Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans.

Emerging evidence indicates a central role for the microbiome in immunity. However, causal evidence in humans is sparse. Here, we administered broad-spectrum antibiotics to healthy adults prior and subsequent to seasonal influenza vaccination. Despite a 10,000-fold reduction in gut bacterial load and long-lasting diminution in bacterial diversity, antibody responses were not significantly affected. However, in a second trial of subjects with low pre-existing antibody titers, there was significant impairment in H1N1-specific neutralization and binding IgG1 and IgA responses. In addition, in both studies antibiotics treatment resulted in (1) enhanced inflammatory signatures (including AP-1/NR4A expression), observed previously in the elderly, and increased dendritic cell activation; (2) divergent metabolic trajectories, with a 1,000-fold reduction in serum secondary bile acids, which was highly correlated with AP-1/NR4A signaling and inflammasome activation. Multi-omics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.

LAMA: automated image analysis for the developmental phenotyping of mouse embryos.

Advanced 3D imaging modalities, such as micro-computed tomography (micro-CT), have been incorporated into the high-throughput embryo pipeline of the International Mouse Phenotyping Consortium (IMPC). This project generates large volumes of raw data that cannot be immediately exploited without significant resources of personnel and expertise. Thus, rapid automated annotation is crucial to ensure that 3D imaging data can be integrated with other multi-dimensional phenotyping data. We present an automated computational mouse embryo phenotyping pipeline that harnesses the large amount of wild-type control data available in the IMPC embryo pipeline in order to address issues of low mutant sample number as well as incomplete penetrance and variable expressivity. We also investigate the effect of developmental substage on automated phenotyping results. Designed primarily for developmental biologists, our software performs image pre-processing, registration, statistical analysis and segmentation of embryo images. We also present a novel anatomical E14.5 embryo atlas average and, using it with LAMA, show that we can uncover known and novel dysmorphology from two IMPC knockout lines.

Prevalence of iron deficiency and anemia in pediatric heart transplant recipients.

INTRODUCTION: The prevalence of iron deficiency and anemia in the setting of modern-day maintenance immunosuppression in pediatric heart transplant (HTx) recipients is unclear. The primary aim was to determine the prevalence of iron deficiency (serum ferritin < 30 ng/mL ± transferrin saturation < 20%) and anemia per World Health Organization diagnostic criteria and associated risk factors. METHODS: Single-center, cross-sectional analysis of 200 consecutive pediatric HTx recipients (<21 years old) from 2005 to 2021. Data were collected at 1-year post-HTx at the time of annual protocol biopsy. RESULTS: Median age at transplant was 3 years (IQR .5-12.2). The median ferritin level was 32 ng/mL with 46% having ferritin < 30 ng/mL. Median transferrin saturation (TSAT) was 22% with 47% having TSAT < 20%. Median hemoglobin was 11 g/dL with 54% having anemia. Multivariable analysis revealed lower absolute lymphocyte count, TSAT < 20%, and estimated glomerular filtration rate <75 mL/min/1.73 m2 were independently associated with anemia. Ferritin < 30 ng/mL in isolation was not associated with anemia. Ferritin < 30 ng/mL may aid in detecting absolute iron deficiency while TSAT < 20% may be useful in identifying patients with functional iron deficiency ± anemia in pediatric HTx recipients. CONCLUSION: Iron deficiency and anemia are highly prevalent in pediatric HTx recipients. Future studies are needed to assess the impact of iron deficiency, whether with or without anemia, on clinical outcomes in pediatric HTx recipients.

Evaluation of acoustic-thermal simulations of in vivo magnetic resonance guided focused ultrasound ablative therapy.

