Barriers to enrollment in a pediatric critical care biorepository.

BACKGROUND: Individuals of minority race/ethnicity have lower rates of participation in genomic research. This study evaluated sociodemographic characteristics associated with decisions to enroll in a pediatric critical care biorepository. METHODS: Parents of children admitted to the PICU between November 2014 and May 2017 were offered to enroll their child in a biorepository using a single-page opt-in consent. Missed enrollment was assessed by failure to complete the form or declining consent on the form. We conducted a retrospective chart review for sociodemographic and clinical information. Bivariate and multivariable regression analyses were performed. RESULTS: In 4055 encounters, representing 2910 patients with complete data, 1480 (50%) completed the consent form and 1223 (83%) enrolled. We found higher odds of incomplete consent for non-English-speaking parents (OR = 2.1, p < 0.0001) and parents of children of all races except non-Hispanic white (OR = 1.27-1.99, p < 0.0001). We found higher odds of declined consent in patients with Medicaid (OR = 1.67, p = 0.003) and parents of children of all races except non-Hispanic white (OR = 1.32-2.9, p < 0.0001). CONCLUSION: Inability to enroll patients in a critical care biorepository may be associated with several sociodemographic factors at various points in recruitment/enrollment. IMPACT: Individuals of minority race/ethnicity are less likely to enroll in genomic research and in critical care research. This study evaluated sociodemographic characteristics associated with decisions to enroll a child in a pediatric critical care biorepository. Sociodemographic factors including race/ethnicity, primary language, and insurance status and patient clinical characteristics are associated with differential enrollment into a pediatric critical care biorepository. More research is needed to understand how study team-participant interactions may play a role in differential enrollment. Barriers to enrollment occur both at the time of approaching and consenting for enrollment.

Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

Calcium-permeable AMPA receptors and silent synapses in cocaine-conditioned place preference.

Exposure to cocaine generates silent synapses in the nucleus accumbens (NAc), whose eventual unsilencing/maturation by recruitment of calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) after drug withdrawal results in profound remodeling of NAc neuro-circuits. Silent synapse-based NAc remodeling was shown to be critical for several drug-induced behaviors, but its role in acquisition and retention of the association between drug rewarding effects and drug-associated contexts has remained unclear. Here, we find that the postsynaptic proteins PSD-93, PSD-95, and SAP102 differentially regulate excitatory synapse properties in the NAc. Mice deficient for either of these scaffold proteins exhibit distinct maturation patterns of silent synapses and thus provided instructive animal models to examine the role of NAc silent synapse maturation in cocaine-conditioned place preference (CPP). Wild-type and knockout mice alike all acquired cocaine-CPP and exhibited increased levels of silent synapses after drug-context conditioning. However, the mice differed in CPP retention and CP-AMPAR incorporation. Collectively, our results indicate that CP-AMPAR-mediated maturation of silent synapses in the NAc is a signature of drug-context association, but this maturation is not required for establishing or retaining cocaine-CPP.

Probabilistic Finite Element Analysis of Human Rib Biomechanics: A Framework for Improved Generalizability.

In dynamic impact events, thoracic injuries often involve rib fractures, which are closely related to injury severity. Previous studies have investigated the behavior of isolated ribs under impact loading conditions, but often neglected the variability in anatomical shape and tissue material properties. In this study, we used probabilistic finite element analysis and statistical shape modeling to investigate the effect of population-wide variability in rib cortical bone tissue mechanical properties and rib shape on the biomechanical response of the rib to impact loading. Using the probabilistic finite element analysis results, a response surface model was generated to rapidly investigate the biomechanical response of an isolated rib under dynamic anterior-posterior load given the variability in rib morphometry and tissue material properties. The response surface was used to generate pre-fracture force-displacement computational corridors for the overall population and a population sub-group of older mid-sized males. When compared to the experimental data, the computational mean response had a RMSE of 4.28N (peak force 94N) and 6.11N (peak force 116N) for the overall population and sub-group respectively, whereas the normalized area metric when comparing the experimental and computational corridors ranged from 3.32% to 22.65% for the population and 10.90% to 32.81% for the sub-group. Furthermore, probabilistic sensitivities were computed in which the contribution of uncertainty and variability of the parameters of interest was quantified. The study found that rib cortical bone elastic modulus, rib morphometry and cortical thickness are the random variables that produce the largest variability in the predicted force-displacement response. The proposed framework offers a novel approach for accounting biological variability in a representative population and has the potential to improve the generalizability of findings in biomechanical studies.

