Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Back from the sideline, but back to baseline? A pediatric case study examining neuropsychological functioning after sustaining multiple sport-related concussions.

Most individuals recover quickly from a concussion; however, youth who sustain multiple concussions may be at risk for long-term cognitive impairments. This case study examines the neuropsychological performance of a 13-year-old malewith five head injuries. After his first concussion during study participation (fourth injury overall), several improvements were observed, likely due to practice effects, yet after sustaining another concussion <2 years later,declines were observed in visuoconstruction, verbal memory, and intellectual functioning. Across serial re-evaluation, his vocabulary knowledge declined, and fewer improvements were observed than anticipated when accounting for serial practice effects, highlighting the possible cumulative impact of multiple concussions.

Sex differences in symptom presentation and functional outcomes: a pilot study in a matched sample of veterans with mild TBI.

Primary Objective: Research focused on mild traumatic brain injury in active military and veteran populations details the psychological, neurological and functional outcomes of mTBI, in a primarily male (~95%) cohort. This may misrepresent female symptoms and outcomes. Here we assess for genuine sex differences in symptom presentation and functional outcomes.Research Design: We used matched pairs to preclude potential sex bias in outcome data.Methods and Procedures: We matched 49 female/male pairs on; 1) mechanism of injury, 2) time from injury to assessment and 3) age at assessment. Statistics were t-tests, chi-square, correlations and post hoc linear regression.Main outcomes and results: Outcome assessment revealed four significant (p < .05) sex differences; Living situation, Marital status, Vocation and Branch of service. Only the Neurobehavioral Symptom Inventory (NSI) composite cognitive domain factor was significantly different between females (mean: 10.26) and males (mean: 7.58). Linear regression confirmed a significant effect of sex for the cognitive composite (p = .002).Conclusion: We conclude that sex has a moderate effect on mTBI post-concussive symptom presentation. The significant sex difference in the NSI cognitive domain characterizes sex-related symptomology profiles providers can focus on for better rehabilitation management. Replication in the larger cohort would improve generalizability.Abbreviation: TBI: Traumatic Brain Injuries; mTBI: mild Traumatic Brain Injuries; OIF: Operation Iraqi Freedom; OEF: Operation Enduring Freedom; VA: Veterans Affairs Health Care System; PSC: Polytrauma System of Care; PRC: Polytrauma Rehabilitation Center; PTRP: Polytrauma Transitional Rehabilitation Program; PNS: Polytrauma Network Site; PTSD: Post Traumatic Stress Disorder; DoD: Department of Defense; NSI: Neurobehavioral Symptom Inventory; LOC: loss of consciousness; AOC: alteration of consciousness; PTA: posttraumatic amnesia; CPRS: computerized patient record system; CTBIE: Comprehensive TBI Evaluation; OCD: obsessive compulsive disorder; ETOH: alcohol abuse.

H3K27 Methylation Dynamics during CD4 T Cell Activation: Regulation of JAK/STAT and IL12RB2 Expression by JMJD3.

The changes to the epigenetic landscape in response to Ag during CD4 T cell activation have not been well characterized. Although CD4 T cell subsets have been mapped globally for numerous epigenetic marks, little has been done to study their dynamics early after activation. We have studied changes to promoter H3K27me3 during activation of human naive and memory CD4 T cells. Our results show that these changes occur relatively early (1 d) after activation of naive and memory cells and that demethylation is the predominant change to H3K27me3 at this time point, reinforcing high expression of target genes. Additionally, inhibition of the H3K27 demethylase JMJD3 in naive CD4 T cells demonstrates how critically important molecules required for T cell differentiation, such as JAK2 and IL12RB2, are regulated by H3K27me3. Our results show that H3K27me3 is a dynamic and important epigenetic modification during CD4 T cell activation and that JMJD3-driven H3K27 demethylation is critical for CD4 T cell function.

Illumina mate-paired DNA sequencing-library preparation using Cre-Lox recombination.

Standard Illumina mate-paired libraries are constructed from 3- to 5-kb DNA fragments by a blunt-end circularization. Sequencing reads that pass through the junction of the two joined ends of a 3-5-kb DNA fragment are not easy to identify and pose problems during mapping and de novo assembly. Longer read lengths increase the possibility that a read will cross the junction. To solve this problem, we developed a mate-paired protocol for use with Illumina sequencing technology that uses Cre-Lox recombination instead of blunt end circularization. In this method, a LoxP sequence is incorporated at the junction site. This sequence allows screening reads for junctions without using a reference genome. Junction reads can be trimmed or split at the junction. Moreover, the location of the LoxP sequence in the reads distinguishes mate-paired reads from spurious paired-end reads. We tested this new method by preparing and sequencing a mate-paired library with an insert size of 3 kb from Saccharomyces cerevisiae. We present an analysis of the library quality statistics and a new bio-informatics tool called DeLoxer that can be used to analyze an IlluminaCre-Lox mate-paired data set. We also demonstrate how the resulting data significantly improves a de novo assembly of the S. cerevisiae genome.