PURPOSE: To evaluate numerical simulations of focused ultrasound (FUS) with a rabbit model, comparing simulated heating characteristics with magnetic resonance temperature imaging (MRTI) data collected during in vivo treatment. METHODS: A rabbit model was treated with FUS sonications in the biceps femoris with 3D MRTI collected. Acoustic and thermal properties of the rabbit muscle were determined experimentally. Numerical models of the rabbits were created, and tissue-type-specific properties were assigned. FUS simulations were performed using both the hybrid angular spectrum (HAS) method and k-Wave. Simulated power deposition patterns were converted to temperature maps using a Pennes' bioheat equation-based thermal solver. Agreement of pressure between the simulation techniques and temperature between the simulation and experimental heating was evaluated. Contributions of scattering and absorption attenuation were considered. RESULTS: Simulated peak pressures derived using the HAS method exceeded the simulated peak pressures from k-Wave by 1.6 ± 2.7%. The location and FWHM of the peak pressure calculated from HAS and k-Wave showed good agreement. When muscle acoustic absorption value in the simulations was adjusted to approximately 54% of the measured attenuation, the average root-mean-squared error between simulated and experimental spatial-average temperature profiles was 0.046 ± 0.019 °C/W. Mean distance between simulated and experimental COTMs was 3.25 ± 1.37 mm. Transverse FWHMs of simulated sonications were smaller than in in vivo sonications. Longitudinal FWHMs were similar. CONCLUSIONS: Presented results demonstrate agreement between HAS and k-Wave simulations and that FUS simulations can accurately predict focal position and heating for in vivo applications in soft tissue.

Maternal Childhood Adversity and Infant Epigenetic Aging: Moderation by Restless Sleep During Pregnancy.

Maternal exposure to childhood adversity is associated with detrimental health outcomes throughout the lifespan and may have implications for offspring. Evidence links maternal adverse childhood experiences (ACEs) to detrimental birth outcomes, yet the impact on the infant's epigenome is unclear. Moreover, maternal sleep habits during pregnancy may influence this association. Here, we explore whether restless sleep during pregnancy moderates the association between exposure to maternal childhood adversity and infant epigenetic age acceleration in 332 mother-infant dyads (56% female; 39% Black; 25% Hispanic). During the 2nd trimester, mothers self-reported childhood adversity and past-week restless sleep; DNA methylation from umbilical vein endothelial cells was used to estimate five epigenetic clocks. Multivariable linear regression was used to test study hypotheses. Despite no evidence of main effects, there was evidence of an interaction between maternal ACEs and restless sleep in predicting infant epigenetic age acceleration using the EPIC Gestational Age clock. Only infants whose mothers reported exposure to both ACEs and restless sleep demonstrated accelerated epigenetic aging. Results provide preliminary evidence that maternal childhood adversity and sleep may influence the infant epigenome.

Parents' and Caregivers' Support for in-School COVID-19 Mitigation Strategies: A Socioecological Perspective.

Informed by the social ecological model, which asserts that health behaviors and beliefs are the result of multiple levels of influence, we examined factors related to parents' support for in-school COVID-19 mitigation strategies. Using data from a survey of 567 parents/caregivers of public elementary and middle school students in eight Maryland counties, we employed regression models to examine relationships between parent-, child-, family-, school-, and community-level factors and acceptability of mitigation strategies. Acceptance of COVID-19 mitigation strategies was positively correlated with child- and family-level factors, including child racial identity (parents of Black children were more accepting than those of White children, odds ratio [OR]: 2.5, 95% confidence interval [CI] = [1.5, 4.1]), parent receipt of the COVID-19 vaccine (OR: 2.4, 95% CI = [1.5, 3.7]), and parent Democrat or Independent political affiliation (compared with Republican affiliation, OR: 4.2, 95% CI = [2.6, 6.7]; OR: 2.2, 95%CI = [1.3, 3.8], respectively). Acceptance was also positively associated with parents' perceptions of their school's mitigation approach, including higher school mitigation score, indicating more intensive mitigation policies (OR: 1.1, 95% CI = [1.0, 1.1]), better school communication about COVID-19 (OR: 1.7, 95% CI = [1.4, 1.9]) and better school capacity to address COVID-19 (OR: 1.9, 95% CI = [1.5, 2.4]). Community-level factors were not associated with acceptance. Child- and parent-level factors identified suggest potential groups for messaging regarding mitigation strategies. School-level factors may play an important role in parents' acceptance of in-school mitigation strategies. Schools' capacity to address public health threats may offer an underappreciated and modifiable setting for disseminating and reinforcing public health guidance.

The Role of Primary Care in Advancing Civic Engagement and Health Equity: A Conceptual Framework.

