Rare genetic variants explain missing heritability in smoking.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Maternal immune response and placental antibody transfer after COVID-19 vaccination across trimester and platforms.

The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. These results provide novel insight into the impact of platform and trimester of vaccination on maternal humoral immune response and transplacental antibody transfer.

Pediatric biorepository participation during the COVID-19 pandemic: predictors of enrollment and biospecimen donation.

BACKGROUND: Patient-level predictors of enrollment in pediatric biorepositories are poorly described. Especially in pandemic settings, understanding who is likely to enroll in a biorepository is critical to interpreting analyses conducted on biospecimens. We describe predictors of pediatric COVID-19 biorepository enrollment and biospecimen donation to identify gaps in COVID-19 research on pediatric biospecimens. METHODS: We compared data from enrollees and non-enrollees aged 0-25 years with suspected or confirmed COVID-19 infection who were approached for enrollment in the Massachusetts General Hospital pediatric COVID-19 biorepository between April 12, 2020, and May 28, 2020, from community or academic outpatient or inpatient settings. Demographic and clinical data at presentation to care were from automatic and manual chart extractions. Predictors of enrollment and biospecimen donation were assessed with Poisson regression models. RESULTS: Among 457 individuals approached, 214 (47%) enrolled in the biorepository. A COVID-19 epidemiologic risk factor was recorded for 53%, and 15% lived in a US Centers for Disease Control and Prevention-defined COVID-19 hotspot. Individuals living in a COVID-19 hotspot (relative risk (RR) 2.4 [95% confidence interval (CI): 1.8-3.2]), with symptoms at presentation (RR 1.8 [95% CI: 1.2-2.7]), or admitted to hospital (RR 1.8 [95% CI: 1.2-2.8]) were more likely to enroll. Seventy-nine percent of enrollees donated any biospecimen, including 97 nasopharyngeal swabs, 119 oropharyngeal swabs, and 105 blood, 16 urine, and 16 stool specimens, respectively. Age, sex, race, ethnicity, and neighborhood-level socioeconomic status based on zip code did not predict enrollment or biospecimen donation. CONCLUSIONS: While fewer than half of individuals approached consented to participate in the pediatric biorepository, enrollment appeared to be representative of children affected by the pandemic. Living in a COVID-19 hotspot, symptoms at presentation to care and hospital admission predicted biorepository enrollment. Once enrolled, most individuals donated a biospecimen.

Trauma-Informed Care for Hospitalized Adolescents.

Purpose of Review: Exposure to trauma accelerates during the adolescence, and due to increased behavioral and psychiatric vulnerability during this developmental period, traumatic events during this time are more likely to cause a lasting impact. In this article, we use three case studies of hospitalized adolescents to illustrate the application of trauma-informed principles of care with this unique population. Recent Findings: Adolescents today are caught in the crosshairs of two syndemics-racism and other structural inequities and the COVID-19 pandemic. Increased hospitalizations and mental health diagnoses during the past two years signal toxic levels of stress affecting this group. Trauma-informed care promotes health, healing, and equity. Summary: This concept of the "trauma-informed approach" is still novel; through examples and practice, providers can learn to universally apply the trauma-informed care framework to every patient encounter to address the harmful effects of trauma and promote recovery and resilience.

Leveraging Podcasts to Introduce Medical Students to the Broader Community of Health Care Professionals.

