Autistic Traits Modulate Social Synchronizations Between School-Aged Children: Insights From Three fNIRS Hyperscanning Experiments.

The current study investigated how autistic traits modulate peer interactions using functional near-infrared spectroscopy (fNIRS) hyperscanning. Across three experiments, we tested the effect of copresence, joint activity, and a tangible goal during cooperative interactions on interbrain coherence (IBC) in school-aged children between 9 and 11 years old. Twenty-three dyads of children watched a video alone or together in Experiment 1, engaged in joint or self-paced book reading in Experiment 2, and pretended to play a Jenga game or played for real in Experiment 3. We found that all three formats of social interactions increased IBC in the frontotemporoparietal networks, which have been reported to support social interaction. Further, our results revealed the shared and unique interbrain connections that were predictive of the lower and higher parent-reported autism-spectrum quotient scores, which indicated child autistic traits. Results from a convergence of three experiments provide the first evidence to date that IBC is modulated by child autistic traits.

Early-stage use of hearing aids preserves auditory cortical structure in children with sensorineural hearing loss.

Hearing is critical to spoken language, cognitive, and social development. Little is known about how early auditory experiences impact the brain structure of children with bilateral sensorineural hearing loss. This study examined the influence of hearing aid use and residual hearing on the auditory cortex of children with severe to profound congenital sensorineural hearing loss. We evaluated cortical preservation in 103 young pediatric cochlear implant candidates (55 females and 48 males) by comparing their multivoxel pattern similarity of auditory cortical structure with that of 78 age-matched children with typical hearing. The results demonstrated that early-stage hearing aid use preserved the auditory cortex of children with bilateral congenital sensorineural hearing loss. Children with less residual hearing experienced a more pronounced advantage from hearing aid use. However, this beneficial effect gradually diminished after 17 months of hearing aid use. These findings support timely fitting of hearing aids in conjunction with early implantation to take advantage of neural preservation to maximize auditory and spoken language development.

Research priorities in regional anaesthesia: an international Delphi study.

BACKGROUND: Regional anaesthesia use is growing worldwide, and there is an increasing emphasis on research in regional anaesthesia to improve patient outcomes. However, priorities for future study remain unclear. We therefore conducted an international research prioritisation exercise, setting the agenda for future investigators and funding bodies. METHODS: We invited members of specialist regional anaesthesia societies from six continents to propose research questions that they felt were unanswered. These were consolidated into representative indicative questions, and a literature review was undertaken to determine if any indicative questions were already answered by published work. Unanswered indicative questions entered a three-round modified Delphi process, whereby 29 experts in regional anaesthesia (representing all participating specialist societies) rated each indicative question for inclusion on a final high priority shortlist. If ≥75% of participants rated an indicative question as 'definitely' include in any round, it was accepted. Indicative questions rated as 'definitely' or 'probably' by <50% of participants in any round were excluded. Retained indicative questions were further ranked based on the rating score in the final Delphi round. The final research priorities were ratified by the Delphi expert group. RESULTS: There were 1318 responses from 516 people in the initial survey, from which 71 indicative questions were formed, of which 68 entered the modified Delphi process. Eleven 'highest priority' research questions were short listed, covering themes of pain management; training and assessment; clinical practice and efficacy; technology and equipment. CONCLUSIONS: We prioritised unanswered research questions in regional anaesthesia. These will inform a coordinated global research strategy for regional anaesthesia and direct investigators to address high-priority areas.

Ambulatory total hip and knee arthroplasty: a literature review and perioperative considerations.

