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Item Sleep and Negative Affect Across Toddlerhood in the Context of Stress(Springer, 2022-06) Sperber, Jessica F.; McQuillan, Maureen E.; Hoyniak, Caroline P.; Staples, Angela D.; Rudasill, Kathleen M.; Molfese, Victoria J.; Bates, John E.; Pediatrics, School of MedicineNegative affect is associated with both high stress and poor sleep, but questions remain about the direction of these associations across time and interactions between stress and sleep, especially in early childhood. The present study examined sleep deficits, family stress, and observed negative affect in a sample of toddlers at 30, 36, and 42 months (N = 504). Negative affect was observed during a parent–child free play task. Sleep was measured via actigraphy. Stress was measured using a cumulative risk index of socioeconomic status, single parent status, household chaos, role overload, parenting hassles, social support, and stressful events. Findings showed few associations between sleep and negative affect, except for toddlers experiencing high levels of family stress. Toddlers experiencing both high stress and poor sleep demonstrated the highest levels of negative affect in the lab at 30 months. Adequate sleep may serve as a protective factor for children in high-stress families.Item Survival outcomes of in-hospital cardiac arrest in pediatric patients in the USA(Springer, 2021-08) Hamzah, Mohammed; Othman, Hasan F.; Almasri, Murad; Al-Subu, Awni; Lutfi, Riad; Pediatrics, School of MedicineWe report on in-hospital cardiac arrest outcomes in the USA. The data were obtained from the National (Nationwide) Inpatient Sample datasets for the years 2000–2017, which includes data from participating hospitals in 47 US states and the District of Columbia. We included pediatric patients (< 18 years of age) with cardiac arrest, and we excluded patients with no cardiopulmonary resuscitation during the hospitalization. Primary outcome of the study was in-hospital mortality after cardiac arrest. A multivariable logistic regression was performed to identify factors associated with survival. A total of 20,654 patients were identified, and 8226 (39.82%) patients survived to discharge. The median length of stay and cost of hospitalization were significantly higher in the survivors vs. non-survivors (LOS 18 days vs. 1 day, and cost $187,434 vs. $45,811, respectively, p < 0.001). In a multivariable model, patients admitted to teaching hospitals, elective admissions, and those admitted on weekdays had higher survival (aOR=1.19, CI: 1.06–1.33; aOR=2.65, CI: 2.37–2.97; and aOR=1.17, CI: 1.07–1.27, respectively). There was no difference in mortality between patients with extracorporeal cardiopulmonary resuscitation (E-CPR) and those with conventional cardiopulmonary resuscitation. E-CPR patients were likely to have congenital heart surgery (51.0% vs. 20.8%). Conclusion: We highlighted the survival predictors in these events, which can guide future studies aimed at improving outcomes in pediatric cardiac arrest.Item Immature teratoma in an adolescent with Proteus syndrome: A novel association(Wiley, 2021-05-04) Underwood, John S.; Ours, Christopher; Burns, R. Cartland; Ferguson, Michael J.; Pediatrics, School of MedicineProteus syndrome (PS) is a complex disorder characterized by variable clinical findings of overgrowth and tumor susceptibility. This report presents the first known association between PS and an ovarian germ cell tumor in an adolescent with immature teratoma. A review of the diagnosis of PS and associated tumors is included.Item Epigenetics and Heart Development(Frontiers Media, 2021-05-06) George, Rajani M.; Firulli, Anthony B.; Pediatrics, School of MedicineEpigenetic control of gene expression during cardiac development and disease has been a topic of intense research in recent years. Advances in experimental methods to study DNA accessibility, transcription factor occupancy, and chromatin conformation capture technologies have helped identify regions of chromatin structure that play a role in regulating access of transcription factors to the promoter elements of genes, thereby modulating expression. These chromatin structures facilitate enhancer contacts across large genomic distances and function to insulate genes from cis-regulatory elements that lie outside the boundaries for the gene of interest. Changes in transcription factor occupancy due to changes in chromatin accessibility have been implicated in congenital heart disease. However, the factors controlling this process and their role in changing gene expression during development or disease remain unclear. In this review, we focus on recent advances in the understanding of epigenetic factors controlling cardiac morphogenesis and their role in diseases.Item Deletion of a Hand1 lncRNA-Containing Septum Transversum Enhancer Alters lncRNA Expression but Is Not Required for Hand1 Expression(MDPI, 2021-05-04) George, Rajani M.; Firulli, Anthony B.; Pediatrics, School of MedicineWe have previously identified a Hand1 transcriptional enhancer that drives expression within the septum transversum, the origin of the cells that contribute to the epicardium. This enhancer directly overlaps a common exon of a predicted family of long non-coding RNAs (lncRNA) that are specific to mice. To interrogate the necessity of this Hand1 enhancer, as well as the importance of these novel lncRNAs, we deleted the enhancer sequences, including the common exon shared by these lncRNAs, using genome editing. Resultant homozygous Hand1 enhancer mutants (Hand1ΔST/ΔST) present with no observable phenotype. Assessment