Background
The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we ...performed a meta–genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD).
Methods
We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15–18 months), late-phase expressive (toddlerhood, 24–38 months), and late-phase receptive (toddlerhood, 24–38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism–based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models.
Results
Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08–0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = −0.74), highlighting developmental heterogeneity.
Conclusions
The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.
The ability for a host to recognize infection is critical for virus clearance and often begins with induction of inflammation. The PB1-F2 of pathogenic influenza A viruses (IAV) contributes to the ...pathophysiology of infection, although the mechanism for this is unclear. The NLRP3-inflammasome has been implicated in IAV pathogenesis, but whether IAV virulence proteins can be activators of the complex is unknown. We investigated whether PB1-F2-mediated activation of the NLRP3-inflammasome is a mechanism contributing to overt inflammatory responses to IAV infection. We show PB1-F2 induces secretion of pyrogenic cytokine IL-1β by activating the NLRP3-inflammasome, contributing to inflammation triggered by pathogenic IAV. Compared to infection with wild-type virus, mice infected with reverse engineered PB1-F2-deficient IAV resulted in decreased IL-1β secretion and cellular recruitment to the airways. Moreover, mice exposed to PB1-F2 peptide derived from pathogenic IAV had enhanced IL-1β secretion compared to mice exposed to peptide derived from seasonal IAV. Implicating the NLRP3-inflammasome complex specifically, we show PB1-F2 derived from pathogenic IAV induced IL-1β secretion was Caspase-1-dependent in human PBMCs and NLRP3-dependent in mice. Importantly, we demonstrate PB1-F2 is incorporated into the phagolysosomal compartment, and upon acidification, induces ASC speck formation. We also show that high molecular weight aggregated PB1-F2, rather than soluble PB1-F2, induces IL-1β secretion. Furthermore, NLRP3-deficient mice exposed to PB1-F2 peptide or infected with PB1-F2 expressing IAV were unable to efficiently induce the robust inflammatory response as observed in wild-type mice. In addition to viral pore forming toxins, ion channel proteins and RNA, we demonstrate inducers of NLRP3-inflammasome activation may include disordered viral proteins, as exemplified by PB1-F2, acting as host pathogen 'danger' signals. Elucidating immunostimulatory PB1-F2 mediation of NLRP3-inflammasome activation is a major step forward in our understanding of the aetiology of disease attributable to exuberant inflammatory responses to IAV infection.
Five studies investigated the cognitive and emotional processes by which self-compassionate people deal with unpleasant life events. In the various studies, participants reported on negative events ...in their daily lives, responded to hypothetical scenarios, reacted to interpersonal feedback, rated their or others' videotaped performances in an awkward situation, and reflected on negative personal experiences. Results from Study 1 showed that self-compassion predicted emotional and cognitive reactions to negative events in everyday life, and Study 2 found that self-compassion buffered people against negative self-feelings when imagining distressing social events. In Study 3, self-compassion moderated negative emotions after receiving ambivalent feedback, particularly for participants who were low in self-esteem. Study 4 found that low-self-compassionate people undervalued their videotaped performances relative to observers. Study 5 experimentally induced a self-compassionate perspective and found that self-compassion leads people to acknowledge their role in negative events without feeling overwhelmed with negative emotions. In general, these studies suggest that self-compassion attenuates people's reactions to negative events in ways that are distinct from and, in some cases, more beneficial than self-esteem.
Background and Purpose
Severe influenza A virus (IAV) infections are associated with damaging hyperinflammation that can be fatal. There is an urgent need to identify new therapeutic agents to treat ...severe and pathogenic IAV infections. Repurposing of drugs with an existing and studied pharmacokinetic and safety profile is a highly attractive potential strategy. We have previously demonstrated that the NLRP3 inflammasome plays time‐dependent roles during severe IAV infection with early protective responses and later dysregulation leading to excessive inflammation, contributing to disease severity.
Experimental Approach
We tested two existing drugs, probenecid and AZ11645373, to target P2X7 receptor signalling and dampen NLRP3 inflammasome responses during severe IAV infection. In vitro, the drugs were assessed for their ability to limit NLRP3 inflammasome‐dependent IL‐1β secretion in macrophage cultures. In vivo, their effects were assessed on hyperinflammation and disease during severe IAV infection in C57BL/6 mice.
Key Results
Treatment of macrophages with probenecid or AZ11645373 in vitro diminished NLRP3 inflammasome‐dependent IL‐1β secretion. Intranasal therapeutic treatment of mice displaying severe influenza disease with probenecid or AZ11645373 reduced pro‐inflammatory cytokine production, cellular infiltrates in the lung, and provided protection against disease. Importantly, these drugs could be administered at either early or late stage of disease and provide therapeutic efficacy.
Conclusions and Implications
Our study demonstrates that the anti‐inflammatory drugs probenecid and AZ11645373, which have documented pharmacokinetics and safety profiles in humans, are effective at dampening hyperinflammation and severe influenza disease providing potentially new therapeutic strategies for treating severe or pathogenic IAV infections.