PURPOSE: Total joint arthroplasty (TJA), particularly for the hip and knee, is one of the most commonly performed surgical procedures. The advancement/evolution of surgical and anesthesia techniques have allowed TJA to be performed on an ambulatory/same-day discharge basis. In this Continuing Professional Development module, we synthesize the perioperative evidence that may aid the development of successful ambulatory TJA pathways. SOURCE: We searched MEDLINE, Embase, CENTRAL, and the Cochrane Database of Systematic Reviews for ambulatory or fast-track TJA articles. In the absence of direct evidence for the ambulatory setting, we extrapolated the evidence from the in-patient TJA literature. PRINCIPAL FINDINGS: Patient selection encompassing patient, medical, and social factors is fundamental for successful same-day discharge of patients following TJA. Evidence for the type of intraoperative anesthesia favours neuraxial technique for achieving same day discharge criteria and reduced perioperative complications. Availability of short-acting local anesthetic for neuraxial anesthesia would affect the anesthetic choice. Nonetheless, modern general anesthesia with multimodal analgesia and antithrombotics in a well selected population can be considered. Regional analgesia forms an integral part of the multimodal analgesia regime to reduce opioid consumption and facilitate same-day hospital discharge, reducing hospital readmission. For ambulatory total knee arthroplasty, a combination of adductor canal block with local anesthetic periarticular infiltration provided is a suitable regional analgesic regimen. CONCLUSION: Anesthesia for TJA has evolved as such that same-day discharge will become the norm for selected patients. It is essential to establish pathways for early discharge to prevent adverse effects and readmission in this population. As more data are generated from an increased volume of ambulatory TJA, more robust evidence will emerge for the ideal anesthetic components to optimize outcomes.

RéSUMé: OBJECTIF: L'arthroplastie par prothèse totale (APT), en particulier de la hanche et du genou, constitue l'une des interventions chirurgicales les plus couramment pratiquées. L'avancement et l'évolution des techniques chirurgicales et d'anesthésie ont permis de réaliser une APT en ambulatoire/sur la base d'un congé le jour même. Dans ce module de développement professionnel continu, nous proposons une synthèse des données probantes périopératoires qui pourraient contribuer à l'élaboration de trajectoires réussies pour l'APT en ambulatoire. SOURCES: Nous avons réalisé des recherches dans MEDLINE, Embase, CENTRAL et dans la base de données Cochrane des revues systématiques à la recherche d'articles sur les APT ambulatoires ou accélérées. En l'absence de données probantes directes dans un contexte ambulatoire, nous avons extrapolé les données probantes à partir de la littérature sur les APT en milieu hospitalier. CONSTATATIONS PRINCIPALES: La sélection des patient·es englobant les facteurs patient·es, médicaux et sociaux est fondamentale pour un congé réussi le jour même après une APT. Les données probantes portant sur le type d'anesthésie peropératoire privilégient la technique neuraxiale pour respecter les critères de congé le jour même et réduire les complications périopératoires. La disponibilité d'un anesthésique local à courte durée d'action pour l'anesthésie neuraxiale affecterait le choix de l'anesthésique. Néanmoins, dans une population bien sélectionnée, l'anesthésie générale moderne avec analgésie multimodale et antithrombotiques peut être envisagée. L'analgésie régionale fait partie intégrante d'un régime d'analgésie multimodale visant à réduire la consommation d'opioïdes et à faciliter le congé de l'hôpital le jour même, ce qui réduit le nombre de réadmissions. En ce qui concerne l'arthroplastie totale du genou en ambulatoire, la combinaison d'un bloc du canal des adducteurs et d'une infiltration périarticulaire d'anesthésique local constitue un régime approprié d'analgésie régionale. CONCLUSION: L'anesthésie pour les APT a évolué de telle sorte que le congé le jour même deviendra la norme pour certain·es patient·es. Il est essentiel d'établir des trajectoires de congé précoce afin de prévenir les effets indésirables et la réadmission dans cette population. Au fur et à mesure que davantage de données seront générées à partir d'un volume accru d'APT en ambulatoire, des données probantes plus solides émergeront pour appuyer les composantes idéales de l'anesthésie pour optimiser les devenirs.

Commonality and variation in mental representations of music revealed by a cross-cultural comparison of rhythm priors in 15 countries.

Music is present in every known society but varies from place to place. What, if anything, is universal to music cognition? We measured a signature of mental representations of rhythm in 39 participant groups in 15 countries, spanning urban societies and Indigenous populations. Listeners reproduced random 'seed' rhythms; their reproductions were fed back as the stimulus (as in the game of 'telephone'), such that their biases (the prior) could be estimated from the distribution of reproductions. Every tested group showed a sparse prior with peaks at integer-ratio rhythms. However, the importance of different integer ratios varied across groups, often reflecting local musical practices. Our results suggest a common feature of music cognition: discrete rhythm 'categories' at small-integer ratios. These discrete representations plausibly stabilize musical systems in the face of cultural transmission but interact with culture-specific traditions to yield the diversity that is evident when mental representations are probed across many cultures.