Policy Points Health and civic engagement are reciprocally and longitudinally linked: Poor health is associated with less civic engagement. Well-established social drivers of health and health inequality such as inadequate access to health care, poverty, racism, housing instability, and food insecurity are also drivers of lower civic engagement. A robust primary care system can play a key role in advancing civic engagement (e.g., voting, volunteerism, community service, and political involvement) at the population level but has received little attention. Policy and practice solutions at the individual and structural levels should support and leverage potential synergies among health equity, civic engagement, and primary care. CONTEXT: Health and civic engagement are linked. Healthier people may be able to participate more fully in civic life, although those with poorer health may be motivated to address the roots of their health challenges using collective action. In turn, civically active people may experience better health, and societies with more equitable health and health care may experience healthier civic life. Importantly, a robust primary care system is linked to greater health equity. However, the role of primary care in advancing civic engagement has received little study. METHODS: We synthesize current literature on the links among health, civic engagement, and primary care. We propose a conceptual framework to advance research and policy on the role of primary care in supporting civic engagement as a means for individuals to actualize their health and civic futures. FINDINGS: Current literature supports relationships between health equity and civic engagement. However, this literature is primarily cross-sectional and confined to voting. Our integrative conceptual framework highlights the interconnectedness of primary care structures, health equity, and civic engagement and supports the crucial role of primary care in advancing both civic and health outcomes. Primary care is a potentially fruitful setting for cultivating community and individual health and power by supporting social connectedness, self-efficacy, and collective action. CONCLUSIONS: Health and civic engagement are mutually reinforcing. Commonalities between social determinants of health and civic engagement constitute an important convergence for policy, practice, and research. Responsibility for promoting both health and civic engagement is shared by providers, community organizations, educators, and policymakers, as well as democratic and health systems, yet these entities rarely work in concert. Future work can inform policy and practice to bolster primary care as a means for promoting health and civic engagement.

Corrigendum: High-throughput discovery of novel developmental phenotypes.

This corrects the article DOI: 10.1038/nature19356.

Self-control in first grade predicts success in the transition to adulthood.

Childhood self-control has been linked with better health, criminal justice, and economic outcomes in adulthood in predominately white cohorts outside of the United States. We investigated whether self-control in first grade predicted success in the transition to adulthood in a longitudinal cohort of first graders who participated in a universal intervention trial to prevent poor achievement and reduce aggression in Baltimore schools. We also explored whether the intervention moderated the relationship between self-control and young adult outcomes. Teachers rated self-control using the Teacher Observation of Classroom Adaptation-Revised. Study outcomes were on-time high school graduation, college participation, teen pregnancy, substance use disorder, criminal justice system involvement, and incarceration (ages 19-26). Latent profile analysis was used to identify classes of childhood self-control. A high self-control class (n = 279, 48.1%), inattentive class (n = 201, 35.3%), and inattentive/hyperactive class (n = 90, 16.6%) were identified. Children with better self-control were more likely to graduate on time and attend college; no significant class differences were found for teen pregnancy, substance use disorder, criminal justice system involvement, or incarceration. A classroom-based intervention reduced criminal justice system involvement and substance use disorder among children with high self-control. Early interventions to promote child self-control may have long-term individual and social benefits.

What children do while they wait: The role of self-control strategies in delaying gratification.

Self-control plays an essential role in children's emotional and behavioral adjustment. A central behavioral indicator of self-control is the ability to delay gratification. Few studies have focused on understanding the heterogeneity of self-control behaviors that underlie children's ability to delay gratification. Therefore, we examined the role of spontaneous self-control behaviors (fidgeting, vocalizations, and anticipation/attentional focus toward a reward) in relation to 5-year old children's delay ability using Mischel's delay task (N = 144; Mage = 5.4 years, SD = 0.29). Latent mixture modeling was used to derive three distinct classes of self-control behaviors observed during the delay task: (1) Passive (low fidgeting, low vocalizations, but moderate anticipation), (2) Active (moderate fidgeting, moderate vocalizations, but high anticipation), and (3) Disruptive (high fidgeting, high vocalizations, and high anticipation). Children in the Passive class were more likely to delay the full task time compared with children in the Active class (odds ratio = 1.50, 95 % confidence interval = 1.28-1.81). There were no other differences in delay ability by self-control class. Children whose level of fidgeting and vocalizations matched their level of anticipation (i.e., Passive and Disruptive regulators) were able to delay more successfully than children who were mostly driven by anticipation (Active regulators). Some variation in children's delay ability and use of self-control strategies was explained by sociodemographic differences, specifically maternal age. Findings suggest probing processes underlying children's self-control to identify potential targets for intervention.

