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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.

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 = 1,173). 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 related 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.

BackgroundBrain MRIs acquired in clinical settings represent a valuable and underutilized scientific resource for investigating neurodevelopment. Utilization of these clinical scans has been limited because of their clinical acquisition and technical heterogeneity. These barriers have curtailed the interpretability and scientific value of retrospective studies of clinically acquired brain MRIs, compared to studies of prospectively acquired research quality brain MRIs.PurposeTo develop a scalable and rigorous approach to generate clinical brain growth chart models, to benchmark neuroanatomical differences in clinical MRIs, and to validate clinically-derived brain growth charts against those derived from large-scale research studies.Materials and MethodsWe curated a set of clinical MRIScans withLimitedImagingPathology (SLIP) – so-called “clinical controls” – from an urban pediatric healthcare system acquired between 2005 and 2020. The curation process included manual review of signed radiology reports, as well as automated and manual quality review of images without gross pathology. We measured global and regional volumetric imaging phenotypes in the SLIP sample using two alternative, advanced image processing pipelines, and quantitatively compared clinical brain growth charts to research brain growth charts derived from >123,000 MRIs.ResultsThe curated SLIP dataset included 372 patients scanned between the ages of 28 days post-birth and 22.2 years across nine 3T MRI scanners. Clinical brain growth charts were highly similar to growth charts derived from large-scale research datasets, in terms of the normative developmental trajectories predicted by the models. The clinical indication of the scans did not significantly bias the output of clinical brain charts. Tens of thousands of additional healthcare system scans meet inclusion criteria to be included in future brain growth charts.ConclusionBrain charts derived from clinical-controls are highly similar to brain charts from research-controls, suggesting that curated clinical scans could be used to supplement research datasets.Summary StatementBrain growth charts of pediatric clinical MRIs with limited imaging pathology (N=372) are highly correlated with charts from a large aggregated set of research controls (N>120,000).Key ResultsA cohort of brain MRI scans with limited reported imaging pathology (N=372, 186 female; ages 0.07 - 22.2 years, median = 10.2) were identified using signed radiology reports and processed using two segmentation pipelines. Growth charts generated from these scans are highly correlated with growth charts from a large aggregated set of research controls (r range 0.990 - 0.999). There was no evidence of bias due to the reason for each scan.

Acute stress during pregnancy can have adverse effects on maternal health and increase the risk for postpartum depression and impaired mother-infant bonding. The COVID-19 pandemic represents an acute environmental stressor during which it is possible to explore risk and resilience factors that contribute to postpartum outcomes. To investigate prenatal risk and resilience factors as predictors of postpartum depression and impaired mother-infant bonding, this study recruited a diverse cohort of 833 pregnant women from an urban medical center in Philadelphia, Pennsylvania, and assessed them once during pregnancy in the early phase of the COVID-19 pandemic (April-July 2020) and again at approximately twelve weeks postpartum. Adverse childhood experiences, prenatal depression and anxiety, and COVID-19-related distress predicted a greater likelihood of postpartum depression. Prenatal depression was the only unique predictor of impaired maternal-infant bonding after postpartum depression was controlled for. Women reporting greater emotion regulation, self-reliance, and nonhostile relationships had healthier postpartum outcomes. Policies to increase the number of nonspecialty providers providing perinatal mental health services as well as reimbursement for integrated care and access to mental health screening and care are needed to improve lifelong outcomes for women and their children.

Purpose: Suicidal ideation and attempts in youth are a growing health concern, and more data are needed regarding their biological underpinnings. Asthma is a common chronic inflammatory disorder in youth and has been associated with suicidal ideation and attempts in adolescent and adult populations, but data in younger children and early adolescents are lacking. We wished to study associations of asthma with childhood suicidality considering asthma’s potential as a clinically relevant model for childhood chronic immune dysregulation. Methods: Using data from the Adolescent Brain Cognitive Development (ABCD) Study (n = 11,876, 47.8% female, mean age 9.9 years at baseline assessment and 12.0 years at two-year follow-up), we assessed associations between asthma and suicidal ideation and attempts through baseline to two-year follow-up. Results: Asthma history as defined by parent report (n = 2282, 19.2% of study population) was associated with suicide attempts (SA) (odds ratio (OR) = 1.44, p = 0.01), and this association remained significant even when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.46, p = 0.028). History of asthma attacks was associated with both suicidal ideation (SI) and SA when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.27, p = 0.042; OR = 1.83, p = 0.004, respectively). The association of asthma attack with SA remained significant when controlling for self-reported psychopathology (OR = 1.92, p = 0.004). The total number of asthma attacks was associated with both SI and SA (OR = 1.03, p = 0.043; OR = 1.06, p = 0.05, respectively). Conclusions: Findings suggest an association between asthma and suicidality in early adolescence. Further research is needed to investigate mechanisms underlying this relationship.