Abstract
Excessive inflammation and tissue damage during severe influenza A virus (IAV) infection can lead to the development of fatal pulmonary disease. Pyroptosis is a lytic and pro-inflammatory ...form of cell death executed by the pore-forming protein gasdermin D (GSDMD). In this study, we investigated a potential role for GSDMD in promoting the development of severe IAV disease. IAV infection resulted in cleavage of GSDMD in vivo and in vitro in lung epithelial cells. Mice genetically deficient in GSDMD (
Gsdmd
−/−
) developed less severe IAV disease than wildtype mice and displayed improved survival outcomes. GSDMD deficiency significantly reduced neutrophil infiltration into the airways as well as the levels of pro-inflammatory cytokines TNF, IL-6, MCP-1, and IL-1α and neutrophil-attracting chemokines CXCL1 and CXCL2. In contrast, IL-1β and IL-18 responses were not largely impacted by GSDMD deficiency. In addition,
Gsdmd
−/−
mice displayed significantly improved influenza disease resistance with reduced viral burden and less severe pulmonary pathology, including decreased epithelial damage and cell death. These findings indicate a major role for GSDMD in promoting damaging inflammation and the development of severe IAV disease.
Social participation is known to enhance well-being. Caregiving responsibilities are more intense when caring for an older adult with than without dementia and may affect caregivers' ability for ...social participation. We estimate social participation restrictions among caregivers for older persons with versus without dementia, variation within racial/ethnic group, and the mediating effect of care hours.
We use the 2017 National Health and Aging Trends Study (NHATS) and National Study of Caregiving (NSOC) to study family caregivers for older adults. We estimate the prevalence of social participation (e.g., visiting family/friends, religious activities, group/club activities, going out) that were important to the caregiver but missed due to caregiving. We use logistic models to test for differences in restrictions by the older adult's dementia status overall and within race/ethnic group, adjusting for caregiver and care receiver characteristics.
One-third of family caregivers for older adults with dementia reported restrictions due to caregiving, double the prevalence among caregivers of an older adult without dementia (33.3% vs 16.0%; p < .001). This doubling gap persisted in adjusted models (odds ratio OR = 2.4; p < .01) but mainly for White, non-Hispanic caregivers (OR = 3.2; p < .001). Substantially greater caregiving hours for people with versus without dementia was found (104 vs 60 hr per month), which is responsible for about 21% of the total difference in restrictions (p < .05).
More time spent among caregivers of persons with versus without dementia may be an important factor undermining social participation, but hours only partially explain the gap. Future interventions should consider how to facilitate social participation among caregivers.
Self-collected specimens can expand access to SARS-CoV-2 testing. At a large inner-city hospital 1,082 participants self-collected saliva and anterior nasal swab (ANS) samples before healthcare ...workers collected nasopharyngeal swab (NPS) samples on the same day. To characterize patient preferences for self-collection, this investigation explored ability, comfort, and ease of ANS and saliva self-collection for SARS-CoV-2 testing along with associated patient characteristics, including medical history and symptoms of COVID-19. With nearly all participants successfully submitting a specimen, favorable ratings from most participants (at least >79% in ease and comfort), and equivocal preference between saliva and ANS, self-collection is a viable SARS-CoV-2 testing option.
During October 2021-June 2023, a total of 392 cases of acute hepatitis of unknown etiology in children in the United States were reported to Centers for Disease Control and Prevention as part of ...national surveillance. We describe demographic and clinical characteristics, including potential involvement of adenovirus in development of acute hepatitis, of 8 fatally ill children who met reporting criteria. The children had diverse courses of illness. Two children were immunocompromised when initially brought for care. Four children tested positive for adenovirus in multiple specimen types, including 2 for whom typing was completed. One adenovirus-positive child had no known underlying conditions, supporting a potential relationship between adenovirus and acute hepatitis in previously healthy children. Our findings emphasize the importance of continued investigation to determine the mechanism of liver injury and appropriate treatment. Testing for adenovirus in similar cases could elucidate the role of the virus.
In 2006, routine immunization of US infants against rotavirus was initiated. We assessed national, regional, and local trends in rotavirus testing and detection before and after vaccine introduction.
...We examined data for July 2000 through June 2008 from a national network of approximately 70 US laboratories to compare geographical and temporal aspects of rotavirus season timing and peak activity. To assess trends in rotavirus testing and detection, we restricted the analyses to 33 laboratories that reported for >or=26 weeks per season from 2000 to 2008.
Nationally, the onset and peak of the 2007-2008 rotavirus season were delayed 15 and 8 weeks, respectively, compared with prevaccine seasons from 2000-2006. Delays were observed in each region. The 2007-2008 rotavirus season lasted 14 weeks compared with a median of 26 weeks during the prevaccine era. Of 33 laboratories, 32 reported fewer positive results and a lower proportion of positive test results in 2007-2008 compared with the median in 2000-2006, with a 67% decline in the number and a 69% decline in the proportion of rotavirus-positive test results. The proportion of positive test results in 2007-2008 compared with the median in 2000-2006 declined >50% in 79% of the laboratories and >75% in 39% of the laboratories.
The 2007-2008 US rotavirus season seems substantially delayed, shorter, and diminished in magnitude compared with seasons before vaccine implementation. The extent of change seems greater than expected on the basis of estimated vaccine coverage, suggesting indirect benefits to unvaccinated individuals. Monitoring in future seasons is needed to confirm these trends.
Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging ...(dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta‐Analysis Military‐Relevant Brain Injury working group, we conducted a mega‐analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment‐related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.
Through collaborative mega‐analysis, we examined alterations in white matter asymmetry in deployment‐related traumatic brain injury in a sample of nearly 2600. We found greater asymmetry of the cingulum bundle that was not accounted for by other confounding variables. Cingulum microstructural organization was also associated with cognitive function.
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