Hyperprolactinemia-induced acute ischemic stroke.

Strokes are the fifth leading cause of death in the United States with almost 800,000 patients seeking emergency care each year-most of whom are seen for ischemic strokes. Acute ischemic strokes (AIS) can be caused by emboli in diseases such as atrial fibrillation as well as thrombus formation in the form of platelet deposition in patients with atherosclerotic disease. Platelet activation by immunomodulators including thromboxane A2 (TXA2), serotonin, and thrombin have been extensively delineated; however, the activation by hormones such as prolactin has only recently been revealed. We present a case of a 25-year-old male with a history of pituitary microadenoma and hyperprolactinemia who presented with an acute ischemic stroke in the setting of medication non-compliance. To our knowledge, this is the first known case of AIS in a patient with known hyperprolactinemia who presented with a stroke due to be medication non-compliance.

Financial stress as a mediator of the association between maternal childhood adversity and infant birth weight, gestational age, and NICU admission.

BACKGROUND: To examine whether financial stress during pregnancy mediates the association between maternal exposure to adverse childhood experiences (ACEs) and three birth outcomes (i.e., gestational age, birth weight, and admission to the neonatal intensive care unit [NICU]). METHODS: Data were obtained from a prospective cohort study of pregnant women and their infants in Florida and North Carolina. Mothers (n = 531; Mage at delivery = 29.8 years; 38% Black; 22% Hispanic) self-reported their exposure to childhood adversity and financial stress during pregnancy. Data on infant gestational age at birth, birth weight, and admission to the NICU were obtained from medical records within 7 days of delivery. Mediation analysis was used to test study hypotheses, adjusting for study cohort, maternal race, ethnicity, body mass index, and tobacco use during pregnancy. RESULTS: There was evidence of an indirect association between maternal exposure to childhood adversity and infant gestational age at birth (b = -0.03, 95% CI = -0.06 - -0.01) and infant birth weight (b = -8.85, 95% CI = -18.60 - -1.28) such that higher maternal ACE score was associated with earlier gestational age and lower infant birth weight through increases in financial distress during pregnancy. There was no evidence of an indirect association between maternal exposure to childhood adversity and infant NICU admission (b = 0.01, 95% CI = -0.02-0.08). CONCLUSIONS: Findings demonstrate one pathway linking maternal childhood adversity to a potentially preterm birth or shorter gestational age, in addition to low birth weight at delivery, and present an opportunity for targeted intervention to support expecting mothers who face financial stress.

Surveillance of the Initiation of, Participation in, and Completion of Cardiac Rehabilitation in Minnesota, 2017-2018.

INTRODUCTION: Cardiac rehabilitation (CR) is an evidence-based secondary prevention program designed to improve cardiovascular health after a cardiac event. The objective of our study was to identify gaps in CR use among publicly and privately insured people in Minnesota to assist in developing shared goals among public health, cardiac rehabilitation professionals, and program delivery sites to improve CR delivery. METHODS: We applied a published claims-based surveillance methodology to the Minnesota All Payer Claims Database to assess eligibility for, initiation of, participation in, and completion of CR by patients with qualifying events in 2017. We stratified results by sociodemographic and geographic factors and qualifying condition and used adjusted prevalence ratios to make statistical comparisons. RESULTS: Less than half (47.6%) of qualifying patients initiated CR within 1 year of their qualifying event; the rate was higher among men (vs women), adults aged 45 to 64 years (vs ≥65 y), and patients with commercial or Medicaid insurance coverage (vs Medicare). Among those who initiated CR, only 14.0% completed the full series of 36 sessions. Participation in at least 12 sessions and completion of 36 sessions was less likely among adults aged 18 to 64 (vs 65-74 y) and among patients covered by Medicaid (vs Medicare). Patterns of CR initiation, participation, and completion also varied geographically. CONCLUSION: This analysis expands on previous Medicare fee-for-service population CR surveillance and provides a first detailed look at the CR landscape in Minnesota, renewing attention to CR as a key secondary prevention strategy. Collaboration and sharing with partners has established the Minnesota Department of Health as a valuable partner in driving health system change to improve equitable provision of CR in Minnesota.