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.

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 (

This cross-sectional study sought to quantify the frequency of change in race category in the electronic medical record (EMR) of a pediatric population.

BACKGROUND AND OBJECTIVE The reported impacts of the COVID-19 pandemic on child maltreatment in the United States have been mixed. Encounter trends for child physical abuse within pediatric emergency departments may provide insights. Thus, this study sought to determine the change in the rate of emergency department encounters related to child physical abuse. METHODS A retrospective study within the Pediatric Emergency Care Applied Research Network Registry. Encounters related to child physical abuse were identified by 3 methods: child physical abuse diagnoses among all ages, age-restricted high-risk injury, or age-restricted skeletal survey completion. The primary outcomes were encounter rates per day and clinical severity before (January 2018–March 2020) and during the COVID-19 pandemic (April 2020–March 2021). Multivariable Poisson regression models were fit to estimate rate ratios with marginal estimation methods. RESULTS Encounter rates decreased significantly during the pandemic for 2 of 3 identification methods. In fully adjusted models, encounter rates were reduced by 19% in the diagnosis-code cohort (adjusted rate ratio: 0.81 [99% confidence interval: 0.75–0.88], P CONCLUSIONS Encounter rates for child physical abuse were reduced or unchanged. Reductions were greatest for lower-severity encounters and preschool and school-aged children. This pattern calls for critical assessment to clarify whether pandemic changes led to true reductions versus decreased recognition of child physical abuse.

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 maltreatment and end-of-life care independently represent two of the most emotion-laden and uncomfortable aspects of pediatric patient care. Their overlap can be uniquely distressing. This review explores ethical and legal principles in such cases and provides practical advice for clinicians. The review focuses on three archetypal scenarios of overlap: life-limiting illness in a child for whom parental rights have been terminated; life-threatening injury under CPS investigation; and complex end-of-life care which may warrant CPS involvement. While each scenario presents unique challenges, one consistent theme is the centrality of effective communication. This includes empathic communication with families and thoughtful communication with providers and community stakeholders. In almost all cases, everyone genuinely wants to do what is in the best interest of the child in these unthinkable circumstances. Transparent and collaborative communication can ensure that broad perspectives are considered to ensure that each child gets the best possible care in a manner adherent with ethical and legal standards, as they apply to each case.

BackgroundSuicidal thoughts and behavior (STB) in children are a growing health concern, and more data is needed regarding their biological underpinnings. Immune processes such as inflammation have been associated with STB, primarily in adults. Asthma is a common chronic inflammatory disorder in children and has been associated with STB in adolescent and adult populations, but data in children is lacking. We wished to study associations of asthma with childhood STB given asthma’s potential as a clinically relevant model for childhood chronic immune dysregulation.MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study (N=11,878, 52% males, mean age 9.9 years at baseline assessment and 10.9 years at 1-year follow up), we assessed associations between asthma and STB at both baseline and 1-year follow up.ResultsWe found that asthma at baseline assessment (n=2,214, 18.6%) is associated with STB, controlling for multiple confounders including demographics, socioeconomic factors and environmental confounders such as air pollution (odds ratio (OR)=1.2, 95%CI 1.01-1.42, P=0.039). Indicators of recently active asthma were not significantly associated with suicidality at baseline assessment (currently taking asthma medication: OR=1.22, 95%CI 0.93-1.60, P=0.146), or at 1-year follow up (past year asthma-related clinical visit: OR=1.13, 95%CI 0.87-1.47, P=0.357). Proxy-measures of asthma severity (number of asthma medications or clinical visits) did not reveal a significant dose response relationship with STB.ConclusionsFindings suggest an association between history of asthma and STB in children, which may not be related to asthma disease state. Further research is needed to investigate mechanisms underlying this relationship.