Brain templates for Chinese babies from newborn to three months of age.

The infant brain develops rapidly and this area of research has great clinical implications. Neurodevelopmental disorders such as autism and developmental delay have their origins, potentially, in abnormal early brain maturation. Searching for potential early neural markers requires a priori knowledge about infant brain development and anatomy. One of the most common methods of characterizing brain features requires normalization of individual images into a standard stereotactic space and conduct of group-based analyses in this space. A population representative brain template is critical for these population-based studies. Little research is available on constructing brain templates for typical developing Chinese infants. In the present work, a total of 120 babies from 5 to 89 days of age were included with high resolution structural magnetic resonance imaging scans. T1-weighted and T2-weighted templates were constructed using an unbiased registration approach for babies from newborn to 3 months of age. Age-specific templates were also estimated for babies aged at 0, 1, 2 and 3 months old. Then we conducted a series of evaluations and statistical analyses over whole tissue segmentations and brain parcellations. Compared to the use of population mismatched templates, using our established templates resulted in lower deformation energy to transform individual images into the template space and produced a smaller registration error, i.e., smaller standard deviation of the registered images. Significant volumetric growth was observed across total brain tissues and most of the brain regions within the first three months of age. The total brain tissues exhibited larger volumes in baby boys compared to baby girls. To the best of our knowledge, this is the first study focusing on the construction of Chinese infant brain templates. These templates can be used for investigating birth related conditions such as preterm birth, detecting neural biomarkers for neurological and neurodevelopmental disorders in Chinese populations, and exploring genetic and cultural effects on the brain.

Structure-function relationship study for sulfated protein therapeutics using hydrophobic interaction chromatography and mass spectrometry.

Protein tyrosine sulfation is a post-translational modification (PTM) that is rarely reported in recombinant therapeutic proteins. However, when sulfation does occur, the additional negative charge from the modification can influence intermolecular interactions and antigen-binding activity, making it a critical quality attribute that necessitates stringent control. In this study, we developed a unique hydrophobic interaction chromatography (HIC) method for the separation and quantification of a therapeutic bispecific antibody with varying degrees of sulfation. Despite the increased surface hydrophilicity of sulfated species, the HIC method provides enhanced retention. Baseline resolution was attained based on the degree of sulfation, independent of other PTMs such as C-terminal amidation and forced deamidation. Further structure-function relationship studies of enriched sulfated bispecific antibody species were conducted using mass spectrometry and fluorescence-linked immunosorbent assay (FLISA). These studies revealed that the tyrosine sulfation modification, which occurs in the complementarity-determining region (CDR), is a critical quality attribute and can adversely impact the antibody's binding to its cognate antigen. The evaluation of sulfation assay using HIC method confirmed it is an effective means for controlling this critical quality attribute.

Airway management of lingual tonsillar hypertrophy: A narrative review.

Lingual tonsillar hypertrophy is rarely identified on routine airway assessment but may cause difficulties in airway management. We conducted a narrative review of case reports of lingual tonsillar hypertrophy to examine associated patient factors, success rates of airway management techniques and complications. We searched the literature for anaesthetic management of cases with lingual tonsillar hypertrophy. We found 89 patients in various case reports, from which we derived 92 cases to analyse. 64% of cases were assessed as having a normal airway. Difficult and impossible face mask ventilation occurred in 29.6% and 1.4% of cases, respectively. Difficult intubation and failed intubation occurred in 89.1% and 21.7% of cases, respectively. Multiple attempts (up to six) at intubation were performed, with no successful intubation after the third attempt with direct laryngoscopy. Some 16.5% of patients were woken up and 4.3% required emergency front of neck access. Complications included oesophageal intubation (10.9%), bleeding (9.8%) and severe hypoxia (3.2%). Our findings show that severe cases of lingual hypertrophy may cause an unanticipated difficult airway and serious complications, including hypoxic brain damage and death. A robust airway strategy is required which includes limiting the number of attempts at laryngoscopy, and early priming and performance of emergency front of neck access if required. In patients with known severe lingual tonsillar hypertrophy, awake intubation should be considered.

