Brain Growth Charts for Quantitative Analysis of Pediatric Clinical Brain MRI Scans with Limited Imaging Pathology.

Background Clinically acquired brain MRI scans represent a valuable but underused resource for investigating neurodevelopment due to their technical heterogeneity and lack of appropriate controls. These barriers have curtailed retrospective studies of clinical brain MRI scans compared with more costly prospectively acquired research-quality brain MRI scans. Purpose To provide a benchmark for neuroanatomic variability in clinically acquired brain MRI scans with limited imaging pathology (SLIPs) and to evaluate if growth charts from curated clinical MRI scans differed from research-quality MRI scans or were influenced by clinical indication for the scan. Materials and Methods In this secondary analysis of preexisting data, clinical brain MRI SLIPs from an urban pediatric health care system (individuals aged ≤22 years) were scanned across nine 3.0-T MRI scanners. The curation process included manual review of signed radiology reports and automated and manual quality review of images without gross pathology. Global and regional volumetric imaging phenotypes were measured using two image segmentation pipelines, and clinical brain growth charts were quantitatively compared with charts derived from a large set of research controls in the same age range by means of Pearson correlation and age at peak volume. Results The curated clinical data set included 532 patients (277 male; median age, 10 years [IQR, 5-14 years]; age range, 28 days after birth to 22 years) scanned between 2005 and 2020. Clinical brain growth charts were highly correlated with growth charts derived from research data sets (22 studies, 8346 individuals [4947 male]; age range, 152 days after birth to 22 years) in terms of normative developmental trajectories predicted by the models (median r = 0.979). Conclusion The clinical indication of the scans did not significantly bias the output of clinical brain charts. Brain growth charts derived from clinical controls with limited imaging pathology were highly correlated with brain charts from research controls, suggesting the potential of curated clinical MRI scans to supplement research data sets. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Ertl-Wagner and Pai in this issue.

Expansion and commentary on a two generation approach to prenatal opioid exposure - a commentary on Conradt et al. (2023).

Early child neurodevelopment, including psychopathology, is influenced by a myriad of factors and interactions. These factors are both intrinsic to the caregiver-child dyad such as genetics and epigenetics as well as extrinsic such as social environment and enrichment. Additional layers of complexity may be at play within families with parental substance use, as outlined by Conradt et al. (2023) in their review article titled "Prenatal Opioid Exposure: A Two-Generation Approach to Conceptualizing Risk for Child Psychopathology.". Conradt et al. provide an overarching synthesis of many findings related to substance use that goes beyond the in utero exposure to the transgenerational interface of pregnancy and early childhood, including biologic sensitivities such as genetic predisposition, overrepresentation of social risk factors including early adversities of caregivers and poverty, and transgenerational interactional susceptibilities. Altered dyadic interactions may relate to joint changes in neurobehavior and are not isolated from the influence of infant genetics, epigenetics, and environment. The early neurodevelopmental correlates of prenatal substance exposure including risks of childhood psychopathology are then a composite of many different forces. This nuanced reality, described as an "inter-generational cascade," does not centralize parental substance use or prenatal exposure as a singularly causative moment but positions it within the ecologic milieu of the total lived experience.

The impact of postpartum social support on postpartum mental health outcomes during the COVID-19 pandemic.

Social support is an influential component of postpartum recovery, adjustment, and bonding, which was disrupted by social distancing recommendations related to the COVID-19 pandemic. This study reports on changes in the availability of social support for postpartum women during the pandemic, investigates how those changes may have contributed to postpartum mental health, and probes how specific types of social support buffered against poor postpartum mental health and maternal-infant bonding impairment. Participants were 833 pregnant patients receiving prenatal care in an urban USA setting and using an electronic patient portal to access self-report surveys at two time points, during pregnancy (April-July 2020) and at ~12 weeks postpartum (August 2020-March 2021). Measures included an assessment of COVID-19 pandemic-related change in social support, sources of social support, ratings of emotional and practical support, and postpartum outcomes including depression, anxiety, and maternal-infant bonding. Overall self-reported social support decreased during the pandemic. Decreased social support was associated with an increased risk of postpartum depression, postpartum anxiety, and impaired parent-infant bonding. Among women reporting low practical support, emotional support appeared to protect against clinically significant depressive symptoms and impaired bonding with the infant. Decreases in social support are associated with a risk for poor postpartum mental health outcomes and impaired maternal-infant bonding. Evaluation and promotion of social support are recommended for healthy adjustment and functioning of postpartum women and families.

