Advocate Children's Hospital

Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased expression of SIRT3 has been linked to an extended life span in humans. Here, we have shown that Sirt3 protects the mouse heart by blocking the cardiac hypertrophic response. Although Sirt3-deficient mice appeared to have normal activity, they showed signs of cardiac hypertrophy and interstitial fibrosis at 8 weeks of age. Application of hypertrophic stimuli to these mice produced a severe cardiac hypertrophic response, whereas Sirt3-expressing Tg mice were protected from similar stimuli. In primary cultures of cardiomyocytes, Sirt3 blocked cardiac hypertrophy by activating the forkhead box O3a-dependent (Foxo3a-dependent), antioxidant-encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. Reduced ROS levels suppressed Ras activation and downstream signaling through the MAPK/ERK and PI3K/Akt pathways. This resulted in repressed activity of transcription factors, specifically GATA4 and NFAT, and translation factors, specifically eukaryotic initiation factor 4E (elf4E) and S6 ribosomal protein (S6P), which are involved in the development of cardiac hypertrophy. These results demonstrate that SIRT3 is an endogenous negative regulator of cardiac hypertrophy, which protects hearts by suppressing cellular levels of ROS.

OBJECTIVES: This study was designed to determine the frequency of 22q11 deletions in a large, prospectively ascertained sample of patients with conotruncal defects and to evaluate the deletion frequency when additional cardiac findings are also considered. BACKGROUND: Chromosome 22q11 deletions are present in the majority of patients with DiGeorge, velocardiofacial and conotruncal anomaly face syndromes in which conotruncal defects are a cardinal feature. Previous studies suggest that a substantial number of patients with congenital heart disease have a 22q11 deletion. METHODS: Two hundred fifty-one patients with conotruncal defects were prospectively enrolled into the study and screened for the presence of a 22q11 deletion. RESULTS: Deletions were found in 50.0% with interrupted aortic arch (IAA), 34.5% of patients with truncus arteriosus (TA), and 15.9% with tetralogy of Fallot (TOF). Two of 6 patients with a posterior malalignment type ventricular septal defect (PMVSD) and only 1 of 20 patients with double outlet right ventricle were found to have a 22q11 deletion. None of the 45 patients with transposition of the great arteries had a deletion. The frequency of 22q11 deletions was higher in patients with anomalies of the pulmonary arteries, aortic arch or its major branches as compared to patients with a normal left aortic arch regardless of intracardiac anatomy. CONCLUSIONS: A substantial proportion of patients with IAA, TA, TOF and PMVSD have a deletion of chromosome 22q11. Deletions are more common in patients with aortic arch or vessel anomalies. These results begin to define guidelines for deletion screening of patients with conotruncal defects.

Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of PARP1, which is independent of DNA damage. SIRT1 physically binds to and deacetylates PARP1. Increased acetylation of PARP1 was also detected in hearts of SIRT1(-/-) mice, compared to that detected in the hearts of SIRT1(+/+) mice, confirming a role of SIRT1 in regulating the PARP1 acetylation in vivo. SIRT1-dependent deacetylation blocks PARP1 activity, and it protects cells from PARP1-mediated cell death. We also show that SIRT1 negatively regulates the activity of the PARP1 gene promoter, thus suggesting that the deacetylase controls the PARP1 activity at the transcriptional level as well. These data demonstrate that the activity of PARP1 is under the control of SIRT1, which is necessary for survival of cells under stress conditions.

Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play a significant role in the cardiac dysfunction in diabetic cardiomyopathy. The mechanism of SERCA2a repression is, however, not known. This study was designed to examine the effect of resveratrol (RSV), a potent activator of SIRT1, on cardiac function and SERCA2a expression in chronic type 1 diabetes. Adult male mice were injected with streptozotocin (STZ) and fed with either a regular diet or a diet enriched with RSV. STZ administration produced progressive decline in cardiac function, associated with markedly reduced SERCA2a and SIRT1 protein levels and increased collagen deposition; RSV treatment to these mice had a tremendous beneficial effect both in terms of improving SERCA2a expression and on cardiac function. In cultured cardiomyocytes, RSV restored SERCA2 promoter activity, which was otherwise highly repressed in high-glucose media. Protective effects of RSV were found to be dependent on its ability to activate Silent information regulator (SIRT) 1. In cardiomyocytes, overexpression of SIRT1 was found sufficient to activate SERCA2 promoter in a dose-dependent manner. In contrast, pretreatment of cardiomyocytes with SIRT1 antagonist, splitomycin, blocked these beneficial effects of RSV. In addition, SIRT1 knockout (+/-) mice were also found to be more sensitive to STZ-induced decline in SERCA2a mRNA. The data demonstrate that, in chronic diabetes, 1) the enzymatic activity of cardiac SIRT1 is reduced, which contributes to reduced expression of SERCA2a and 2) through activation of SIRT1, RSV enhances expression of SERCA2a and improves cardiac function.

Over the past decade, there have been widespread efforts to raise awareness about maltreatment of children. Pediatric providers have received education about factors that make a child more vulnerable to being abused and neglected. The purpose of this clinical report is to ensure that children with disabilities are recognized as a population at increased risk for maltreatment. This report updates the 2007 American Academy of Pediatrics clinical report "Maltreatment of Children With Disabilities." Since 2007, new information has expanded our understanding of the incidence of abuse in this vulnerable population. There is now information about which children with disabilities are at greatest risk for maltreatment because not all disabling conditions confer the same risks of abuse or neglect. This updated report will serve as a resource for pediatricians and others who care for children with disabilities and offers guidance on risks for subpopulations of children with disabilities who are at particularly high risk of abuse and neglect. The report will also discuss ways in which the medical home can aid in early identification and intervene when abuse and neglect are suspected. It will also describe community resources and preventive strategies that may reduce the risk of abuse and neglect.