The development of tone discrimination in infancy: Evidence from a cross-linguistic, multi-lab report.

We report the findings of a multi-language and multi-lab investigation of young infants' ability to discriminate lexical tones as a function of their native language, age and language experience, as well as of tone properties. Given the high prevalence of lexical tones across human languages, understanding lexical tone acquisition is fundamental for comprehensive theories of language learning. While there are some similarities between the developmental course of lexical tone perception and that of vowels and consonants, findings for lexical tones tend to vary greatly across different laboratories. To reconcile these differences and to assess the developmental trajectory of native and non-native perception of tone contrasts, this study employed a single experimental paradigm with the same two pairs of Cantonese tone contrasts (perceptually similar vs. distinct) across 13 laboratories in Asia-Pacific, Europe and North-America testing 5-, 10- and 17-month-old monolingual (tone, pitch-accent, non-tone) and bilingual (tone/non-tone, non-tone/non-tone) infants. Across the age range and language backgrounds, infants who were not exposed to Cantonese showed robust discrimination of the two non-native lexical tone contrasts. Contrary to this overall finding, the statistical model assessing native discrimination by Cantonese-learning infants failed to yield significant effects. These findings indicate that lexical tone sensitivity is maintained from 5 to 17 months in infants acquiring tone and non-tone languages, challenging the generalisability of the existing theoretical accounts of perceptual narrowing in the first months of life. RESEARCH HIGHLIGHTS: This is a multi-language and multi-lab investigation of young infants' ability to discriminate lexical tones. This study included data from 13 laboratories testing 5-, 10-, and 17-month-old monolingual (tone, pitch-accent, non-tone) and bilingual (tone/non-tone, non-tone/non-tone) infants. Overall, infants discriminated a perceptually similar and a distinct non-native tone contrast, although there was no evidence of a native tone-language advantage in discrimination. These results demonstrate maintenance of tone discrimination throughout development.

Infant-directed speech facilitates word learning through attentional mechanisms: An fNIRS study of toddlers.

The speech register that adults especially caregivers use when interacting with infants and toddlers, that is, infant-directed speech (IDS) or baby talk, has been reported to facilitate language development throughout the early years. However, the neural mechanisms as well as why IDS results in such a developmental faciliatory effect remain to be investigated. The current study uses functional near-infrared spectroscopy (fNIRS) to evaluate two alternative hypotheses of such a facilitative effect, that IDS serves to enhance linguistic contrastiveness or to attract the child's attention. Behavioral and fNIRS data were acquired from twenty-seven Cantonese-learning toddlers 15-20 months of age when their parents spoke to them in either an IDS or adult-directed speech (ADS) register in a naturalistic task in which the child learned four disyllabic pseudowords. fNIRS results showed significantly greater neural responses to IDS than ADS register in the left dorsolateral prefrontal cortex (L-dlPFC), but opposite response patterns in the bilateral inferior frontal gyrus (IFG). The differences in fNIRS responses to IDS and to ADS in the L-dlPFC and the left parietal cortex (L-PC) showed significantly positive correlations with the differences in the behavioral word-learning performance of toddlers. The same fNIRS measures in the L-dlPFC and right PC (R-PC) of toddlers were significantly correlated with pitch range differences of parents between the two speech conditions. Together, our results suggest that the dynamic prosody in IDS increased toddlers' attention through greater involvement of the left frontoparietal network that facilitated word learning, compared to ADS. RESEARCH HIGHLIGHTS: This study for the first time examined the neural mechanisms of how infant-directed speech (IDS) facilitates word learning in toddlers. Using fNIRS, we identified the cortical regions that were directly involved in IDS processing. Our results suggest that IDS facilitates word learning by engaging a right-lateralized prosody processing and top-down attentional mechanisms in the left frontoparietal networks. The language network including the inferior frontal gyrus and temporal cortex was not directly involved in IDS processing to support word learning.