The Influence of Pandemic-Related Worries During Pregnancy on Child Development at 12 Months.

The COVID-19 pandemic has been linked to increased risk for perinatal anxiety and depression among parents, as well as negative consequences for child development. Less is known about how worries arising from the pandemic during pregnancy are related to later child development, nor if resilience factors buffer negative consequences. The current study addresses this question in a prospective longitudinal design. Data was collected from a sub-study (n = 184) of a longitudinal study of pregnant individuals (total n = 1173). During pregnancy (April 17-July 8, 2020) and the early postpartum period (August 11, 2020-March 2, 2021), participants completed online surveys. At 12 months postpartum (June 17, 2021-March 23, 2022), participants completed online surveys and a virtual laboratory visit, which included parent-child interaction tasks. We found more pregnancy-specific pandemic worries were prospectively related to lower levels of child socioemotional development based on parent report (B = - 1.13, SE = .43, p = .007) and observer ratings (B = - 0.13, SE = .07, p = .045), but not to parent-reported general developmental milestones. Parental emotion regulation in the early postpartum period moderated the association between pregnancy-specific pandemic worries and child socioemotional development such that pregnancy-specific pandemic worries did not relate to worse child socioemotional development among parents with high (B = - .02, SE = .10, t = - .14, p = .89) levels of emotion regulation. Findings suggest the negative consequences of parental worry and distress during pregnancy on the early socioemotional development of children in the context of the COVID-19 pandemic. Results highlight that parental emotion regulation may represent a target for intervention to promote parental resilience and support optimized child development.

Clinician-reported childbirth outcomes, patient-reported childbirth trauma, and risk for postpartum depression.

Childbirth trauma is common and increases risk for postpartum depression (PPD). However, we lack brief measures to reliably identify individuals who experience childbirth trauma and who may be at greater prospective risk for PPD. To address this gap, we used data from a racially diverse prospective cohort (n=1082). We collected survey data during pregnancy and at 12 weeks postpartum, as well as clinician-reported data from medical records. A new three-item measure of patient-reported childbirth trauma was a robust and independent risk factor for PPD, above and beyond other known risk factors for PPD, including prenatal anxiety and depression. Cesarean birth, greater blood loss, and preterm birth were each associated with greater patient-reported childbirth trauma. Finally, there were prospective indirect pathways whereby cesarean birth and higher blood loss were related to higher patient-reported childbirth trauma, in turn predicting greater risk for PPD. Early universal postpartum screening for childbirth trauma, targeted attention to individuals with childbirth complications, and continued screening for depression and anxiety can identify individuals at risk for PPD. Such efforts can inform targeted interventions to improve maternal mental health, which plays a vital role in infant development.

Child Abuse Imaging and Findings in the Time of COVID-19.

OBJECTIVE: To assess the impact of the COVID-19 pandemic on physical abuse in young children, we compared the following before and during the pandemic: (1) skeletal survey volume, (2) percent of skeletal surveys revealing clinically unsuspected (occult) fractures, and (3) clinical severity of presentation. We hypothesized that during the pandemic, children with minor abusive injuries would be less likely to present for care, but severely injured children would present at a comparable rate to prepandemic times. We expected that during the pandemic, the volume of skeletal surveys would decrease but the percentage revealing occult fractures would increase and that injury severity would increase. METHODS: We conducted a retrospective study of children younger than 2 years undergoing skeletal surveys because of concern for physical abuse at a tertiary children's hospital. Subjects were identified by querying a radiology database during the March 15, 2019-October 15, 2019 (pre-COVID-19) period and the March 15, 2020-October 15, 2020 (COVID-19) period, followed by chart review to refine our population and abstract clinical and imaging data. RESULTS: Pre-COVID-19, 160 skeletal surveys were performed meeting the inclusion criteria, compared with 125 during COVID-19, representing a 22% decrease. No change was observed in identification of occult fractures (6.9% pre-COVID vs 6.4% COVID, P = 0.87). Clinical severity of presentation did not change, and child protective services involvement/referral decreased during COVID. CONCLUSIONS: Despite a >20% decrease in skeletal survey performance early in the pandemic, the percent of skeletal surveys revealing occult fractures did not increase. Our results suggest that decreases in medical evaluations for abuse did not stem from decreased presentation of less severely injured children.