Disentangling effects of remote mild traumatic brain injury characteristics and posttraumatic stress on processing speed and executive function in veterans.

Mild traumatic brain injury (mTBI) and posttraumatic stress are prevalent in military service members and share objective and subjective cognitive symptoms, complicating recovery. We investigated the effects of remote mTBI characteristics and current posttraumatic stress symptoms on neuropsychological performance in 152 veterans with a history of remote mTBI and current cognitive concerns. Participants completed clinical neuropsychological evaluations within a Veterans Affairs Level-II TBI/Polytrauma outpatient clinic (i.e. tertiary trauma care center for US military veterans outside of a research or teaching hospital setting). Archival data analysis of mTBI injury characteristics, clinical diagnoses, scores on the Posttraumatic Stress Disorder Checklist-Military Version (PCL-M) and performance on tests of processing speed, attention and executive function was conducted. Hierarchical linear regression demonstrated that elevated PCL-M scores were associated with slower performance on trail making test (TMT) Parts A and B (p < .016). PCL-M symptoms moderated the effect of alteration of consciousness (AOC) on TMT performance, with endorsement of AOC associated with better performance, but only when PCL-M scores were high (p < .005). Follow-up mediation analyses demonstrated that PCL-M score fully mediated the relationship between AOC and TMT-A performance and partially mediated the relationship between AOC and TMT-B performance. Post-hoc analyses meant to separate the impact of processing speed on TMT-B were all non-significant. Remote mTBI characteristics, specifically AOC, were not associated with decrements in cognitive performance. Posttraumatic symptoms were associated with worse processing speed, suggesting that psychological distress and psychopathology are contributing factors in understanding and treating persistent cognitive distress following remote mTBI.

Characterizing cell type specific transcriptional differences between the living and postmortem human brain.

Single-nucleus RNA sequencing (snRNA-seq) is often used to define gene expression patterns characteristic of brain cell types as well as to identify cell type specific gene expression signatures of neurological and mental illnesses in postmortem human brains. As methods to obtain brain tissue from living individuals emerge, it is essential to characterize gene expression differences associated with tissue originating from either living or postmortem subjects using snRNA-seq, and to assess whether and how such differences may impact snRNA-seq studies of brain tissue. To address this, human prefrontal cortex single nuclei gene expression was generated and compared between 31 samples from living individuals and 21 postmortem samples. The same cell types were consistently identified in living and postmortem nuclei, though for each cell type, a large proportion of genes were differentially expressed between samples from postmortem and living individuals. Notably, estimation of cell type proportions by cell type deconvolution of pseudo-bulk data was found to be more accurate in samples from living individuals. To allow for future integration of living and postmortem brain gene expression, a model was developed that quantifies from gene expression data the probability a human brain tissue sample was obtained postmortem. These probabilities are established as a means to statistically account for the gene expression differences between samples from living and postmortem individuals. Together, the results presented here provide a deep characterization of both differences between snRNA-seq derived from samples from living and postmortem individuals, as well as qualify and account for their effect on common analyses performed on this type of data.

Persistent complement dysregulation with signs of thromboinflammation in active Long Covid.

Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.

Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.

Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

Multiomic foundations of human prefrontal cortex tissue function.

The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations - termed the "transcriptional program associated with neurotransmission" (TPAWN) - were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.

Identification of an NF-κB p50/p65-responsive site in the human MIR155HG promoter.

BACKGROUND: MicroRNA-155 (miR-155) is the diced product of the MIR155HG gene. miR-155 regulates the expression of many immune-specific transcripts, is overexpressed in many human lymphomas, and has oncogenic activity in mouse transgenic models. MIR155HG has been proposed to be a target gene for transcription factor NF-κB largely due to the positive correlation between high nuclear NF-κB activity and increased miR-155 expression following treatment with NF-κB inducers or in subsets of hematopoietic cancers. Nevertheless, direct regulation of the human MIR155HG promoter by NF-κB has not been convincingly demonstrated previously. RESULTS: This report shows that induction of NF-κB activity rapidly leads to increased levels of both primary MIR155HG mRNA and mature miR-155 transcripts. We have mapped an NF-κB-responsive element to a position approximately 178 nt upstream of the MIR155HG transcription start site. The -178 site is specifically bound by the NF-κB p50/p65 heterodimer and is required for p65-induced reporter gene activation. Moreover, the levels of miR-155 in nine human B-lymphoma cell lines generally correlate with increased nuclear NF-κB proteins. CONCLUSION: Overall, the identification of an NF-κB-responsive site in the MIR155HG proximal promoter suggests that MIR155HG is a direct NF-κB target gene in vivo. Understanding NF-κB-mediated regulation of miR-155 could lead to improved immune cell-related diagnostic tools and targeted therapies.