Recommandations pour des soins préventifs pour promouvoir l'équité en matière de santé.

CONTEXTE: Malgré des investissements importants dans un système de soins de santé public qui comprend des services préventifs, on continue d'observer des disparités évitables en matière de santé au Canada. L'équipe avait pour objectif de formuler des recommandations pour des soins de santé préventifs qui puissent améliorer l'équité en matière de santé par la priorisation des interventions efficaces à l'intention des groupes défavorisés. MÉTHODES: La ligne directrice a été élaborée par un comité composé de spécialistes en soins primaires et de membres de la patientèle, avec la contribution d'un groupe de patientes-et patientspartenaires ayant vécu diverses expériences. Après avoir sélectionné les sujets à prioriser, nous avons recensé les revues systématiques, les essais randomisés et contrôlés récents sur les méthodes de dépistage et d'autres études pertinentes sur l'efficacité du dépistage et de la prise en charge. Nous avons utilisé l'approche GRADE (Grading of Recommendations, Assessment, Development and Evaluation) pour formuler les recommandations et avons suivi le guide AGREE II (Appraisal of Guidelines for Research and Evaluation) pour rédiger le rapport. Il en a été de même avec les principes du Guidelines International Network pour la gestion des intérêts concurrents. Les recommandations ont été passées en revue par un comité externe d'experts en contenu avant d'être distribuées à des intervenants à l'échelle nationale pour approbation. RECOMMANDATIONS: Nous avons formulé 15 recommandations concernant le dépistage et d'autres soins préventifs et 1 recommandation de nature politique visant à améliorer l'accès aux soins primaires. Ainsi, nous recommandons de prioriser une stratégie de communication pour le dépistage du cancer colorectal à partir de l'âge de 45 ans et pour l'évaluation du risque de maladie cardiovasculaire pour lutter contre les iniquités en matière de santé et promouvoir la santé. Les interventions particulières qui devraient être déployées pour lutter contre les iniquités comprennent l'autodépistage du virus du papillome humain (VPH) et du VIH, et le test de libération de l'interféron γ pour l'infection tuberculeuse. Le dépistage de la dépression, de la toxicomanie, de la violence conjugale et de la pauvreté devrait également permettre aux personnes touchées d'accéder plus facilement à des interventions éprouvées. Nous recommandons une prise de contact systématique avec des professionnels de la santé en soins primaires pour les personnes défavorisées. INTERPRÉTATION: Les interventions préventives éprouvées peuvent aider à combattre les iniquités en matière de santé si la priorité est accordée aux personnes défavorisées. Les médecins, les organisations de santé et les gouvernements devraient adopter des mesures fondées sur des données probantes et en faire le suivi s'ils veulent promouvoir l'équité en matière de santé partout au Canada.

Preventive care recommendations to promote health equity.

BACKGROUND: Avoidable disparities in health outcomes persist in Canada despite substantial investments in a publicly funded health care system that includes preventive services. Our objective was to provide preventive care recommendations that promote health equity by prioritizing effective interventions for people experiencing disadvantages. METHODS: The guideline was developed by a primary care provider-patient panel, with input from a patient-partner panel with diverse lived experiences. After selecting priority topics, we searched for systematic reviews and recent randomized controlled trials of screening and other relevant studies of screening accuracy and management efficacy. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to develop recommendations and followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) reporting guidance. We managed competing interests using the Guideline International Network principles. The recommendations were externally reviewed by content experts and circulated for endorsement by national stakeholders. RECOMMENDATIONS: We developed 15 screening and other preventive care recommendations and 1 policy recommendation on improving access to primary care. We recommend prioritized outreach for colorectal cancer screening starting at age 45 years and for cardiovascular disease risk assessment, to help address inequities and promote health. Specific interventions that should be rolled out in ways that address inequities include human papillomavirus (HPV) self-testing, HIV self-testing and interferon-γ release assays for tuberculosis infection. Screening for depression, substance use, intimate partner violence and poverty should help connect people experiencing specific disadvantages with proven interventions. We recommend automatic connection to primary care for people experiencing disadvantages. INTERPRETATION: Proven preventive care interventions can address health inequities if people experiencing disadvantages are prioritized. Clinicians, health care organizations and governments should take evidence-based actions and track progress in promoting health equity across Canada.