BACKGROUND: The number of adolescents with chronic health conditions (CHCs) continues to increase. Medication nonadherence is a global challenge among adolescents across chronic conditions and is associated with poor health outcomes. While there has been growing interest in the use of mHealth technology to improve medication adherence among adolescents with CHCs, particularly text messaging and mobile phone apps, there has been no prior systematic review of their efficacy. OBJECTIVE: The purpose of this review was to systematically evaluate the most recent evidence for the efficacy of text messaging and mobile phone apps as interventions to promote medication adherence among adolescents with CHCs. METHODS: PubMed, Embase, CENTRAL, PsycINFO, Web of Science, Google Scholar, and additional databases were searched from 1995 until November 2015. An additional hand search of related themes in the Journal of Medical Internet Research was also conducted. The Preferred Reporting Results of Systematic Reviews and Meta-Analyses guidelines were followed. Two reviewers independently screened titles/abstracts, assessed full-text articles, extracted data from included articles, and assessed their quality using Grades of Recommendation, Assessment, Development, and Evaluation criteria. Included studies were described in original research articles that targeted adherence in adolescents with CHCs (12-24 years-old). RESULTS: Of the 1423 records examined, 15 met predefined criteria: text messaging (n=12) and mobile phone apps (n=3). Most studies were performed in the United States (11/15, 73%), were randomized-controlled trials (8/15, 53%), had a sample size <50 (11/15, 73%), and included adherence self-report and/or biomarkers (9/15, 60%). Only four studies were designed based on a theoretical framework. Approaches for text messaging and mobile phone app interventions varied across studies. Seven articles (7/15, 47%) reported significant improvement in adherence with moderate to large standardized mean differences. Most of the included studies were of low or moderate quality. Studies varied in sample size, methods of adherence assessment, and definition of adherence, which prohibited performing a meta-analysis. CONCLUSIONS: The use of text messaging and mobile phone app interventions to improve medication adherence among adolescents with CHCs has shown promising feasibility and acceptability, and there is modest evidence to support the efficacy of these interventions. Further evaluation of short- and long-term efficacy and cost-effectiveness of these interventions is warranted given the early and evolving state of the science.

BACKGROUND: Fetal tachycardia complicated by ventricular dysfunction and hydrops fetalis carries a significant risk of morbidity and mortality. Transplacental digoxin is effective therapy in a small percentage, but there is no consensus with regard to antiarrhythmic treatment if digoxin fails. This study evaluates the safety, efficacy, and outcome of amiodarone therapy for digoxin-refractory fetal tachycardia with heart failure. METHODS AND RESULTS: Fetuses with incessant tachycardia and either hydrops fetalis (n=24) or ventricular dysfunction (n=2) for whom digoxin monotherapy and secondary antiarrhythmic agents (n=13) were not effective were treated transplacentally with a loading dose of oral amiodarone for 2 to 7 days, followed by daily maintenance therapy for <1 to 15 weeks. Digoxin therapy was continued throughout gestation. Newborns were studied by transesophageal pacing or ECG monitoring to determine the mechanism of tachycardia. Three fetuses were delivered urgently in tachycardia during amiodarone loading, and 3 required additional antiarrhythmic agents for sustained cardioversion. Amiodarone or amiodarone combinations converted 14 of 15 (93%) with reentrant supraventricular tachycardia, 2 of 2 with ventricular or junctional ectopic tachycardia, and 3 of 9 (33%) with atrial flutter. Amiodarone-related adverse effects were transient in 5 infants and 8 mothers. Mean gestational age at delivery was 37 weeks, with 100% survival. CONCLUSIONS: Orally administered amiodarone is safe and effective treatment for drug-refractory fetal tachycardia, specifically reentrant supraventricular tachycardia, junctional ectopic, or ventricular tachycardia, even when accompanied by hydrops fetalis or ventricular dysfunction.

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

Importance: Bruising caused by physical abuse is the most common antecedent injury to be overlooked or misdiagnosed as nonabusive before an abuse-related fatality or near-fatality in a young child. Bruising occurs from both nonabuse and abuse, but differences identified by a clinical decision rule may allow improved and earlier recognition of the abused child. Objective: To refine and validate a previously derived bruising clinical decision rule (BCDR), the TEN-4 (bruising to torso, ear, or neck or any bruising on an infant <4.99 months of age), for identifying children at risk of having been physically abused. Design, Setting, and Participants: This prospective cross-sectional study was conducted from December 1, 2011, to March 31, 2016, at emergency departments of 5 urban children's hospitals. Children younger than 4 years with bruising were identified through deliberate examination. Statistical analysis was completed in June 2020. Exposures: Bruising characteristics in 34 discrete body regions, patterned bruising, cumulative bruise counts, and patient's age. The BCDR was refined and validated based on these variables using binary recursive partitioning analysis. Main Outcomes and Measures: Injury from abusive vs nonabusive trauma was determined by the consensus judgment of a multidisciplinary expert panel. Results: A total of 21 123 children were consecutively screened for bruising, and 2161 patients (mean [SD] age, 2.1 [1.1] years; 1296 [60%] male; 1785 [83%] White; 1484 [69%] non-Hispanic/Latino) were enrolled. The expert panel achieved consensus on 2123 patients (98%), classifying 410 (19%) as abuse and 1713 (79%) as nonabuse. A classification tree was fit to refine the rule and validated via bootstrap resampling. The resulting BCDR was 95.6% (95% CI, 93.0%-97.3%) sensitive and 87.1% (95% CI, 85.4%-88.6%) specific for distinguishing abuse from nonabusive trauma based on body region bruised (torso, ear, neck, frenulum, angle of jaw, cheeks [fleshy], eyelids, and subconjunctivae), bruising anywhere on an infant 4.99 months and younger, or patterned bruising (TEN-4-FACESp). Conclusions and Relevance: In this study, an affirmative finding for any of the 3 BCDR TEN-4-FACESp components in children younger than 4 years indicated a potential risk for abuse; these results warrant further evaluation. Clinical application of this tool has the potential to improve recognition of abuse in young children with bruising.