The modest impact of the COVID-19 pandemic on training expectations at internship programs offering specialization in neuropsychology.

Objective: Given the decreased clinical training opportunities during the COVID-19 pandemic, this study aimed to provide insights into how training directors and supervising neuropsychologists from internships offering neuropsychology training adjusted expectations of competitive applicants. Method: Respondents (n = 50) from internships offering at least an "exposure" in neuropsychology completed questions about how training expectations of competitive applicants have changed because of the COVID-19 pandemic. Results: Most respondents reported decreased expectations for clinical hours and research productivity and increased expectations for telehealth experience and involvement in working with culturally diverse populations. Additionally, more than half of respondents from programs at university-affiliated and Veteran Affairs medical centers indicated reduced expectations for average number of integrated reports. Furthermore, compared to respondents at Veteran Affairs medical centers, respondents at university-affiliated medical centers stated decreased expectations for average number of paper presentations. Conclusions: The COVID-19 pandemic has motivated subtle changes in expectations of competitive neuropsychology-oriented internship applicants, specific to clinical experience, research productivity, and prioritization of certain application materials. Qualitative responses suggest that many respondents endeavored to improve applicant screening rather than lower expectations for applicants. As a result, consistent with previous recommendations, the importance of fit between trainee and training program should continue to be emphasized by prospective applicants. These findings have important implications for trainees for the next several years, as graduate students at all stages of training ultimately progress to the internship application stage.

Developmental Trajectories of Internalizing and Externalizing Symptoms in Youth and Associated Gender Differences: A Directed Network Perspective.

Psychopathology in youth is highly prevalent and associated with psychopathology in adulthood. However, the developmental trajectories of psychopathology symptoms, including potential gender differences, are markedly underspecified. The present study employed a directed network approach to investigate longitudinal relationships and gender differences among eight transdiagnostic symptom domains across three years, in a homogenous age sample of youth participants (n = 6,414; mean baseline age = 10.0 years; 78.6% White; Adolescent Brain Cognitive Development study). Anxious/depressed problems and aggressive behaviors were central symptoms and most predictive of increases in other symptom clusters at later timepoints. Rule-breaking behaviors, aggressive behaviors, and withdrawn/depressed problems emerged as bridge symptoms between externalizing and internalizing problems. Results supported cascade models in which externalizing problems predicted future internalizing problems, but internalizing problems also significantly predicted future externalizing problems, which is contrary to cascade models. Network structure, symptom centrality, and patterns of bridge symptoms differed between female and male participants, suggesting gender differences in the developmental trajectories of youth psychopathology. Results provide new insights into symptom trajectories and associated gender differences that may provide promising pathways for understanding disorder (dis)continuity and co-occurrence. The central and bridge symptoms identified here may have important implications for screening and early intervention for youth psychopathology.

Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae.

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.

A study of gene expression in the living human brain.

A goal of medical research is to determine the molecular basis of human brain health and illness. One way to achieve this goal is through observational studies of gene expression in human brain tissue. Due to the unavailability of brain tissue from living people, most such studies are performed using tissue from postmortem brain donors. An assumption underlying this practice is that gene expression in the postmortem human brain is an accurate representation of gene expression in the living human brain. Here, this assumption - which, until now, had not been adequately tested - is tested by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples. Expression levels differed significantly for nearly 80% of genes, and a systematic examination of alternative explanations for this observation determined that these differences are not a consequence of cell type composition, RNA quality, postmortem interval, age, medication, morbidity, symptom severity, tissue pathology, sample handling, batch effects, or computational methods utilized. Analyses integrating the data generated for this study with data from earlier landmark studies that used tissue from postmortem brain donors showed that postmortem brain gene expression signatures of neurological and mental illnesses, as well as of normal traits such as aging, may not be accurate representations of these gene expression signatures in the living brain. By using tissue from large cohorts living people, future observational studies of human brain biology have the potential to (1) determine the medical research questions that can be addressed using postmortem tissue as a proxy for living tissue and (2) expand the scope of medical research to include questions about the molecular basis of human brain health and illness that can only be addressed in living people (e.g., "What happens at the molecular level in the brain as a person experiences an emotion?").

NF-kappaB down-regulates expression of the B-lymphoma marker CD10 through a miR-155/PU.1 pathway.