The form and function processing of lexical tone and intonation in tone-language-speaking children with autism spectrum disorder.

Studies on how the form versus function aspect of tone and intonation is processed by autistic individuals have mainly focused on speakers of non-tonal languages (e.g., English) with equivocal results. While the samples' heterogeneous cognitive abilities may be contributing factors, the phenotype of tone and intonation processing in autism may also vary with one's language background. Thirty-eight cognitively able autistic and 32 non-autistic Mandarin-speaking children completed tone and intonation perception tasks, each containing a function and form condition. Results suggested that the abilities to discriminate tone and intonation were not impaired at either the form or function level in these autistic children, and that these abilities were positively associated with one another in both autistic and non-autistic groups. The more severe the autism symptoms, the worse the form- and function-level of tone and intonation processing. While enhanced tone and intonation processing has been found in a subgroup of autistic children, it may not be a general characteristic of the autistic population with long-term tone language experience. These findings reveal typical tone and intonation processing at both the form and function levels in cognitively able Mandarin-speaking autistic children and provide evidence for associated tone and intonation processing abilities across levels.

Deficits in neural encoding of speech in preterm infants.

Preterm children show developmental cognitive and language deficits that can be subtle and sometimes undetectable until later in life. Studies of brain development in children who are born preterm have largely focused on vascular and gross anatomical characteristics rather than pathophysiological processes that may contribute to these developmental deficits. Neural encoding of speech as reflected in EEG recordings is predictive of future language development and could provide insights into those pathophysiological processes. We recorded EEG from 45 preterm (≤ 34 weeks of gestation) and 45 term (≥ 38 weeks) Chinese-learning infants 0-12 months of (corrected) age during natural sleep. Each child listened to three speech stimuli that differed in lexically meaningful pitch (2 native and 1 non-native speech categories). EEG measures associated with synchronization and gross power of the frequency following response (FFR) were examined. ANCOVAs revealed no main effect of stimulus nativeness but main effects of age, consistent with earlier studies. A main effect of prematurity also emerged, with synchronization measures showing stronger group differences than power. By detailing differences in FFR measures related to synchronization and power, this study brings us closer to identifying the pathophysiological pathway to often subtle language problems experienced by preterm children.

The Extent of Hearing Input Affects the Plasticity of the Auditory Cortex in Children With Hearing Loss: A Preliminary Study.

PURPOSE: This study investigated to what extent residual hearing and rehabilitation options (e.g., hearing aids [HAs]) affect the auditory cortex in children with hearing loss. METHOD: Twenty-one children with bilateral congenital sensorineural hearing loss who were candidates for cochlear implantation were recruited. Voxel-based morphometry analysis was conducted to assess the gray matter (GM) volume in the auditory cortex. Children's residual hearing was measured by pure-tone audiometry at different frequencies. Multiple linear regression models were conducted to examine the effects of residual hearing and the use of HAs on GM volume in the auditory cortex with the control of age and gender. RESULTS: Children with more residual hearing at high frequencies had larger GM volume ratio (corrected by total intracranial volume) in the left Heschl's gyrus (r = -.545, p = .013). An interaction effect between residual hearing and the use of HAs suggested that the effect of residual hearing on GM ratio was moderated by the use of HAs (ß = -.791, p = .020). Compared with children with less residual hearing, children who had more residual hearing benefited more from longer use of HAs in terms of a larger GM ratio. CONCLUSIONS: Our preliminary findings highlight the impact of residual hearing on the neuroanatomy of the auditory cortex in children with hearing loss. Moreover, our results call for more auditory input via HAs for children with more residual hearing to preserve the auditory cortex before cochlear implantation. For children with less residual hearing who might receive limited benefit from HAs, an early cochlear implant would be necessary.

Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma.