Acute stress during pregnancy can have adverse effects on maternal health and increase the risk for postpartum depression and impaired mother-infant bonding. The COVID-19 pandemic represents an acute environmental stressor during which it is possible to explore risk and resilience factors that contribute to postpartum outcomes. To investigate prenatal risk and resilience factors as predictors of postpartum depression and impaired mother-infant bonding, this study recruited a diverse cohort of 833 pregnant women from an urban medical center in Philadelphia, Pennsylvania, and assessed them once during pregnancy in the early phase of the COVID-19 pandemic (April–July 2020) and again at approximately twelve weeks postpartum. Adverse childhood experiences, prenatal depression and anxiety, and COVID-19-related distress predicted a greater likelihood of postpartum depression. Prenatal depression was the only unique predictor of impaired maternal-infant bonding after postpartum depression was controlled for. Women reporting greater emotion regulation, self-reliance, and nonhostile relationships had healthier postpartum outcomes. Policies to increase the number of nonspecialty providers providing perinatal mental health services as well as reimbursement for integrated care and access to mental health screening and care are needed to improve lifelong outcomes for women and their children.

Psychiatric and cognitive phenotypes have been associated with a range of specific, rare copy number variants (CNVs). Moreover, IQ is strongly associated with CNV risk scores that model the predicted risk of CNVs across the genome. But the utility of CNV risk scores for psychiatric phenotypes has been sparsely examined.To determine how CNV risk scores, common genetic variation indexed by polygenic scores (PGSs), and environmental factors combine to associate with cognition and psychopathology in a community sample.The Philadelphia Neurodevelopmental Cohort is a community-based study examining genetics, psychopathology, neurocognition, and neuroimaging. Participants were recruited through the Children's Hospital of Philadelphia pediatric network. Participants with stable health and fluency in English underwent genotypic and phenotypic characterization from November 5, 2009, through December 30, 2011. Data were analyzed from January 1 through July 30, 2021.The study examined (1) CNV risk scores derived from models of burden, predicted intolerance, and gene dosage sensitivity; (2) PGSs from genomewide association studies related to developmental outcomes; and (3) environmental factors, including trauma exposure and neighborhood socioeconomic status.The study examined (1) neurocognition, with the Penn Computerized Neurocognitive Battery; (2) psychopathology, with structured interviews based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children; and (3) brain volume, with magnetic resonance imaging.Participants included 9498 youths aged 8 to 21 years; 4906 (51.7%) were female, and the mean (SD) age was 14.2 (3.7) years. After quality control, 18 185 total CNVs greater than 50 kilobases (10 517 deletions and 7668 duplications) were identified in 7101 unrelated participants genotyped on Illumina arrays. In these participants, elevated CNV risk scores were associated with lower overall accuracy on cognitive tests (standardized β = 0.12; 95% CI, 0.10-0.14; P = 7.41 × 10-26); lower accuracy across a range of cognitive subdomains; increased overall psychopathology; increased psychosis-spectrum symptoms; and higher deviation from a normative developmental model of brain volume. Statistical models of developmental outcomes were significantly improved when CNV risk scores were combined with PGSs and environmental factors.In this study, elevated CNV risk scores were associated with lower cognitive ability, higher psychopathology including psychosis-spectrum symptoms, and greater deviations from normative magnetic resonance imaging models of brain development. Together, these results represent a step toward synthesizing rare genetic, common genetic, and environmental factors to understand clinically relevant outcomes in youth.

Complex trauma is a significant public health problem in the United States (U.S.), occurring in families with chronic and compounding exposures to traumatic stressors like substance misuse, intimate partner violence (IPV) and child maltreatment (Cook et al., 2017). Yet, few programs exist to treat their intersection, challenging our ability to respond effectively and restore positive trajectories for children and families. In this context, there is a need for innovative approaches to treat these intersecting phenomena. In this conceptual paper, we identify three innovative programs that offer integrative approaches to these intersecting challenges. We analyze common elements among these programs, offering a theoretical foundation for fundamental elements of transformative services. Finally, we consider how the Families First Prevention Act could be leveraged for states to adopt and implement these programs. The goal of this conceptual paper is to advance empirical and practical discussions regarding programmatic and policy options for more effectively responding to substance misuse, and IPV in families, and the associated traumas incurred by maltreated children and their caregivers.