The Five Cs of Positive Youth Development: Configurations of Thriving in Four U.S. Adolescent Samples.

Positive youth development (PYD) models are widespread, but the empirical evidence for them is primarily nomothetic (i.e., investigations of universal patterns). Contemporary developmental theory suggests that concepts and processes within PYD models should also be explored with respect to specificity. This study demonstrates how the Five Cs Model, a predominant PYD model, can be advanced using group-differential methods. Secondary data from four studies of adolescents were used to test: (1) Whether there were subgroups who varied in their patterns of scores across the Five Cs, and (2) Whether subgroups also varied in Contribution behaviors. Unexpectedly, the four data sets used could not be combined, yielding an opportunity to discuss consistencies and inconsistencies in findings across the four data sets through contextual and sample differences. Findings demonstrate how understanding specificity in theorized concepts and processes in PYD models can complement studies of universal patterns, which are both necessary to advance PYD research and practice.

Using Epigenetic Clocks to Characterize Biological Aging in Studies of Children and Childhood Exposures: a Systematic Review.

Biological age, measured via epigenetic clocks, offers a unique and useful tool for prevention scientists to explore the short- and long-term implications of age deviations for health, development, and behavior. The use of epigenetic clocks in pediatric research is rapidly increasing, and there is a need to review the landscape of this work to understand the utility of these clocks for prevention scientists. We summarize the current state of the literature on the use of specific epigenetic clocks in childhood. Using systematic review methods, we identified studies published through February 2023 that used one of three epigenetic clocks as a measure of biological aging. These epigenetic clocks could either be used as a predictor of health outcomes or as a health outcome of interest. The database search identified 982 records, 908 of which were included in a title and abstract review. After full-text screening, 68 studies were eligible for inclusion. While findings were somewhat mixed, a majority of included studies found significant associations between the epigenetic clock used and the health outcome of interest or between an exposure and the epigenetic clock used. From these results, we propose the use of epigenetic clocks as a tool to understand how exposures impact biologic aging pathways and development in early life, as well as to monitor the effectiveness of preventive interventions that aim to reduce exposure and associated adverse health outcomes.

Measuring Positive Development among College Students in the United States: Investigating Cross-Sectional and Longitudinal Measurement Invariance across Different Racial Groups.

Measures that are applicable to assess the positive youth development (PYD) of racially diverse college students are needed. The present study tested if a revised version of the very short form of the PYD measure (PYD-VSF) was applicable to college students from five racial groups in the U. S. (White, Black, Latinx, Asian, and other) across three measurement occasions. Participants were 5,735 college students who completed the PYD-VSF at least once across the three waves of a longitudinal study. Confirmatory factor analyses (CFA) indicated that a first-order Five Cs structure, a higher-order structure, and a bifactor structure all provided good fit to the data. Multi-group CFA across racial groups found that the first-order structure fit the data better than the higher-order and the bifactor models, and it showed configural-, factor loading-, intercept-, and residual-invariance. Longitudinal CFA models of the first-order structure supported configural-, factor loading-, intercept-, and residual-invariance. The revised PYD-VSF measure has shown the potential to assess PYD among college students of diverse racial-ethnic backgrounds.

Longitudinal Relations among Identity Distinctiveness, Continuity, and Integration among Dutch Adolescents.

Identity distinctiveness, continuity, and coherence are all components of adolescents' identity development, but their longitudinal relations have rarely been examined. Data were analyzed on these three constructs collected over three years from 349 Dutch adolescents (Mage = 14.7, SDage = 0.7, 215 [61.6%] girls and 133 [38.1%] boys). A cross-lagged panel model of the three constructs showed that stability was relatively high for distinctiveness and continuity, whereas coherence was less stable. Distinctiveness and continuity were correlated positively within time, but cross-lagged associations were mostly not significant: Only distinctiveness and coherence negatively predicted each other across waves. Results suggest that distinctiveness, continuity, and coherence may be interrelated, but may not drive the development of each other.