Brief resolved unexplained events vs. child maltreatment: a review of clinical overlap and evaluation.

Within their first year, a number of infants present for medical evaluation because of unexplained changes in color, tone, breathing, or level of responsiveness. This broad collection of symptoms has an accordingly large differential diagnosis that includes both brief resolved unexplained event (BRUE) and child maltreatment. The overlap between clinical presentation for BRUE and maltreatment can present a diagnostic challenge - especially given the significant consequences for infants and families for diagnostic error at that juncture. In this review, we provide overviews of the presenting features and findings in cases of BRUE and child maltreatment with a focus on areas of overlap and differentiation.

Trends in Pediatric Emergency Department Utilization after Institution of Coronavirus Disease-19 Mandatory Social Distancing.

We conducted a descriptive time-series study of pediatric emergency healthcare use during the onset of severe acute respiratory syndrome coronavirus 2 pandemic after a state-wide stay-at-home order. Our study demonstrated decreased volume, increased acuity, and generally consistent chief complaints compared with the prior 3 years (2017 through 2019). Ingestions became a significantly more common chief complaint in 2020.

BRG1-mediated immune tolerance: facilitation of Treg activation and partial independence of chromatin remodelling.

Treg activation in response to environmental cues is necessary for regulatory T cells (Tregs) to suppress inflammation, but little is known about the transcription mechanisms controlling Treg activation. We report that despite the known proinflammatory role of the chromatin-remodelling factor BRG1 in CD4 cells, deleting Brg1 in all αß T cell lineages led to fatal inflammation, which reflected essential roles of BRG1 in Tregs. Brg1 deletion impaired Treg activation, concomitant with the onset of the inflammation. Remarkably, as the inflammation progressed, Tregs became increasingly activated, but the activation levels could not catch up with the severity of inflammation. In vitro assays indicate that BRG1 regulates a subset of TCR target genes including multiple chemokine receptor genes. Finally, using a method that can create littermates bearing either a tissue-specific point mutation or deletion, we found the BRG1 ATPase activity partially dispensable for BRG1 function. Collectively, these data suggest that BRG1 acts in part via remodelling-independent functions to sensitize Tregs to inflammatory cues, thus allowing Tregs to promptly and effectively suppress autoimmunity.

Inducible mouse models illuminate parameters influencing epigenetic inheritance.

Environmental factors can stably perturb the epigenome of exposed individuals and even that of their offspring, but the pleiotropic effects of these factors have posed a challenge for understanding the determinants of mitotic or transgenerational inheritance of the epigenetic perturbation. To tackle this problem, we manipulated the epigenetic states of various target genes using a tetracycline-dependent transcription factor. Remarkably, transient manipulation at appropriate times during embryogenesis led to aberrant epigenetic modifications in the ensuing adults regardless of the modification patterns, target gene sequences or locations, and despite lineage-specific epigenetic programming that could reverse the epigenetic perturbation, thus revealing extraordinary malleability of the fetal epigenome, which has implications for 'metastable epialleles'. However, strong transgenerational inheritance of these perturbations was observed only at transgenes integrated at the Col1a1 locus, where both activating and repressive chromatin modifications were heritable for multiple generations; such a locus is unprecedented. Thus, in our inducible animal models, mitotic inheritance of epigenetic perturbation seems critically dependent on the timing of the perturbation, whereas transgenerational inheritance additionally depends on the location of the perturbation. In contrast, other parameters examined, particularly the chromatin modification pattern and DNA sequence, appear irrelevant.

A general approach for controlling transcription and probing epigenetic mechanisms: application to the CD4 locus.

