predictive value ranged from 0 to 100%. Specificity was above 90% for all complications. There was important variation in inter-rater agreement. For four of the five complications with substantial agreement between administrative data and clinical audit, sensitivity was only moderate (61.5%-75%). Using International Statistical Classification of Diseases and Related Health Problems (10th edition) Australian Modification codes to identify postoperative complications at our hospital has high specificity but is likely to underestimate the incidence compared to clinical audit. Further, retrospective clinical audit itself is not a highly reliable method of identifying complications. We believe a perioperative clinical quality registry is necessary to validly and reliably measure major postoperative complications in Australia for benchmarking of hospital performance and before public reporting of outcomes should be considered.

Collaboration between patient organisations and a clinical research sponsor in a rare disease condition: learnings from a community advisory board and best practice for future collaborations.

Introduction Transparent collaborations between patient organisations (POs) and clinical research sponsors (CRS) can identify and address the unmet needs of patients and caregivers. These insights can improve clinical trial participant experience and delivery of medical innovations necessary to advance health outcomes and standards of care. We share our experiences from such a collaboration undertaken surrounding the SENSCIS® clinical trial (NCT02597933), and discuss its impact during, and legacy beyond, the trial.Summary We describe the establishment of a community advisory board (CAB): a transparent, multiyear collaboration between the scleroderma patient community and a CRS. We present shared learnings from the collaboration, which is split into three main areas: (1) the implementation and conduct of the clinical trial; (2) analysis and dissemination of the results; and (3) aspects of the collaboration not related to the trial.1. The scleroderma CAB reviewed and provided advice on trial conduct and reporting. This led to the improvement and optimisation of trial procedures; meaningful, patient-focused adaptations were made to address challenges relevant to scleroderma-associated interstitial lung disease patients.2. To ensure that results of the trial were accessible to lay audiences and patients, written lay summaries were developed by the trial sponsor with valuable input from the CAB to ensure that language and figures were understandable.3. The CAB and the CRS also collaborated to co-develop opening tools for medication blister packs and bottles. In addition, to raise disease awareness among physicians, patients and caregivers, educational materials to improve diagnosis and management of scleroderma were co-created and delivered by the CAB and CRS.Conclusions This collaboration between POs and a CRS, in a rare disease condition, led to meaningful improvements in patient safety, comfort and self-management and addressed information needs. This collaboration may serve as a template of best practice for future collaborations between POs, research sponsors and other healthcare stakeholders.