Loss of O-GlcNAcase catalytic activity leads to defects in mouse embryogenesis.

O-GlcNAcylation is an essential post-translational modification that has been implicated in neurodevelopmental and neurodegenerative disorders. O-GlcNAcase (OGA), the sole enzyme catalyzing the removal of O-GlcNAc from proteins, has emerged as a potential drug target. OGA consists of an N-terminal OGA catalytic domain and a C-terminal pseudo histone acetyltransferase (HAT) domain with unknown function. To investigate phenotypes specific to loss of OGA catalytic activity and dissect the role of the HAT domain, we generated a constitutive knock-in mouse line, carrying a mutation of a catalytic aspartic acid to alanine. These mice showed perinatal lethality and abnormal embryonic growth with skewed Mendelian ratios after day E18.5. We observed tissue-specific changes in O-GlcNAc homeostasis regulation to compensate for loss of OGA activity. Using X-ray microcomputed tomography on late gestation embryos, we identified defects in the kidney, brain, liver, and stomach. Taken together, our data suggest that developmental defects during gestation may arise upon prolonged OGA inhibition specifically because of loss of OGA catalytic activity and independent of the function of the HAT domain.

CX3CR1 Is a Receptor for Human Respiratory Syncytial Virus in Cotton Rats.

Respiratory syncytial virus (RSV) has been reported to use CX3CR1 in vitro as a receptor on cultured primary human airway epithelial cultures. To evaluate CX3CR1 as the receptor for RSV in vivo, we used the cotton rat animal model because of its high permissiveness for RSV infection. Sequencing the cotton rat CX3CR1 gene revealed 91% amino acid similarity to human CX3CR1. Previous work found that RSV binds to CX3CR1 via its attachment glycoprotein (G protein) to infect primary human airway cultures. To determine whether CX3CR1-G protein interaction is necessary for RSV infection, recombinant RSVs containing mutations in the CX3CR1 binding site of the G protein were tested in cotton rats. In contrast to wild-type virus, viral mutants did not grow in the lungs of cotton rats. When RSV was incubated with an antibody blocking the CX3CR1 binding site of G protein and subsequently inoculated intranasally into cotton rats, no virus was found in the lungs 4 days postinfection. In contrast, growth of RSV was not affected after preincubation with heparan sulfate (the receptor for RSV on immortalized cell lines). A reduction in CX3CR1 expression in the cotton rat lung through the use of peptide-conjugated morpholino oligomers led to a 10-fold reduction in RSV titers at day 4 postinfection. In summary, these results indicate that CX3CR1 functions as a receptor for RSV in cotton rats and, in combination with data from human airway epithelial cell cultures, strongly suggest that CX3CR1 is a primary receptor for naturally acquired RSV infection. IMPORTANCE The knowledge about a virus receptor is useful to better understand the uptake of a virus into a cell and potentially develop antivirals directed against either the receptor molecule on the cell or the receptor-binding protein of the virus. Among a number of potential receptor proteins, human CX3CR1 has been demonstrated to act as a receptor for respiratory syncytial virus (RSV) on human epithelial cells in tissue culture. Here, we report that the cotton rat CX3CR1, which is similar to the human molecule, acts as a receptor in vivo. This study strengthens the argument that CX3CR1 is a receptor molecule for RSV.

Defining the Healthy Infant Metabolome: Liquid Chromatography Tandem-Mass Spectrometry Analysis of Dried Blood Spot Extracts from the Prospective Research on Early Determinants of Illness and Children's Health Trajectories Birth Cohort Study.

Newborn screening using dried plasma spots offers preanalytical advantages over conventional cards for plasma-associated targets of interest. Herein we present dried plasma spot-based methods for measuring metabolites using a 250+ compound liquid chromatography tandem mass spectrometry library. Quality assurance reduced this library to 134, and from these, 30 compounds determined the normal newborn reference ranges.