Synthetic regulatory proteins such as tetracycline (tet)-controlled transcription factors are potentially useful for repression as well as ectopic activation of endogenous genes and also for probing their regulatory mechanisms, which would offer a versatile genetic tool advantageous over conventional gene targeting methods. In this study, we provide evidence supporting this concept using Cd4 as a model. CD4 is expressed in double-positive and CD4 cells but irreversibly silenced in CD8 cells. The silencing is mediated by heterochromatin established during CD8 lineage development via transient action of the Cd4 silencer; once established, the heterochromatin becomes self-perpetuating independently of the Cd4 silencer. Using a tet-sensitive Cd4 allele harboring a removable Cd4 silencer, we found that a tet-controlled repressor recapitulated the phenotype of Cd4-deficient mice, inhibited Cd4 expression in a reversible and dose-dependent manner, and could surprisingly replace the Cd4 silencer to induce irreversible Cd4 silencing in CD8 cells, thus suggesting the Cd4 silencer is not the (only) determinant of heterochromatin formation. In contrast, a tet-controlled activator reversibly disrupted Cd4 silencing in CD8 cells. The Cd4 silencer impeded this disruption but was not essential for its reversal, which revealed a continuous role of the silencer in mature CD8 cells while exposing a remarkable intrinsic self-regenerative ability of heterochromatin after forced disruption. These data demonstrate an effective approach for gene manipulation and provide insights into the epigenetic Cd4 regulatory mechanisms that are otherwise difficult to obtain.

Improving health and well-being for infants with prenatal substance exposure.

Substance use disorders (SUD) among caregiving adults has inexorable linkage to the health and well-being of millions of children in the U.S. This piece provides an overview of such linkages, examples of relevant policies and regulations, and the role of pediatric healthcare within the health trajectories of children and families at this intersection. A commonality throughout this work is need for non-stigmatizing engagement and support to facilitate connections to care and reduce barriers.

"Instead of just taking my baby, they could've actually given me a chance": Experiences with plans of safe care among birth parents impacted by perinatal substance use.

BACKGROUND: Federal legislation mandates healthcare providers to notify child protective service (CPS) agencies and offer a voluntary care plan called a "plan of safe care" (POSC) for all infants born affected by prenatal substance use. While POSCs aim to provide supportive services for families impacted by substance use, little is known about birth parents' perceptions and experiences. OBJECTIVE: To examine birth parents' perceptions and experiences regarding POSC. PARTICIPANTS AND SETTING: Parents offered a POSC in Philadelphia in the prior year were included. METHODS: This is a qualitative interview study. Participants were recruited from birth hospitals and community-based programs with telephone consent and interview procedures. Transcripts were analyzed using an inductive, grounded theory approach to identify content themes. RESULTS: Twelve birth parents were interviewed (30.7 % of eligible, contacted individuals). Fear of CPS involvement and stigma were common. Some birth parents reported that the increased scrutiny related to POSCs negatively impacted their attitudes toward healthcare providers and medications for opioid use disorder (MOUD). While parents found the consolidated resource information helpful, many did not know how to access services. Finally, parents desired more individualized plans tailored to their unique family needs. CONCLUSIONS: Stigma, confusion, and fear of CPS involvement undermine the goal of POSCs to support substance-exposed infants and birth parents. Providers serving this population should be transparent regarding CPS notifications, provide compassionate, non-stigmatizing care, and offer coordination services to support engagement after discharge. Policymakers should consider separating POSCs from CPS to avoid exacerbating fear and mistrust.

Assessment of substance exposures in nail clipping samples: A systematic review.