of lncRNA expression reveals that Hand1ΔST/ΔST mutants effectively eliminate detectable lncRNA expression. Expression analysis within Hand1ΔST/ΔST mutant hearts indicates higher levels of Hand1 than in controls. The generation of Hand1 compound heterozygous mutants with the Hand1LacZ null allele (Hand1ΔST/LacZ) also did not reveal any observable phenotypes. Together these data indicate that deletion of this Hand1 enhancer and by consequence a family of murine-specific lncRNAs does not impact embryonic development in observable ways.Item Acute Peroneal Neuropathy and Foot Drop in Two Adolescent Female Athletes with New-Onset Diabetes(Wolters Kluwer, 2022-02) Jaeger, Joel A.; Gohil, Anisha; Nebesio, Todd D.; Pediatrics, School of MedicineThe common peroneal nerve is derived from the sciatic nerve. It travels superficially along the lateral aspect of the knee near the fibular head where it bifurcates into the superficial and deep peroneal nerves. These nerves also provide sensation to the lateral lower leg and dorsal foot. The superficial and deep peroneal nerves innervate the muscles of the lateral lower leg and anterior lower leg compartments, respectively. Loss of the soft tissue and subcutaneous fat pad that surrounds and cushions the peroneal nerve near the fibular head leaves it susceptible to injury (1). This can affect the common peroneal nerve or either of its two branches, the deep or superficial peroneal nerves (2). Damage to the nerve by stretching or compression may result in loss of sensation and motor function, resulting in foot drop (3). Acute peroneal neuropathy in the context of rapid weight loss (also known as “slimmer's paralysis”) has been reported in prisoners of war, extreme dieting, and after bariatric surgery (2,4). It also is more common in individuals who habitually cross their legs (2). While seen less commonly than in adults, acute peroneal neuropathy also has been reported in children and adolescents (5). Etiologies in this age group include direct trauma, entrapment from bone tumors, compression from casting, and rapid weight loss (5,6). Causes of sudden and quick weight loss may be due to crash dieting and anorexia nervosa (6). There also are rare reports of slimmer's paralysis being caused by rapid weight loss from untreated type 1 diabetes (7,8). In this report, we present two active adolescent female athletes who presented with ankle pain or weakness that was ultimately due to acute peroneal nerve neuropathy associated with substantial and fast weight loss from undiagnosed type 1 diabetes.Item Anemia as a Marker of Social Determinants of Health: Then and Now(Elsevier, 2022-10) Sherwin, Nomi K.; Ott, Mary A.Item Curing Hemophilia: Repeated Treatments versus a One-Off Fix(Elsevier, 2020-05-06) Li, Ning; Kaczmarek, Radoslaw; Pediatrics, School of MedicineItem Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis(Springer, 2021-04-19) Dittrich, Gesine M.; Froese, Natali; Wang, Xue; Kroeger, Hannah; Wang, Honghui; Szaroszyk, Malgorzata; Malek‑Mohammadi, Mona; Cordero, Julio; Keles, Merve; Korf‑Klingebiel, Mortimer; Wollert, Kai C.; Geffers, Robert; Mayr, Manuel; Conway, Simon J.; Dobreva, Gergana; Bauersachs, Johann; Heineke, Joerg; Pediatrics, School of MedicineHeart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling remain poorly understood. Cardiac fibroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fibroblasts during stress is not known. Here, we show that fibroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specific single or double deletion of Gata4 and Gata6 in stress activated fibroblasts, we found a reduced myocardial capillarization in mice with Gata4/6 double deletion following pressure overload, while single deletion of Gata4 or Gata6 had no effect. Importantly, we confirmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fibroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fibroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identified a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fibroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.Item Equivalent Behavioral Facilitation to Tactile Cues in Children with Autism Spectrum Disorder(MDPI, 2021-05-13) Kadlaskar, Girija; Bergmann, Sophia; McNally Keehn, Rebecca; Seidl, Amanda; Keehn, Brandon; Pediatrics, School of MedicineThe alerting network, a subcomponent of attention, enables humans to respond to novel information. Children with ASD have shown equivalent alerting in response to visual and/or auditory stimuli compared to typically developing (TD) children. However, it is unclear whether children with ASD and TD show equivalent alerting to tactile stimuli. We examined (1) whether tactile cues affect accuracy and reaction times in children with ASD and TD, (2) whether the duration between touch-cues and auditory targets impacts performance, and (3) whether behavioral responses in the tactile cueing task are associated with ASD symptomatology. Six- to 12-year-olds with ASD and TD participated in a tactile-cueing task and were instructed to respond with a button press to a target sound /a/. Tactile cues were presented at 200, 400, and 800 ms (25% each) prior to the auditory target. The remaining trials (25%) were presented without tactile cues. Findings suggested that both groups showed equivalent alerting responses to tactile cues. Additionally, all children were faster to respond to auditory targets at longer cue-target intervals. Finally, there was an association between rate of facilitation and RRB scores in all children, suggesting that patterns of responding to transient phasic cues may be related to ASD symptomatology.