Childhood experiences impact long-term physical and behavioral health outcomes including potential risk for schizophrenia and psychosis. Negative experiences, such as child abuse and neglect, have been specifically associated with risk for schizophrenia and psychosis. This review provides a brief overview of child abuse and neglect, including its position within the larger field of trauma and adversity and its long term consequences. The link to schizophrenia is then explored. Principles of treatment and outcomes for schizophrenia with antecedent child abuse and neglect are then reviewed. Finally, next steps and points of prevention are highlighted.

The COVID-19 pandemic has disproportionately impacted the well-being of vulnerable populations in the US, including Black people. The impact on pregnant women is of special concern for the intrauterine and post-natal development of their offspring. We evaluated in an online survey a sample of 913 pregnant women, 216 Black, 571 White, 126 Other, during a 2-week stay-at-home mandate in the Philadelphia region. We applied logistic regression models and analysis of covariance to examine general and pregnancy-specific worries and negative consequences arising from the COVID-19 pandemic, symptoms of anxiety and depression, and resilience. Black pregnant women reported greater likelihood of having their employment negatively impacted, more concerns about a lasting economic burden, and more worries about their prenatal care, birth experience, and post-natal needs. In the full sample, 11.1% of women met screening criteria for anxiety and 9.9% met criteria for depression. Black women were more likely to meet criteria for depression than White women, but this difference was not significant accounting for covariates. Resilience factors including self-reliance and emotion regulation were higher in Black women. Racial disparities related to COVID-19 in pregnant women can advance the understanding of pregnancy related stressors and improve early identification of mental health needs.

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.

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.

This cross-sectional analysis uses data from the Adoption and Foster Care Analysis and Reporting System to investigate mortality rates among children in the US foster care system compared with those of the general population.

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. Pediatr Blood Cancer 2013;60:1817–1825. © 2013 Wiley Periodicals, Inc.

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.

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.

Research in child abuse pediatrics has advanced clinicians' abilities to discriminate abusive from accidental injuries. Less attention, however, has been paid to cases with uncertain diagnoses. These uncertain cases - the "gray" cases between decisions of abuse and not abuse - represent a meaningful challenge in the practice of child abuse pediatricians. In this study, we describe a series of gray cases, representing 17% of 134 consecutive children who were hospitalized at a single pediatric hospital and referred to a child abuse pediatrician for concerns of possible abuse. Gray cases were defined by scores of 3, 4, or 5 on a 7-point clinical judgment scale of the likelihood of abuse. We evaluated details of the case presentation, including incident history, patient medical and developmental histories, family social histories, medical studies, and injuries from the medical record and sought to identify unique and shared characteristics compared with abuse and accidental cases. Overall, the gray cases had incident histories that were ambiguous, medical and social histories that were more similar to abuse cases, and injuries that were similar to accidental injuries. Thus, the lack of clarity in these cases was not attributable to any single element of the incident, history, or injury. Gray cases represent a clinical challenge in child abuse pediatrics and deserve continued attention in research.

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.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.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.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.

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 αβ 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.

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.

10037 Background: Congenital hepatoblastoma, defined as diagnosis in the first month of life (Ammann RA, Plaschkes JLeibundgut K. Congenital hepatoblastoma: A distinct entity? Med Pediatr Oncol 1999:32:466-468.), has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. Methods: We performed a retrospective review including three patients from the senior authors’ personal series and 23 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94 and HB 99). We then compared this series with the data of all cases of congenital hepatoblastoma previously published in the literature. Results: The overall 2-year survival in our case series was 86% (18/21) with a median followup of 85.5 months (range 44 to 230 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. The infants in our study exhibited a comparable survival rate to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [Tiao GM, Bobey N, Allen S, et al. The current management of hepatoblastoma: A combination of chemotherapy, conventional resection, and liver transplantation. J Pediatr 2005:146:204-211.]. The overall 2-year survival rate of cases previously reported in the literature was 0% (0/11) for patients reported before 1992, and 47% (8/17) for those reported after 1992. 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 HB at this young age is much better than has been historically reported. Conclusions: Congenital hepatoblastoma does not appear to confer a worse prognosis. The overall survival in our series does not appear to be worse than in older children; more rigorous analysis should be conducted in future multicenter trials. It is possible that congenital HB should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy and complete staging is performed.