Diverse functional autoantibodies in patients with COVID-19.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1-6. Although pathological innate immune activation is well-documented in severe disease1, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.

Sex differences in immune responses that underlie COVID-19 disease outcomes.

There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1-5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients' age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.

Longitudinal analyses reveal immunological misfiring in severe COVID-19.

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.

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.

Narratives imagined in response to instrumental music reveal culture-bounded intersubjectivity.

The scientific literature sometimes considers music an abstract stimulus, devoid of explicit meaning, and at other times considers it a universal language. Here, individuals in three geographically distinct locations spanning two cultures performed a highly unconstrained task: they provided free-response descriptions of stories they imagined while listening to instrumental music. Tools from natural language processing revealed that listeners provide highly similar stories to the same musical excerpts when they share an underlying culture, but when they do not, the generated stories show limited overlap. These results paint a more complex picture of music's power: music can generate remarkably similar stories in listeners' minds, but the degree to which these imagined narratives are shared depends on the degree to which culture is shared across listeners. Thus, music is neither an abstract stimulus nor a universal language but has semantic affordances shaped by culture, requiring more sustained attention from psychology.

Lack of association between pandemic chilblains and SARS-CoV-2 infection.

An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.

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.

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.

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.

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.

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.

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.

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.

Germinal center B cell initiation, GC maturation, and the coevolution of its stromal cell niches.

Throughout the developing GC response, B cell survival and fate choices made at the single cell level are dependent on signals received largely through interactions with other cells, often with cognate T cells. The type of signals that a given B cell can encounter is dictated by its location within tissue microarchitecture. The focus of this review is on the initiation and evolution of the GC response at the earliest time points. Here, we review the key factors influencing the progression of GC B cell differentiation that are both stage and context dependent. Finally, we describe the coevolution of niches within and surrounding the GC that influence the outcome of the GC response.

Longitudinal Immune Profiling of a Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection in a Solid Organ Transplant Recipient.

BACKGROUND: The underlying immunologic deficiencies enabling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection are currently unknown. We describe deep longitudinal immune profiling of a transplant recipient hospitalized twice for coronavirus disease 2019 (COVID-19). METHODS: A 66-year-old male renal transplant recipient was hospitalized with COVID-19 March 2020 then readmitted to the hospital with COVID-19 233 days after initial diagnosis. Virologic and immunologic investigations were performed on samples from the primary and secondary infections. RESULTS: Whole viral genome sequencing and phylogenetic analysis revealed that viruses causing both infections were caused by distinct genetic lineages without evidence of immune escape mutations. Longitudinal comparison of cellular and humoral responses during primary SARS-CoV-2 infection revealed that this patient responded to the primary infection with low neutralization titer anti-SARS-CoV-2 antibodies that were likely present at the time of reinfection. CONCLUSIONS: The development of neutralizing antibodies and humoral memory responses in this patient failed to confer protection against reinfection, suggesting that they were below a neutralizing titer threshold or that additional factors may be required for efficient prevention of SARS-CoV-2 reinfection. Development of poorly neutralizing antibodies may have been due to profound and relatively specific reduction in naive CD4 T-cell pools. Seropositivity alone may not be a perfect correlate of protection in immunocompromised patients.

Neural Fingerprints Underlying Individual Language Learning Profiles.

Human language learning differs significantly across individuals in the process and ultimate attainment. Although decades of research exploring the neural substrates of language learning have identified distinct and overlapping neural networks subserving learning of different components, the neural mechanisms that drive the large interindividual differences are still far from being understood. Here we examine to what extent the neural dynamics of multiple brain networks in men and women across sessions of training contribute to explaining individual differences in learning multiple linguistic components (i.e., vocabulary, morphology, and phrase and sentence structures) of an artificial language in a 7 d training and imaging paradigm with functional MRI. With machine-learning and predictive modeling, neural activation patterns across training sessions were highly predictive of individual learning success profiles derived from the four components. We identified four neural learning networks (i.e., the Perisylvian, frontoparietal, salience, and default-mode networks) and examined their dynamic contributions to the learning success prediction. Moreover, the robustness of the predictions systematically changes across networks depending on specific training phases and the learning components. We further demonstrate that a subset of network nodes in the inferior frontal, insular, and frontoparietal regions increasingly represent newly acquired language knowledge, while the multivariate connectivity between these representation regions is enhanced during learning for more successful learners. These findings allow us to understand why learners differ and are the first to attribute not only the degree of success but also patterns of language learning across components, to neural fingerprints summarized from multiple neural network dynamics.SIGNIFICANCE STATEMENT Individual differences in learning a language are widely observed not only within the same component of language but also across components. This study demonstrates that the dynamics of multiple brain networks across four imaging sessions of a 7 d artificial language training contribute to individual differences in learning-outcome profiles derived from four language components. With machine-learning predictive modeling, we identified four neural learning networks, including the Perisylvian, frontoparietal, salience, and default-mode networks, that contribute to predicting individual learning-outcome profiles and revealed language-component-general and component-specific prediction patterns across training sessions. These findings provide significant insights in understanding training-dependent neural dynamics underlying individual differences in learning success across language components.

Generalizable predictive modeling of semantic processing ability from functional brain connectivity.

Semantic processing (SP) is one of the critical abilities of humans for representing and manipulating conceptual and meaningful information. Neuroimaging studies of SP typically collapse data from many subjects, but its neural organization and behavioral performance vary between individuals. It is not yet understood whether and how the individual variabilities in neural network organizations contribute to the individual differences in SP behaviors. We aim to identify the neural signatures underlying SP variabilities by analyzing functional connectivity (FC) patterns based on a large-sample Human Connectome Project (HCP) dataset and rigorous predictive modeling. We used a two-stage predictive modeling approach to build an internally cross-validated model and to test the model's generalizability with unseen data from different HCP samples and other out-of-sample datasets. FC patterns within a putative semantic brain network were significantly predictive of individual SP scores summarized from five SP-related behavioral tests. This cross-validated model can be used to predict unseen HCP data. The model generalizability was enhanced in the language task compared with other tasks used during scanning and was better for females than males. The model constructed from the HCP dataset can be partially generalized to two independent cohorts that participated in different semantic tasks. FCs connecting to the Perisylvian language network show the most reliable contributions to predictive modeling and the out-of-sample generalization. These findings contribute to our understanding of the neural sources of individual differences in SP, which potentially lay the foundation for personalized education for healthy individuals and intervention for SP and language deficits patients.