Serum response factor (SRF) plays a pivotal role in cardiac myocyte development, muscle gene transcription, and hypertrophy. Previously, elevation of intracellular levels of Ca2+ was shown to activate SRF function without involving the Ets family of tertiary complex factors through an unknown regulatory mechanism. Here, we tested the hypothesis that the chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca2+-sensitive manner. Expression of HDAC4 profoundly repressed SRF-mediated transcription in both muscle and nonmuscle cells. Protein interaction studies demonstrated physical association of HDAC4 with SRF in living cells. The SRF/HDAC4 co-association was disrupted by treatment of cells with hypertrophic agonists such as angiotensin-II and a Ca2+ ionophore, ionomycin. Furthermore, activation of Ca2+/calmodulin-dependent protein kinase (CaMK)-IV prevented SRF/HDAC4 interaction and derepressed SRF-dependent transcription activity. The SRF·HDAC4 complex was localized to the cell nucleus, and the activated CaMK-IV disrupted HDAC4/SRF association, leading to export of HDAC4 from the nucleus and stimulation of SRF transcription activity. Thus, these results identify SRF as a functional interacting target of HDAC4 and define a novel tertiary complex factor-independent mechanism for SRF activation by Ca2+/CaMK-mediated signaling. Serum response factor (SRF) plays a pivotal role in cardiac myocyte development, muscle gene transcription, and hypertrophy. Previously, elevation of intracellular levels of Ca2+ was shown to activate SRF function without involving the Ets family of tertiary complex factors through an unknown regulatory mechanism. Here, we tested the hypothesis that the chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca2+-sensitive manner. Expression of HDAC4 profoundly repressed SRF-mediated transcription in both muscle and nonmuscle cells. Protein interaction studies demonstrated physical association of HDAC4 with SRF in living cells. The SRF/HDAC4 co-association was disrupted by treatment of cells with hypertrophic agonists such as angiotensin-II and a Ca2+ ionophore, ionomycin. Furthermore, activation of Ca2+/calmodulin-dependent protein kinase (CaMK)-IV prevented SRF/HDAC4 interaction and derepressed SRF-dependent transcription activity. The SRF·HDAC4 complex was localized to the cell nucleus, and the activated CaMK-IV disrupted HDAC4/SRF association, leading to export of HDAC4 from the nucleus and stimulation of SRF transcription activity. Thus, these results identify SRF as a functional interacting target of HDAC4 and define a novel tertiary complex factor-independent mechanism for SRF activation by Ca2+/CaMK-mediated signaling. Serum response factor (SRF) 1The abbreviations used are: SRF, serum response factor; SRE, serum response element; DAPI, 4′,6-diamidino-2-phenylindole; HAT, histone acetyltransferase(s); HDAC, histone deacetylase; CREB, cAMP-response element-binding protein; PBS, phosphate-buffered saline; CaMK, Ca2+/calmodulin-dependent protein kinase; HA, hemagglutinin; TRITC, tetramethylrhodamine isothiocyanate; TSA, trichostatin A; FITC, fluorescein isothiocyanate; SRF-FL, full-length SRF; ANF, atrial naturatic factor; MHC, myosin heavy chain.1The abbreviations used are: SRF, serum response factor; SRE, serum response element; DAPI, 4′,6-diamidino-2-phenylindole; HAT, histone acetyltransferase(s); HDAC, histone deacetylase; CREB, cAMP-response element-binding protein; PBS, phosphate-buffered saline; CaMK, Ca2+/calmodulin-dependent protein kinase; HA, hemagglutinin; TRITC, tetramethylrhodamine isothiocyanate; TSA, trichostatin A; FITC, fluorescein isothiocyanate; SRF-FL, full-length SRF; ANF, atrial naturatic factor; MHC, myosin heavy chain. is a key regulator of several extracellular stimuli-regulated genes important for cell growth, apoptosis, and differentiation. SRF was first identified by its ability to confer the serum-activated expression of the c-fos gene in replicating cells (1Greenberg M.E. Siegfried Z. Ziff E.B. Mol. Cell. Biol. 1987; 7: 1217-1225Crossref PubMed Scopus (154) Google Scholar). Paradoxically, SRF was also found to regulate expression of several muscle genes, which are expressed specifically in postmitotic myocytes (2Boxer L.M. Prywes R. Roeder R.G. Kedes L. Mol. Cell. Biol. 1989; 9: 515-522Crossref PubMed Scopus (116) Google Scholar). SRF acts through binding as a homodimer to the DNA consensus sequence CC(A/T)6GG, the serum response element (SRE), also referred as the CArG box, which is found essential for tissue-specific expression of numerous striated as well as smooth muscle-specific genes (2Boxer L.M. Prywes R. Roeder R.G. Kedes L. Mol. Cell. Biol. 1989; 9: 515-522Crossref PubMed Scopus (116) Google Scholar, 3Treisman R. Curr. Opin. Gen. Dev. 1994; 4: 96-101Crossref PubMed Scopus (618) Google Scholar). SRF plays a central role in the induction and maintenance of cardiac myogenic program, as exemplified by disruption of the SRF gene, which prevented mesoderm differentiation and cardiac development (4Arsenian S. Weinhold B. Oelgeschlager M. Ruther U. Nordheim A. EMBO J. 1998; 17: 6289-6299Crossref PubMed Scopus (305) Google Scholar). SRF is differentially expressed in embryonic and adult cardiac myocytes, being at least 2 orders of magnitude greater than those detected in cells of endodermal origin (5Belaguli N.S. Schildmeyer L.A. Schwartz R.J. J. Biol. Chem. 1997; 272: 18222-18231Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). SRF has the ability to physically interact and synergistically cooperate with many other known cardiac-myogenic factors, such as GATA-4, Nkx2.5, TEF-1, myocardin, and CRP1/2 (6Belaguli N.S. Sepulveda J.L. Nigam V. Charron F. Nemer M. Schwartz R.J. Mol. Cell. Biol. 2000; 20: 7550-7558Crossref PubMed Scopus (155) Google Scholar, 7Chen C.Y. Schwartz R.J. Mol. Cell. Biol. 1996; 16: 6372-6384Crossref PubMed Google Scholar, 8Gupta M. Kogut P. Davis F.J. Belaguli N.S. Schwartz R.J. Gupta M.P. J. Biol. Chem. 2001; 276: 10413-10422Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 9Wang D. Chang P.S. Wang Z. Sutherland L. Richardson J.A. Small E. Krieg P.A. Olson E.N. Cell. 2001; 105: 851-862Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar, 10Chang D.F. Belaguli N.S. Iyer D. Roberts W.B. Wu S.P. Dong X.R. Marx J.G. Moore M.S. Beckerle M.C. Majesky M.W. Schwartz R.J. Dev. Cell. 2003; 4: 107-118Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). CArG in the of several and protein genes a role of SRF in (6Belaguli N.S. Sepulveda J.L. Nigam V. Charron F. Nemer M. Schwartz R.J. Mol. Cell. Biol. 2000; 20: 7550-7558Crossref PubMed Scopus (155) Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Wang Belaguli N.S. Schwartz R.J. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of also that are the in with of hypertrophic to cardiac response induction of gene of genes in the embryonic activation of ANF, and genes, and of and P. Belaguli N.S. Schwartz R.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Prywes R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, 1998; Full Text Full Text PDF Google Scholar, J. P. J. J. J. 2001; PubMed Google Scholar, J. A. Mol. Cell. Biol. Scopus Google Scholar). the mechanism that SRF to intracellular to the hypertrophic response of cardiac myocytes is shown to regulate the SRF transcription physical interaction of SRF with a of and (6Belaguli N.S. Sepulveda J.L. Nigam V. Charron F. Nemer M. Schwartz R.J. Mol. Cell. Biol. 2000; 20: 7550-7558Crossref PubMed Scopus (155) Google Scholar, 7Chen C.Y. Schwartz R.J. Mol. Cell. Biol. 1996; 16: 6372-6384Crossref PubMed Google Scholar, 8Gupta M. Kogut P. Davis F.J. Belaguli N.S. Schwartz R.J. Gupta M.P. J. Biol. Chem. 2001; 276: 10413-10422Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 9Wang D. Chang P.S. Wang Z. Sutherland L. Richardson J.A. Small E. Krieg P.A. Olson E.N. Cell. 2001; 105: 851-862Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar, 10Chang D.F. Belaguli N.S. Iyer D. Roberts W.B. Wu S.P. Dong X.R. Marx J.G. Moore M.S. Beckerle M.C. Majesky M.W. Schwartz R.J. Dev. Cell. 2003; 4: 107-118Abstract Full Text Full Text PDF PubMed Scopus Google in the DNA protein binding ability of SRF R. Nordheim A. EMBO J. PubMed Scopus Google of SRF B. B. J. Kogut P. E. S. M.S. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google and of SRF J. 2000; PubMed Google Scholar, N.S. Majesky M.W. Schwartz R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar). we shown that an of SRF is expressed in the of both and which as a to SRF-dependent cardiac muscle gene expression F.J. Gupta M. E. V. Gupta M.P. J. 2001; Scholar). the mechanism of SRF in the hypertrophic of cardiac myocytes, several to the role of histone and deacetylases in SRF-mediated cardiac muscle gene the of histone deacetylases the chromatin that the of DNA to transcription enzymes are as the of genes, with transcription factors in expression of the target gene A. Curr. Opin. Biol. 1997; 7: Full Text Full Text PDF Scopus Google Scholar). differentiation of cells to smooth muscle SRF was shown to to target genes with of at smooth muscle-specific regulatory of chromatin 2001; PubMed Scopus Google Scholar). SRF and the cAMP-response element binding protein was shown to the CArG of the gene activation P. L. PubMed Scopus Google Scholar). SRF also physically with the CArG activation of the c-fos gene expression S. S. P. D. A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). activation of SRF function the c-fos was chromatin was that histone is for the of intracellular to response a CArG mechanism R. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). several myogenic factors, and shown to with leading to a in muscle gene activation V. V. Wu Wang Kedes L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, V. J. Kedes L. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar, J. Olson E.N. U. S. A. 2000; PubMed Scopus Google Scholar). these a of SRF-mediated cardiac muscle gene transcription also by histone and is by hypertrophic that cardiac muscle gene in class II as to class the of class which and shown to tissue-specific HDAC4 and are expressed at levels in the and to in cell differentiation and development E. D. J. 2001; PubMed Scopus Google Scholar, U. S. A. PubMed Scopus Google Scholar, M. M. J. J. Mol. Cell. Biol. PubMed Scopus Google Scholar). we that SRF with HDAC4 in cardiac myocytes its in of SRF gene activation to the nucleus of cardiac also that the SRF/HDAC4 association is a target for that intracellular Ca2+ levels and activate hypertrophic of The activity of results in of SRF from leading to export of HDAC4 from the nucleus and of the SRF activity. results that the transcription activity of SRF is by HDAC4 and that is activation of signaling. The of SRF transcription activity in through from a key regulatory mechanism in and intracellular that activate SRF-dependent cardiac muscle gene of cardiac myocytes from as and A. Mol. Cell. Scholar). to myocytes a and at a of in with in with serum and and and cells in at a of and in with serum and to the The was used as a in cells and cell and for and protein protein as as a at the of and by of and E. J. EMBO J. PubMed Scopus Google Scholar). for and expression and C.Y. Schwartz R.J. Mol. Cell. 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Cell. 2001; 105: 851-862Abstract Full Text Full Text PDF PubMed Scopus (732) Google Scholar). of to was with in a protein interaction of the 2 2 and that to the role of Ca2+ the binding of SRF and the protein interaction was by the of of Ca2+ The binding was a The at for with protein interaction and in and to and detected by of and in a and for at a binding with and of was to binding and the was to for at and at with for an The and with by at for in of by for and a protein was a the of SRF for its interaction with with the of SRF and to as and by of was in a kinase and in a was to at to at for of the kinase was to to of the a known with of and as and in of Protein to and by with kinase and The binding was in a of of the of the and of The binding of and at for the and was at in a in a and DNA the was with at for in the to the of the DNA was CArG and cells with DNA and to the with PBS, with for with and with from with a serum and with at for 2 of we the of full-length we the cells the with a and a with a in was by in was and was by and and was a and by with was in the at the of HDAC4 the of the hypothesis that a functional SRF and cells with of expression full-length SRF HDAC4 and the to the The of gene used CArG and several other of HDAC4 the activity of the gene in cells as well as in SRF activated expression of the gene in both cell SRF was with the of SRF was used an which has and of the CArG to was through SRF binding to the CArG The activity of was also repressed by of HDAC4 HDAC4 SRF-mediated activation of the gene activity. 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Opin. 2001; PubMed Scopus Google Scholar). with without expression of HDAC4 with for these of HDAC4 was by and results that the of HDAC4 was by the treatment the ability of HDAC4 to SRF-mediated gene transcription as to in the of SRF-dependent gene transcription was in cells and in by treatment of with the hypothesis that SRF activity is by histone results that activity of HDAC4 the mechanism to of the SRF transcription activity. transcription activity by with such as protein V. J. Kedes L. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). the of HDAC4 SRF function in from with the activity of we the of HDAC4 gene cells with of expression HDAC4 with the shown in of activated the gene activity by of HDAC4 as well as the the in a of the gene activity by Thus, HDAC4 repressed the SRF transcription activity in by the activity of the SRF to HDAC4 has shown to to SRF in living cells S. S. P. D. A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). 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Gupta M. E. V. Gupta M.P. J. 2001; with was and by CArG as a as well as SRF and HDAC4 used to the and of shown in cell and of of HDAC4 with SRF the of complex by as demonstrated by of the cell with and of the of the with in the of the Furthermore, of HDAC4 and SRF the complex and was with results that HDAC4 of the SRF complex to the with a HDAC4 being of the complex the muscle-specific J. Olson E.N. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Ca2+ and that the association is in we in intracellular that regulate interaction of these hypertrophic is Ca2+ the SRF/HDAC4 we of cardiac myocytes with a Ca2+ at of and cell was and to to of the of myocytes of The results from that the HDAC4/SRF association was of treatment with and by the and of treatment of myocytes results by angiotensin-II treatment of was in and results that hypertrophic in intracellular disrupted the Ca2+ with we of Ca2+ SRF/HDAC4 association in an in of and in a binding with of from to by of protein binding by the The results that the physical interaction of the was as the of with binding at Furthermore, the of in the binding with levels of Ca2+ the association of SRF with HDAC4 for of the SRF/HDAC4 association is that the of used in the of other for protein results demonstrated that Ca2+ with SRF/HDAC4 association in with an of binding in the of levels of Ca2+ J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). such a of Ca2+ in a living we in of of the of intracellular Ca2+ levels is the activation of and of SRF and HDAC4 shown to for A. M. M.E. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). has also that in cardiac myocytes as well as in a of CaMK-IV R. F.J. Richardson J.A. Olson E.N. J. 2000; 105: PubMed Scopus Google Scholar). of SRF HDAC4 binding we both to in and in a kinase in the of CaMK-IV and The of protein was by and HDAC4 of was as The of protein interaction ability was by the shown in HDAC4 with and HDAC4 to to and results that of HDAC4 its ability to to SRF, of SRF CaMK-IV of SRF disruption of complex activate the SRF transcription activity by of tested hypothesis by in which cells with of expression SRF with a SRF binding shown in of CaMK-IV the of the SRF activity in a with of SRF function at an of the the CaMK-IV and the of of the SRF a of CaMK-IV the of CaMK-IV of we activated CaMK-IV the intracellular of shown in cells HDAC4 a of which to to association with as with of of HDAC4 in cells U. S. A. PubMed Scopus Google Scholar). of cells both SRF and HDAC4 a in of HDAC4 SRF to in a of cells expression of SRF as well of cardiac myocytes also SRF as well as HDAC4 of both cells SRF and HDAC4 with both in cells and in cardiac myocytes, in of HDAC4 to the and is with from transcription in which was to of the SRF transcription activity. these results that of HDAC4 by CaMK-IV the leading to the export of HDAC4 from the nucleus and of SRF transcription of expressed HDAC4 in cardiac as and and with and with without cells and with and with for The was also by and of from with as in and in cardiac myocytes of CaMK-IV of HDAC4 in these cells and studies identify SRF as a and functional target of a class II histone that SRF physically with HDAC4 in cardiac myocytes as well as in nonmuscle leading to the of HDAC4 to the cell The functional of HDAC4/SRF interaction is of SRF-mediated gene also that protein interaction is to Ca2+ levels and to activation of by hypertrophic of leading to of HDAC4 to and the SRF gene activation of of SRF function by hypertrophic genes, such as of the gene cardiac hypertrophy. HDAC4 SRF deacetylases gene transcription by of the of which results in chromatin as of the of genes by with other transcription factors with transcription E. J. EMBO J. PubMed Scopus Google Scholar, V. F. E. Biol. 2001; PubMed Scopus Google Scholar). of from both in and in a role of HDAC4 in of the SRF transcription activity. HDAC4 with SRF of SRF binding to CArG are to a of and HDAC4 SRF-mediated gene expression of cell muscle nonmuscle cell other of the class II family of functional at of the The is to the and has activity M. M. J. J. Mol. Cell. Biol. PubMed Scopus Google the has in interaction with transcription factors, the family of factors, and the protein V. F. E. Biol. 2001; PubMed Scopus Google Scholar, U. S. A. 2000; PubMed Scopus Google Scholar, Olson E.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). HDAC4 to DNA is these of the protein and protein to which its function is by a of that was than the HDAC4 was to SRF function to a in the of a histone TSA, that the a was the mechanism by which HDAC4 SRF-dependent gene that the of HDAC4 the ability to to other histone deacetylases of class and II and that in SRF function other studies also demonstrated that from the activity of HDAC4 are in transcription as well as in of muscle cell differentiation J. Olson E.N. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Olson E.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). mechanism by which HDAC4 SRF function is by binding of to to the of SRF demonstrated that the of of SRF is for its binding to The has also shown to to the and to activate the transcription activity of as well as SRF S. S. P. D. A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, V. J. Kedes L. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). both the and the of HDAC4 the gene activation by and that the of HDAC4 is to HDAC4 and to to Previously, has shown to with in binding to of J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). for repressed SRF function is that the association of SRF with HDAC4 in the of DNA results in a in SRF that its DNA binding activity shown in its transcription these to are the DNA binding activity of SRF has for by its in J. A. Mol. Cell. Biol. Scopus Google Scholar). of we demonstrated of HDAC4 and SRF in cardiac are of of HDAC4 in cardiac myocytes, its in muscle cells has to the cells in J. Olson E.N. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Olson E.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). we that of HDAC4 plays an important role in the of cardiac we found that HDAC4 has SRF with a of that SRF of HDAC4 to the cell is to a of of the of HDAC4 U. S. A. 2000; PubMed Scopus Google Scholar, S. S. F. R. S. J. 2001; PubMed Google Scholar). Thus, that SRF, to is of of its the cell the of cardiac myocytes, is that levels of SRF are to of HDAC4 expressed HDAC4 is in the nucleus of cardiac myocytes as a of an as activation of the was shown to of HDAC4 in cells Wang P.A. U. S. A. 2000; PubMed Scopus Google Scholar). the is known to an important role in transcription of a of cardiac genes as well as in the induction and of R. F.J. Richardson J.A. Olson E.N. J. 2000; 105: PubMed Scopus Google Scholar). the role of SRF in the activation of cardiac muscle gene expression was that association of SRF with a was by signaling. SRF-dependent transcription of the c-fos gene was shown to activated by intracellular levels of Ca2+ that activation of the Ets family of tertiary complex factors M.E. Mol. Cell. Biol. PubMed Scopus Google Scholar). CaMK-IV and are shown of SRF at of in intracellular Ca2+ levels A. M. M.E. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). an in the activity of SRF in response to levels of from that such as of SRF are in the of such protein of SRF is found that of HDAC4 SRF, by CaMK-IV was of the HDAC4/SRF in the of CaMK-IV was of of the SRF activity. with these we also demonstrated of HDAC4 in response to activity both in cardiac myocytes as well as in cells. the in its intracellular for the of the of in its to the cell nucleus M. J. Biol. 1994; PubMed Scopus Google CaMK-IV was found to a U. S. A. PubMed Scopus Google Scholar). is also that the of SRF with SRF-mediated has demonstrated that and CaMK-IV both at CaMK-IV its transcription was to the of of through of an which is by by CaMK-IV P. P.S. Dev. 1994; PubMed Scopus Google Scholar). of HDAC4 activate SRF transcription is that the of HDAC4 from SRF in response to is by of factor that is The transcription which is activated by to CArG in response to J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). also SRF, leading to in its DNA protein binding activity activation of its gene transcription that is a mechanism to by of with transcription the interaction was also shown to disrupted by levels of Ca2+ and in of the complex and of the transcription activity of J. Olson E.N. U. S. A. 2000; PubMed Scopus Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). are known to hypertrophic response of cardiac myocytes, to which is the to the of complex and activation of SRF-dependent cardiac muscle gene of such a to cardiac gene expression in a of activation of SRF function by from HDAC4 is shown in we identified a role of class II histone HDAC4 in SRF-mediated gene that SRF-dependent transcription is the of histone The SRF·HDAC4 complex is a target of for of SRF transcription SRF plays a role in gene both in and the also for studies to the SRF/HDAC4 association is a and chromatin for HDAC4 D. L. and M. R. for and D. M. for expression also for the