BACKGROUND: Studies of prenatal substance exposure often rely on self-report, urine drug screens, and/or analyses of blood or meconium biomarkers. Accuracy of these measures is limited when assessing exposure over many weeks or months of gestation. Nails are increasingly being considered as a matrix from which to assess substance exposure. This systematic review synthesizes data on the validity of detecting alcohol, nicotine, cannabis, and opioid from nail clippings, with an emphasis on prenatal exposure assessment. METHODS: The systematic review was conducted using PRISMA 2020 guidelines. Seven databases were searched with keywords relevant to the four substances of interest. Results were summarized grouping manuscripts by the exposure of interest with focus on accuracy and feasibility. RESULTS: Of 2384 papers initially identified, 35 manuscripts were included in our qualitative synthesis. Only a few studies specifically looked at pregnant individuals or mother-child dyads. Across the four substances, many studies demonstrated a dose-response relationship between exposure and concentration of analytes in nails. Nail assays appear to detect lower level of exposure compared to hair; however, sample insufficiency, especially for multi-substance assays, remains a limitation. CONCLUSIONS: Based on the reviewed studies, nail clippings are an acceptable and potentially preferable matrix for the evaluation of these four prenatal substances when sampling frequency and/or study design necessitates assessment of past exposures over an extended period. Nails have the advantage of infrequent sampling and minimal invasiveness to assess a broad exposure period. Future studies should examine validity of analytes in toenail versus fingernail clippings.

Pediatric Primary Care of Children With Intrauterine Opioid Exposure: Survey of Academic Teaching Practices.

OBJECTIVE: Intrauterine opioid exposure (IOE) has increased over the last 2 decades and is associated with additional needs after birth. To date, no clinical guidelines address the primary care of children with IOE. We aimed to characterize clinician-reported screening and referral practices, barriers to effective primary care for children with IOE, and clinician- and practice-level characteristics associated with perceived barriers. METHODS: We conducted a cross-sectional survey of pediatric residents, pediatricians, and advanced practitioners at 28 primary care clinics affiliated with 7 pediatric residency programs (April-June 2022). We assessed screening and other clinical practices related to IOE and perceived barriers to addressing parental opioid use disorder (OUD). We used descriptive statistics to analyze survey responses, assessed the distribution of reported barriers, and applied a 2-stage cluster analysis to assess response patterns. RESULTS: Of 1004 invited clinicians, 329 (32.8%) responses were returned, and 325 pediatric residents and pediatricians were included in the final analytic sample. Almost all (99.3%) reported parental substance use screening as important, but only 11.6% screened routinely. Half of the respondents routinely refer children with IOE to early intervention services and social work. Lack of standard screening for substance use was the most frequently selected barrier to addressing parental OUD. Participants reporting fewer barriers to addressing parental OUD identified having greater access to OUD treatment programs and home visiting programs. CONCLUSIONS: Pediatricians report variations in primary care screenings and referrals for children with IOE. Access to parental OUD treatment programs may mitigate perceived barriers to addressing parental OUD in the pediatric office.

Observations of Positive Parenting from Online Parent-Child Interactions at Age 1.

Objective: Brief, reliable, and cost-effective methods to assess parenting are critical for advancing parenting research. Design: We adapted the Three Bags task and Parent Child Interaction Rating System (PCIRS) for rating online visits with 219 parent-child dyads (White, n = 104 [47.5%], Black, n = 115 [52.5%]) and combined the video data with survey data collected during pregnancy and when children were aged 1. Results: The PCIRS codes of positive regard, stimulation of child cognitive development, and sensitivity showed high reliability across the three parent-child interaction tasks. A latent positive parenting factor combining ratings across codes and tasks showed good model fit, which was similar regardless of parent self-identified race or ethnicity, age, socioeconomic disadvantage, marital/partnered status, and parity, as well as methodological factors relevant to the online video assessment method (e.g., phone vs. laptop/tablet). In support of construct validity, observed positive parenting was related to parent-reported positive parenting and child socioemotional development. Finally, parent reports of supportive relationships in pregnancy, but not neighborhood safety or pandemic worries, were prospectively related to higher positive parenting observed at age 1. With the exception of older parental age and married/partnered status, no other parent, child, sociodemographic, or methodological variables were related to higher overall video exclusions across tasks. Conclusions: PCIRS may provide a reliable approach to rate positive parenting at age 1, providing future avenues for developing more ecologically valid assessments and implementing interventions through online encounters that may be more acceptable, accessible, or preferred among parents of young children.

Outcomes for patients with congenital hepatoblastoma.