Virtual Reality in the Pediatric Intensive Care Unit: Patient Emotional and Physiologic Responses.

Context: Patients in the Pediatric Intensive Care Unit (PICU) are limited in their ability to engage in developmentally typical activity. Long-term hospitalization, especially with minimal interpersonal engagement, is associated with risk for delirium and delayed recovery. Virtual reality (VR) has growing evidence as a safe, efficacious, and acceptable intervention for pain and distress management in the context of uncomfortable healthcare procedures, and for enhancing engagement in, and improving outcomes of rehabilitation therapy. Hypothesis: Critically ill children may experience high levels of engagement and physiologic effects while engaging with VR. Methods and Models: This cross-sectional study of 3-17-year-old children admitted to a PICU used a VR headset to deliver 360-degree immersive experiences. This study had a mixed-method approach, including standardized behavioral coding, participant and parent surveys, and participant physiologic responses. Investigators noted comments the child made about VR, observed emotional responses, and documented an engagement score. To determine physiologic response to VR, integer heart rate variability (HRVi) was collected 30 min before, during, and 30 min after VR. Results: One hundred fifteen participants were enrolled from 6/18 to 10/19, and they interacted with VR for a median of 10 min (interquartile range 7-17). Most children enjoyed the experience; 83% of participants smiled and 36% laughed while using VR. Seventy-two percent made positive comments while using VR. The strongest age-related pattern regarding comments was that the youngest children were more likely to share the experience with others. Seventy-nine percent of participants were highly engaged with VR. Ninety-two percent of parents reported that VR calmed their child, and 78% of participants felt that VR was calming. HRVi Minimum scores were significantly higher during VR than pre- (p < 0.001) or post-VR (p < 0.001). There was no significant difference between pre-and post-VR (p = 0.387); therefore, children returned to their pre-intervention state following VR. Interpretations and Conclusions: Children admitted to the PICU are highly engaged with and consistently enjoyed using VR. Both participants and parents found VR to be calming, consistent with intra-intervention physiologic improvements in HRVi. VR is an immersive tool that can augment the hospital environment for children.

Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.

Background: Respiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes. Methods: Nasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared. Findings: Increased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for

Cocaine Triggers Astrocyte-Mediated Synaptogenesis.

BACKGROUND: Synaptogenesis is essential in forming new neurocircuits during development, and this is mediated in part by astrocyte-released thrombospondins (TSPs) and activation of their neuronal receptor, α2δ-1. Here, we show that this developmental synaptogenic mechanism is utilized during cocaine experience to induce spinogenesis and the generation of AMPA receptor-silent glutamatergic synapses in the adult nucleus accumbens shell (NAcSh). METHODS: Using multidisciplinary approaches including astrocyte Ca2+ imaging, genetic mouse lines, viral-mediated gene transfer, and operant behavioral procedures, we monitor the response of NAcSh astrocytes to cocaine administration and examine the role of astrocytic TSP-α2δ-1 signaling in cocaine-induced silent synapse generation as well as the behavioral impact of astrocyte-mediated synaptogenesis and silent synapse generation. RESULTS: Cocaine administration acutely increases Ca2+ events in NAcSh astrocytes, while decreasing astrocytic Ca2+ blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of α2δ-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-α2δ-1-mediated spinogenesis and synapse generation in NAcSh decreases cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction. CONCLUSIONS: These results establish that silent synapses are generated by an astrocyte-mediated synaptogenic mechanism in response to cocaine experience and embed critical cue-associated memory traces that promote cocaine relapse.

Immune response to SARS-CoV-2 in the nasal mucosa in children and adults.

RATIONALE: Despite similar viral load and infectivity rates between children and adults infected with SARS-CoV-2, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the proposed mechanisms. OBJECTIVES: To investigate the host response to SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus (IV) in the nasal mucosa in children and adults. METHODS: Clinical outcomes and gene expression in the nasal mucosa were analyzed in 36 children hospitalized with SARS-CoV-2 infection, 24 children with RSV infection, 9 children with IV infection, 16 adults with mild to moderate SARS-CoV-2 infection, and 7 healthy pediatric and 13 healthy adult controls. RESULTS: In both children and adults, infection with SARS-CoV-2 leads to an interferon response in the nasal mucosa. The magnitude of the interferon response correlated with the abundance of viral reads and was comparable between symptomatic children and adults infected with SARS-CoV-2 and symptomatic children infected with RSV and IV. Cell type deconvolution identified an increased abundance of immune cells in the samples from children and adults with a viral infection. Expression of ACE2 and TMPRSS2 - key entry factors for SARS-CoV-2 - did not correlate with age or presence or absence of viral infection. CONCLUSIONS: Our findings support the hypothesis that differences in the immune response to SARS-CoV-2 determine disease severity, independent of viral load and interferon response at the primary infection primary site.