Aim (1) To systematically review the literature on developmental outcomes from infancy to adolescence of children with complex congenital heart disease (CHD) who underwent early surgery; (2) to run a meta‐regression analysis on the Bayley Scales of Infant Development, Second Edition Mental Developmental Index and Psychomotor Developmental Index (PDI) of infants up to 24 months and IQs of preschool‐aged children to adolescents; (3) to assess associations between perioperative risk factors and outcomes. Method We searched pertinent literature (January 1990 to January 2019) in PubMed, Embase, CINAHL, and PsycINFO. Selection criteria included infants with complex CHD who had primary surgery within the first 9 weeks of life. Methodological quality, including risk of bias and internal validity, were assessed. Results In total, 185 papers met the inclusion criteria; the 100 with high to moderate methodological quality were analysed in detail. Substantial heterogeneity in the group with CHD and in methodology existed. The outcome of infants with single‐ventricle CHD was inferior to those with two‐ventricle CHD (respectively: average scores for PDI 77 and 88; intelligence scores 92 and 98). Perioperative risk factors were inconsistently associated with developmental outcomes. Interpretation The literature on children undergoing surgery in early infancy suggests that infants with a single ventricle are at highest risk of adverse developmental outcomes. What this paper adds Children with complex congenital heart disease (CHD) are at increased risk of impaired developmental outcome. Children with single‐ventricle CHD have worse outcomes than children with two‐ventricle CHD. Children with two‐ventricle CHD gradually grow out of their initial developmental impairment. Perioperative factors are inconsistently associated with outcome.