INTRODUCTION: Safe, patient-centered, and cost-effective care requires effective collaboration within interprofessional teams. Education programs for health care professionals are often siloed, providing students with limited interprofessional education (IPE) opportunities to learn from, with, and about other professions. Podcasts offer a novel approach to facilitate IPE, allowing for asynchronous conversations with interprofessional colleagues. METHODS: We developed four podcasts with various health care professionals for 135 preclinical medical students preparing to transition into clinical rotations. The podcasts were coupled with an hour-long interactive session with the podcast interviewees conducted via videoconference. The curriculum explored the distinct education paths, roles, and responsibilities of various health care disciplines. Strategies for communicating effectively with and learning from interprofessional team members were emphasized. RESULTS: There were 197 unique downloads of the podcasts, and 95 students attended the interactive session. Most students reported that the podcasts and follow-up live session enhanced their learning (100% and 98% of students who completed the postcurriculum survey, respectively). Responses to the postcurriculum survey revealed students learned strategies for engaging in productive interprofessional conversations, the importance of leveraging the distinct roles and responsibilities of diverse health professionals, the value of learning from other health professionals, and the use of respectful language. DISCUSSION: This IPE curriculum built around podcasts enhances medical student learning and represents an innovative approach to improving access to IPE in a virtual learning environment. This modality can be adapted to meet the needs of a wide spectrum of learners and can be coupled with in-person learning.

Pediatric Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Clinical Presentation, Infectivity, and Immune Responses.

OBJECTIVES: As schools plan for re-opening, understanding the potential role children play in the coronavirus infectious disease 2019 (COVID-19) pandemic and the factors that drive severe illness in children is critical. STUDY DESIGN: Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital were offered enrollment in the Massachusetts General Hospital Pediatric COVID-19 Biorepository. Enrolled children provided nasopharyngeal, oropharyngeal, and/or blood specimens. SARS-CoV-2 viral load, ACE2 RNA levels, and serology for SARS-CoV-2 were quantified. RESULTS: A total of 192 children (mean age, 10.2 ± 7.0 years) were enrolled. Forty-nine children (26%) were diagnosed with acute SARS-CoV-2 infection; an additional 18 children (9%) met the criteria for MIS-C. Only 25 children (51%) with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were nonspecific. Nasopharyngeal viral load was highest in children in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002). Age did not impact viral load, but younger children had lower angiotensin-converting enzyme 2 expression (P = .004). Immunoglobulin M (IgM) and Immunoglobulin G (IgG) to the receptor binding domain of the SARS-CoV-2 spike protein were increased in severe MIS-C (P < .001), with dysregulated humoral responses observed. CONCLUSIONS: This study reveals that children may be a potential source of contagion in the SARS-CoV-2 pandemic despite having milder disease or a lack of symptoms; immune dysregulation is implicated in severe postinfectious MIS-C.

Insight into the pediatric and adult dichotomy of COVID-19: Age-related differences in the immune response to SARS-CoV-2 infection.

The difference in morbidity and mortality between adult and pediatric coronavirus disease 2019 infections is dramatic. Understanding pediatric-specific acute and delayed immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for the development of vaccination strategies, immune-targeted therapies, and treatment and prevention of multisystem inflammatory syndrome in children. The goal of this review is to highlight research developments in the understanding of the immune responses to SARS-CoV-2 infections, with a specific focus on age-related immune responses.

Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene.

BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.

Identification of Gene Variants Associated with Melanocyte Stem Cell Differentiation in Mice Predisposed for Hair Graying.

Age-related hair graying is caused by malfunction in the regenerative potential of the adult pigmentation system. The retention of hair color over the life of an organism is dependent on the ability of the melanocyte stem cells and their progeny to produce pigment each time a new hair grows. Age-related hair graying is variable in association with genetic background suggesting that quantitative trait loci influencing this trait can be identified. Identification of these quantitative trait loci may lead to the discovery of novel and interesting genes involved in stem cell biology and/or melanogenesis. With this in mind we developed previously a sensitized, mouse modifier screen and discovered that the DBA/1J background is particularly resistant to melanocyte stem cell differentiation in comparison to the C57BL/6J background. Melanocyte stem cell differentiation generally precedes hair graying and is observed in melanocyte stem cells with age. Using quantitative trait loci analysis, we have now identified three quantitative trait loci on mouse chromosomes 7, 13, and X that are associated with DBA/1J-mediated variability in melanocyte stem cell differentiation. Taking advantage of publicly-available mouse sequence and variant data, in silico protein prediction programs, and whole genome gene expression results we describe a short list of potential candidate genes that we anticipate to be involved in melanocyte stem cell biology in mice.