Wireless, Skin-Interfaced Devices for Pediatric Critical Care: Application to Continuous, Noninvasive Blood Pressure Monitoring.

Indwelling arterial lines, the clinical gold standard for continuous blood pressure (BP) monitoring in the pediatric intensive care unit (PICU), have significant drawbacks due to their invasive nature, ischemic risk, and impediment to natural body movement. A noninvasive, wireless, and accurate alternative would greatly improve the quality of patient care. Recently introduced classes of wireless, skin-interfaced devices offer capabilities in continuous, precise monitoring of physiologic waveforms and vital signs in pediatric and neonatal patients, but have not yet been employed for continuous tracking of systolic and diastolic BP-critical for guiding clinical decision-making in the PICU. The results presented here focus on materials and mechanics that optimize the system-level properties of these devices to enhance their reliable use in this context, achieving full compatibility with the range of body sizes, skin types, and sterilization schemes typically encountered in the PICU. Systematic analysis of the data from these devices on 23 pediatric patients, yields derived, noninvasive BP values that can be quantitatively validated against direct recordings from arterial lines. The results from this diverse cohort, including those under pharmacological protocols, suggest that wireless, skin-interfaced devices can, in certain circumstances of practical utility, accurately and continuously monitor BP in the PICU patient population.

The Importance of Engaging Children in Research Decision-Making: A Preliminary Mixed-Methods Study.

Studies demonstrate deficiencies in parents' and children's comprehension of research and lack of child engagement in research decision-making. We conducted a cross-sectional and interview-based study of 31 parent-child dyads to describe decision-making preferences, experiences, and comprehension of parents and children participating in research. Parents and children reported that parents played a greater role in decisions about research participation than either parents or children preferred. The likelihood of child participation was associated with the extent of input the parent permitted the child to have in the decision-making process, the child's comprehension, whether the study team asked the child about participation, whether the child read study-related materials, the parent's marital status, and the child's race. Children had lower comprehension than adults. Comprehension was related to age, education, verbal intelligence, and reading of study-related information. Parent understanding was associated with prospect for benefit and illness severity. Child participation may be improved by increasing parent-child communication, emphasizing important relational roles between parent and child, respecting the developing autonomy of the child, increasing engagement with the study team, providing appropriate reading materials, and assessing comprehension.

Burden or Opportunity? Parent Experiences When Approached for Research in a Pediatric Intensive Care Unit.

Despite an ongoing need for pediatric research, low study enrollment may impede study completion, particularly in critical care. We conducted a prospective cross-sectional survey and chart review study to assess parent experiences with research in a pediatric intensive care unit (PICU). Of the 80 parents who completed the study survey, 54% were approached to participate in a research study in the PICU, and 93% agreed to participate. Motivators included altruism, low burden, low risk, and research that would benefit the child. Barriers included risks to the child, the child's being too sick to participate, feeling overwhelmed, not having enough time to participate, the research's being burdensome, and the research's not being explained well. PICU parents had mostly favorable attitudes toward research participation. Compared with non-Hispanic survey respondents, respondents of Hispanic ethnicity less often reported having been approached for research, which further evidences the need to track research recruitment processes to help avoid underinclusion of members of minority populations.

Biobanking in the Pediatric Critical Care Setting: Adolescent/Young Adult Perspectives.

Biorepository research in children raises numerous ethical questions that are heightened in the pediatric intensive care unit (PICU) setting. We conducted a cross-sectional, interview-based study of 20 adolescent/young adult (A/YA) PICU patients and 75 parents of PICU patients to elucidate perspectives on biorepository research. A/YAs had a positive attitude toward biobanking. In young adults, comprehension was higher for knowledge of a choice to withdraw and participate in the research and lower for purpose, procedures, risks, and benefits of participation. All but one A/YA wanted to have a say in whether their samples would be used. Parent views on child assent were mixed; 55% of parents favored child involvement in decisions. Efforts should be made to improve comprehension by A/YAs and involvement of A/YAs in decisions.