BACKGROUND: Congenital hepatoblastoma, diagnosed in the first month of life, has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. PROCEDURE: We retrospectively reviewed two patients from the senior authors' personal series and 25 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94, and HB 99). We compared this series with cases of congenital hepatoblastoma previously published in the literature. RESULTS: The 3-year survival in our case series was 86% (18/21) with a follow-up of 44-230 months (median 85.5 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. Survival was comparable to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [von Schweinitz et al., Eur J Cancer 1997; 33:1243-1249]. The 2-year survival of cases reported in the literature was 0% (0/9) and 42% (10/24) for patients reported before and after 1990, respectively. CONCLUSIONS: Congenital hepatoblastoma does not appear to confer a worse prognosis. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of hepatoblastoma at this young age is much better than has been historically reported. More rigorous analysis should be conducted in future multicenter trials. It is possible that congenital hepatoblastoma should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy.

LoxP-FRT Trap (LOFT): a simple and flexible system for conventional and reversible gene targeting.

BACKGROUND: Conditional gene knockout (cKO) mediated by the Cre/LoxP system is indispensable for exploring gene functions in mice. However, a major limitation of this method is that gene KO is not reversible. A number of methods have been developed to overcome this, but each method has its own limitations. RESULTS: We describe a simple method we have named LOFT [LoxP-flippase (FLP) recognition target (FRT) Trap], which is capable of reversible cKO and free of the limitations associated with existing techniques. This method involves two alleles of a target gene: a standard floxed allele, and a multi-functional allele bearing an FRT-flanked gene-trap cassette, which inactivates the target gene while reporting its expression with green fluorescent protein (GFP); the trapped allele is thus a null and GFP reporter by default, but is convertible into a wild-type allele. The floxed and trapped alleles can typically be generated using a single construct bearing a gene-trap cassette doubly flanked by LoxP and FRT sites, and can be used independently to achieve conditional and constitutive gene KO, respectively. More importantly, in mice bearing both alleles and also expressing the Cre and FLP recombinases, sequential function of the two enzymes should lead to deletion of the target gene, followed by restoration of its expression, thus achieving reversible cKO. LOFT should be generally applicable to mouse genes, including the growing numbers of genes already floxed; in the latter case, only the trapped alleles need to be generated to confer reversibility to the pre-existing cKO models. LOFT has other applications, including the creation and reversal of hypomorphic mutations. In this study we proved the principle of LOFT in the context of T-cell development, at a hypomorphic allele of Baf57/Smarce1 encoding a subunit of the chromatin-remodeling Brg/Brahma-associated factor (BAF) complex. Interestingly, the FLP used in the current work caused efficient reversal in peripheral T cells but not thymocytes, which is advantageous for studying developmental epigenetic programming of T-cell functions, a fundamental issue in immunology. CONCLUSIONS: LOFT combines well-established basic genetic methods into a simple and reliable method for reversible gene targeting, with the flexibility of achieving traditional constitutive and conditional KO.

Child Welfare System-Level Factors Associated with All-Cause Mortality Among Children in Foster Care in the United States, 2009-2018.

Little is known about the impact of child welfare system-level factors on child mortality as an outcome within foster care. Using data from the Adoption and Foster Care Analysis and Reporting System, 2009-2018, we examined the associations between county-level sociodemographic, foster care performance, and judicial reform characteristics with all-cause mortality rates. Results of random effects negative binomial regression analyses showed that higher proportions of younger children (<1 year: IRR = 1.06, 95% CI [1.02, 1.11]; 5-9 years: IRR = 1.05, 95% CI [1.01, 1.09]); children of color (i.e., non-Hispanic Asian: IRR = 1.07, 95% CI [1.01, 1.13]; multiracial: IRR = 1.03, 95% CI [1.01, 1.04]; non-Hispanic Black: IRR = 1.02, 95% CI [1.01, 1.02]; Hispanic: IRR = 1.01, 95% CI [1.01, 1.02]); and male children (IRR = 1.10, 95% CI [1.05, 1.15]) were associated with higher mortality risks at the county level. Current class action lawsuits (IRR = 0.79, 95% CI [0.63, 0.99]) and active consent decrees (IRR = 0.77, 95% CI [0.63, 0.94]) were associated with lower mortality risks. None of the foster care performance characteristics (e.g., foster care entry, placement stability, permanency) were associated with mortality risks. These findings have implications for addressing health disparities and reforming foster care systems through programmatic and policy efforts.