We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.

OBJECTIVES: We sought to develop a scoring system that predicts the risk of serious adverse events (SAE's) for individual pediatric patients undergoing cardiac catheterization procedures. BACKGROUND: Systematic assessment of risk of SAE in pediatric catheterization can be challenging in view of a wide variation in procedure and patient complexity as well as rapidly evolving technology. METHODS: A 10 component scoring system was originally developed based on expert consensus and review of the existing literature. Data from an international multi-institutional catheterization registry (CCISC) between 2008 and 2013 were used to validate this scoring system. In addition we used multivariate methods to further refine the original risk score to improve its predictive power of SAE's. RESULTS: Univariate analysis confirmed the strong correlation of each of the 10 components of the original risk score with SAE attributed to a pediatric cardiac catheterization (P < 0.001 for all variables). Multivariate analysis resulted in a modified risk score (CRISP) that corresponds to an increase in value of area under a receiver operating characteristic curve (AUC) from 0.715 to 0.741. CONCLUSION: The CRISP score predicts risk of occurrence of an SAE for individual patients undergoing pediatric cardiac catheterization procedures.

Background Patients with single-ventricle physiology who undergo the Fontan procedure are at risk for thrombotic events associated with significant morbidity and mortality. The UNIVERSE Study evaluated the efficacy and safety of a novel liquid rivaroxaban formulation, using a body weight-adjusted dosing regimen, versus acetylsalicylic acid (ASA) in children post-Fontan. Methods and Results The UNIVERSE Study was a randomized, multicenter, 2-part, open-label study of rivaroxaban, in children who had undergone a Fontan procedure, to evaluate its dosing regimen, safety, and efficacy. Part A was the single-arm part of the study that determined the pharmacokinetics/pharmacodynamics and safety of rivaroxaban in 12 participants before proceeding to part B, whereby 100 participants were randomized 2:1 to open-label rivaroxaban versus ASA. The study period was 12 months. A total of 112 participants were enrolled across 35 sites in 10 countries. In part B, for safety outcomes, major bleeding occurred in one participant on rivaroxaban (epistaxis that required transfusion). Clinically relevant nonmajor bleeding occurred in 6% of participants on rivaroxaban versus 9% on ASA. Trivial bleeding occurred in 33% of participants on rivaroxaban versus 35% on ASA. For efficacy outcomes, 1 participant on rivaroxaban in part B had a pulmonary embolism (2% overall event rate); and for ASA, 1 participant had ischemic stroke and 2 had venous thrombosis (9% overall event rate). Conclusions In this study, participants who received rivaroxaban for thromboprophylaxis had a similar safety profile and fewer thrombotic events, albeit not statistically significant, compared with those in the ASA group. Registration URL: https://www.clinicaltrials.gov. Identifier: NCT02846532.

Over the past decade, there have been widespread efforts to raise awareness about maltreatment of children. Pediatric providers have received education about factors that make a child more vulnerable to being abused and neglected. The purpose of this clinical report is to ensure that children with disabilities are recognized as a population at increased risk for maltreatment. This report updates the 2007 American Academy of Pediatrics clinical report “Maltreatment of Children With Disabilities.” Since 2007, new information has expanded our understanding of the incidence of abuse in this vulnerable population. There is now information about which children with disabilities are at greatest risk for maltreatment because not all disabling conditions confer the same risks of abuse or neglect. This updated report will serve as a resource for pediatricians and others who care for children with disabilities and offers guidance on risks for subpopulations of children with disabilities who are at particularly high risk of abuse and neglect. The report will also discuss ways in which the medical home can aid in early identification and intervene when abuse and neglect are suspected. It will also describe community resources and preventive strategies that may reduce the risk of abuse and neglect.