OBJECTIVE: Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting. DESIGN: Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481). RESULTS: Anti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8+ T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8+ T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types. CONCLUSION: We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.

A large-scale repository of spoken narratives in French, German and Spanish from Cantonese-speaking learners.

Interdisciplinary research on foreign language learning has important implications for learning and education. In this paper, we present the Repository of Third Language (L3) Spoken Narratives from Modern Language Learners in Hong Kong (L3HK Repository). This database contains 906 audio recordings and annotated transcripts of spoken narratives in French, German, and Spanish that were elicited from Cantonese-speaking (L1) young adults using a wordless picture book, "Frog, Where Are You?". All participants spoke English as the second language (L2) and learned the target language as a third language (L3). We collected their demographic information, answers to a motivation questionnaire, parental socioeconomic status, and music background. Furthermore, for a subset of participants, we collected their L1 and L2 proficiency scores and additional experimental data on working memory and music perception. This database is valuable for examining cross-sectional changes in foreign language learning. The extensive data on phenotypes provide opportunities to explore learner-internal and learner-external factors in foreign language learning outcomes. These data may also be helpful for those who work on speech recognition.

Native Language Perceptual Sensitivity Predicts Nonnative Speech Perception Differently in Younger and Older Singaporean Bilinguals.

PURPOSE: We investigate in this study how individual variability in native language speech perception (termed Perceptual Sensitivity) influences nonnative speech perception in Singaporean Tamil-English bilinguals. Further, we assess if and how contextual and demographic factors influence Perceptual Sensitivity in the acquired languages and if the influence of Perceptual Sensitivity on nonnative speech perception is different across younger and older bilinguals. METHOD: Perceptual Sensitivity in the native languages was examined by implementing Tamil and English gating tasks in 87 Singaporean Tamil-English bilinguals from two age groups (younger: 19-33 years; older: 55-70 years). Mandarin lexical tone discrimination was implemented as a measure of nonnative speech perception. RESULTS: There was a wide range of variability in Perceptual Sensitivity scores in both languages across both age groups. Perceptual Sensitivity in the first native language (L1 Tamil) was a robust predictor of nonnative speech perception across both age groups, especially for the older bilinguals. However, general intelligence emerged as a stronger predictor than Tamil Perceptual Sensitivity in younger bilinguals. The influence of Tamil Perceptual Sensitivity on lexical tone perception was not tone-specific, supporting a general enhancement of lexical tone perception with better Tamil Perceptual Sensitivity. There was an influence of demographic factors on English Perceptual Sensitivity in older bilinguals, but not for Tamil and not in younger bilinguals. CONCLUSIONS: Our findings corroborate with previous studies in showing that native language Perceptual Sensitivity is positively associated with and predicts nonnative speech perception in younger and older adulthood regardless of language similarity but to varying degrees. Specifically, the influence of Perceptual Sensitivity on nonnative speech perception is stronger in older adulthood, suggesting a possible shift in reliance on crystallized language knowledge with age. Proficiency and use, among other demographic and language variables, do not appear to influence L1 Perceptual Sensitivity in a lesser used language (Tamil) as significantly as previously assumed.

PD-1highCXCR5-CD4+ peripheral helper T cells promote CXCR3+ plasmablasts in human acute viral infection.

T cell-B cell interaction is the key immune response to protect the host from severe viral infection. However, how T cells support B cells to exert protective humoral immunity in humans is not well understood. Here, we use COVID-19 as a model of acute viral infections and analyze CD4+ T cell subsets associated with plasmablast expansion and clinical outcome. Peripheral helper T cells (Tph cells; denoted as PD-1highCXCR5-CD4+ T cells) are significantly increased, as are plasmablasts. Tph cells exhibit "B cell help" signatures and induce plasmablast differentiation in vitro. Interestingly, expanded plasmablasts show increased CXCR3 expression, which is positively correlated with higher frequency of activated Tph cells and better clinical outcome. Mechanistically, Tph cells help B cell differentiation and produce more interferon γ (IFNγ), which induces CXCR3 expression on plasmablasts. These results elucidate a role for Tph cells in regulating protective B cell response during acute viral infection.