Cell-surface protein CD10 is a prognostic marker for diffuse large B-cell lymphoma (DLBCL), where high expression of CD10 is found in the germinal center B-cell (GCB) subtype and CD10 expression is low or absent in the activated B-cell (ABC) subtype. As compared with the GCB subtype, patients with ABC DLBCL have a poorer prognosis after standard treatment, and ABC tumor cells have higher NF-κB activity. Herein, we show that increased expression of the NF-κB target micro-RNA miR-155 is correlated with reduced expression of transcription factor PU.1 and CD10 in several B-lymphoma cell lines. Moreover, electromobility shift assays and luciferase reporter assays indicate that PU.1 can directly activate expression from the CD10 promoter. Expression of a DLBCL-derived mutant of the adaptor CARD11 (a constitutive activator of NF-κB) in the GCB-like human BJAB cell line or v-Rel in the chicken DT40 B-lymphoma cell line causes reduced expression of PU.1. The CARD11 mutant also causes a decrease in CD10 levels in BJAB cells. Similarly, overexpression of miR-155, which is known to down-regulate PU.1, leads to reduced expression of CD10 in BJAB cells. Finally, we show that CD10 expression is reduced in BJAB cells after treatment with the NF-κB inducer lipopolysaccharide (LPS). Additionally, miR-155 is induced by LPS treatment or expression of the CARD11 mutant in BJAB cells. These results point to an NF-κB-dependent mechanism for down-regulation of CD10 in B-cell lymphoma: namely, that increased NF-κB activity leads to increased miR-155, which results in decreased PU.1, and consequently reduced CD10 mRNA and protein.

A Survey of Doctoral Internships Offering Clinical Neuropsychology Training: Updated Expectations for Competitive Applicants.

OBJECTIVE: The specialty of clinical neuropsychology has experienced significant professional growth and increasing standardization of educational and training guidelines over the past 20 years. Previous literature demonstrated the importance of routine distribution of selection criteria used by training directors and supervising neuropsychologists for competitive applicants aiming to specialize in neuropsychology during internship. This study examined supervisors' updated expectations for competitive applicants from a more diverse sample of doctoral internship programs offering neuropsychological training. These data also provide cross-sectional and longitudinal comparisons to help trainees tailor their graduate training experiences. METHOD: The sample included training directors and/or supervising neuropsychologists from 80 internship programs (73.4% of submitted surveys). Spearman correlations, analyses of variance, and chi-square tests of independence were conducted for cross-sectional and longitudinal comparisons. RESULTS: Clinical experience in assessment and the personal interview were consistently the two most prioritized criteria across all groups, whereas prioritization of the additional criteria was variable based on the program's characteristics. Internship programs generally preferred practica experience at university-affiliated medical centers, Veterans Affairs medical centers, and private/community-based hospitals. University-affiliated medical centers and internships offering ≥50% neuropsychology training showed similar preferences for applicants with a depth and breadth of graduate school experience in neuropsychology. Longitudinally, the applicant expectations for programs offering ≥50% neuropsychology training remained largely unchanged between 2000 and 2020. CONCLUSIONS: This study updated expectations for competitive applicants from a diverse sample of neuropsychology training programs, underscored the importance of fit between trainee and program, and demonstrated consistency over time for trainees seeking neuropsychology training during internship.

Associations of Family Distress, Family Income, and Acculturation on Pediatric Cognitive Performance Using the NIH Toolbox: Implications for Clinical and Research Settings.

OBJECTIVE: There is a growing recognition that the use of conventional norms (e.g., age, sex, years of education, race) as proxies to capture a broad range of sociocultural variability on cognitive performance is suboptimal, limiting sample representativeness. The present study evaluated the incremental utility of family income, family conflict, and acculturation beyond the established associations of age, gender,maternal years of education, and race on cognitive performance. METHOD: Hierarchical linear regressions evaluated the incremental utility of sociocultural factors on National Institutes of Health Toolbox in a nationally representative sample of pre-adolescent children (n = 11,878; Mage = 10.0 years; Adolescent Brain Cognitive Development Study). A regression-based norming procedure was implemented for significant models. Paired sample t-tests were used to compare original and newly created demographically corrected T-scores. RESULTS: Nearly all regression models predicted performance on the NIH-TB subtests and composite scores (p < .005). Greater family income and lower family conflict predicted better performance, although the effect sizes were small by traditional standards. Acculturation scores did not explain additional variance in cognitive performance. Lastly, there were no significant differences between the original and newly created demographically corrected T-scores (Mdiff < 0.50). CONCLUSIONS: The present study highlights that, although family income, family conflict, and acculturation have been shown to routinely influence cognitive performance in preadolescent children, the NIH-TB appears to be highly robust to individual differences in sociocultural factors in children between ages 9 and 10. Contextual and temporal implications of the present results are discussed.

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery.

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoMΦ). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.