OBJECTIVES: The objective of this study was to determine the prevalence of ICU delirium in children less than 18 years old that underwent cardiac surgery within the last 30 days. The secondary aim of the study was to identify risk factors associated with ICU delirium in postoperative pediatric cardiac surgical patients. DESIGN: A 1-day, multicenter point-prevalence study of delirium in pediatric postoperative cardiac surgery patients. SETTING: Twenty-seven pediatric cardiac and general critical care units caring for postoperative pediatric cardiac surgery patients in North America. PATIENTS: All children less than 18 years old hospitalized in the cardiac critical care units at 06:00 on a randomly selected, study day. INTERVENTIONS: Eligible children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the study team in collaboration with the bedside nurse. MEASUREMENT AND MAIN RESULTS: Overall, 181 patients were enrolled and 40% (n = 73) screened positive for delirium. There were no statistically significant differences in patient demographic information, severity of defect or surgical procedure, past medical history, or postoperative day between patients screening positive or negative for delirium. Our bivariate analysis found those patients screening positive had a longer duration of mechanical ventilation (12.8 vs 5.1 d; p = 0.02); required more vasoactive support (55% vs 26%; p = 0.0009); and had a higher number of invasive catheters (4 vs 3 catheters; p = 0.001). Delirium-positive patients received more total opioid exposure (1.80 vs 0.36 mg/kg/d of morphine equivalents; p < 0.001), did not have an ambulation or physical therapy schedule (p = 0.02), had not been out of bed in the previous 24 hours (p < 0.0002), and parents were not at the bedside at time of data collection (p = 0.008). In the mixed-effects logistic regression analysis of modifiable risk factors, the following variables were associated with a positive delirium screen: 1) pain score, per point increase (odds ratio, 1.3; 1.06-1.60); 2) total opioid exposure, per mg/kg/d increase (odds ratio, 1.35; 1.06-1.73); 3) SBS less than 0 (odds ratio, 4.01; 1.21-13.27); 4) pain medication or sedative administered in the previous 4 hours (odds ratio, 3.49; 1.32-9.28); 5) no progressive physical therapy or ambulation schedule in their medical record (odds ratio, 4.40; 1.41-13.68); and 6) parents not at bedside at time of data collection (odds ratio, 2.31; 1.01-5.31). CONCLUSIONS: We found delirium to be a common problem after cardiac surgery with several important modifiable risk factors.

Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code (IPCCC) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases (ICD-11). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC.The International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature. This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature.The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC, as IPCCC continues to evolve.

BACKGROUND: No evidence-based guidelines exist on the role of cranial-molding orthosis (helmet) therapy for patients with positional plagiocephaly. OBJECTIVE: To address the clinical question: "Does helmet therapy provide effective treatment for positional plagiocephaly?" and to make treatment recommendations based on the available evidence. METHODS: The US National Library of Medicine Medline database and the Cochrane Library were queried by using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I-III). Evidentiary tables were constructed that summarized pertinent study results, and, based on the quality of the literature, recommendations were made (Levels I-III). RESULTS: Fifteen articles met criteria for inclusion into the evidence tables. There was 1 prospective randomized controlled trial (Class II), 5 prospective comparative studies (Class II), and 9 retrospective comparative studies (Class II). CONCLUSION: There is a fairly substantive body of nonrandomized evidence that demonstrates more significant and faster improvement of cranial shape in infants with positional plagiocephaly treated with a helmet in comparison with conservative therapy, especially if the deformity is severe, provided that helmet therapy is applied during the appropriate period of infancy. Specific criteria regarding the measurement and quantification of deformity and the most appropriate time window in infancy for treatment of positional plagiocephaly with a helmet remains elusive. In general, infants with a more severe presenting deformity and infants who are helmeted early in infancy tend to have more significant correction (and even normalization) of head shape. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines-management-patients-positional-plagiocephaly/Chapter_5.

Objective: To develop a management strategy for fetal tachycardia. Methods: Forty-four fetuses (20–40 weeks’ gestation) with nonsinus tachycardia were divided into three groups based on duration of tachycardia and degree of heart failure. Fetuses with intermittent tachycardia were treated expectantly. Fetuses with sustained tachycardia were treated with transplacental antiarrhythmic agents alone if heart failure was mild to moderate, and with direct intramuscular therapy if heart failure was severe. Degree of heart failure was determined by echocardiographic variables of ventricular function, atrioventricular valve insufficiency, and hydrops. Fetal well-being and response to treatment were evaluated by daily heart rate surveillance and frequent fetal echocardiograms and ultrasounds. Results: Fifteen fetuses with intermittent tachycardia (n = 15, group 1) did not progress to sustained tachycardia or heart failure. Fetuses with sustained tachycardia and mild-to-moderate heart failure (n = 14, group 2) were cardioverted or rate controlled with transplacental agents (n = 9); three term fetuses were delivered electively without treatment and two progressed to severe heart failure and were treated in group 3. Seventeen fetuses (15 initially, two progressing) with severe heart failure were cardioverted (in 0.25–21 days; mean 4.3 days) with fetal intramuscular plus transplacental antiarrhythmic therapy (group 3). Overall, 43 of 44 fetuses were delivered at 32 to 41 (mean 37) weeks with minimal morbidity and a mortality rate of 2.2% (95% confidence interval 0.06%, 12.0%). Conclusion: Perinatal mortality and morbidity were low after following a management strategy based on duration of tachycardia, degree of heart failure, and biophysical profile combined with vigilant ongoing fetal surveillance.

BACKGROUND: Studies comparing survival of adolescent and young adult (AYA) patients to that of younger patients with newly diagnosed acute myeloid leukemia (AML) have yielded conflicting results. In order to more accurately characterize relative survival and other outcomes of AYA patients, a cross-study analysis was conducted using data from recent trials conducted by the Children's Cancer Group (CCG) and Children's Oncology Group (COG). METHODS: Data were combined from the CCG-2891, CCG-2941, CCG-2961, and AAML03P1 trials. The data set included 1840 patients, comprising 238 AYA and 1602 younger patients. RESULTS: Overall survival was not significantly different in the 2 groups (AYA, 49% ± 7% versus younger, 54% ± 3% (± 2 standard errors), P = .058). Relapse was lower in AYA patients (30% ± 7% versus 41% ± 3%, P = .002), but treatment-related mortality (TRM) was higher (25% ± 6% versus 12% ± 2%, P < .001). After adjustment for other factors, older age remained strongly associated with TRM (hazard ratio = 2.30, 95% CI = 1.59-3.33, P < .001). Infection accounted for the excess TRM in AYA patients. CONCLUSIONS: Survival in AYA and younger patients with newly diagnosed AML is similar; however, older patients are at higher risk for TRM. More effective strategies for preventing mortality from infection in AYA patients are needed.