Inpatient Care Team Views on Child Life Services: A Scoping Review.

CONTEXT: The utilization of Child Life Services is influenced by interprofessional collaboration and perceptions of other members of the medical team. OBJECTIVES: To summarize studies which address pediatric health care team perspectives on Child Life Services and their utilization in the hospital setting. DATA SOURCES: A comprehensive literature search was conducted with controlled vocabularies and key terms in MEDLINE, Embase, CINAHL, PsycInfo, and Web of Science. STUDY SELECTION: Primary studies published before November 2021 were screened using a predetermined set of inclusion and exclusion criteria. DATA CHARTING: Data charting was performed by 2 independent reviewers. Data extracted include baseline study characteristics, common themes, main outcomes, strengths, and limitations. Because this is not a systematic review, data from included studies was not quantitatively analyzed, but carefully summarized in the manner of a standard scoping review. RESULTS: Nine studies met criteria for inclusion. Common qualitative themes on certified child life specialists include: (1) their broad responsibilities, (2) their positive impact on patients and families, (3) challenges with interprofessional collaboration and integration, and (4) the value of educating others on their roles and responsibilities. CONCLUSIONS: Medical subject headings, controlled vocabulary, or other standardized subject headings that index literature on Child Life Services is limited. However, the existing body of literature supports the positive impact certified child life specialists have on patients and families, despite challenges with complete integration into the interdisciplinary care team. Additional research is required to fully understand and overcome these challenges in continued efforts to further drive patient and family-centered care.

Mutation, drift and selection in single-driver hematologic malignancy: Example of secondary myelodysplastic syndrome following treatment of inherited neutropenia.

Cancer development is driven by series of events involving mutations, which may become fixed in a tumor via genetic drift and selection. This process usually includes a limited number of driver (advantageous) mutations and a greater number of passenger (neutral or mildly deleterious) mutations. We focus on a real-world leukemia model evolving on the background of a germline mutation. Severe congenital neutropenia (SCN) evolves to secondary myelodysplastic syndrome (sMDS) and/or secondary acute myeloid leukemia (sAML) in 30-40%. The majority of SCN cases are due to a germline ELANE mutation. Acquired mutations in CSF3R occur in >70% sMDS/sAML associated with SCN. Hypotheses underlying our model are: an ELANE mutation causes SCN; CSF3R mutations occur spontaneously at a low rate; in fetal life, hematopoietic stem and progenitor cells expands quickly, resulting in a high probability of several tens to several hundreds of cells with CSF3R truncation mutations; therapeutic granulocyte colony-stimulating factor (G-CSF) administration early in life exerts a strong selective pressure, providing mutants with a growth advantage. Applying population genetics theory, we propose a novel two-phase model of disease development from SCN to sMDS. In Phase 1, hematopoietic tissues expand and produce tens to hundreds of stem cells with the CSF3R truncation mutation. Phase 2 occurs postnatally through adult stages with bone marrow production of granulocyte precursors and positive selection of mutants due to chronic G-CSF therapy to reverse the severe neutropenia. We predict the existence of the pool of cells with the mutated truncated receptor before G-CSF treatment begins. The model does not require increase in mutation rate under G-CSF treatment and agrees with age distribution of sMDS onset and clinical sequencing data.

Systems approach to phagocyte production and activation: neutrophils and monocytes.

Granulocyte differentiation and immune response function is a dynamic process governed by a highly coordinated transcriptional program that regulates cellular fate and function, often in a context-dependent manner. Advances in high-throughput technologies and bioinformatics have allowed us to better understand complex biological processes at the genomic and proteomic levels. Components of the environmental milieu, along with the molecular mechanisms that drive the development, activation, and regulation of granulocytes, have since been elucidated. In this chapter, we present the intricate network in which these elements come together and influence one another. In particular, we describe the critical roles of transcription factors like PU.1, CCAAT/enhancer-binding protein (C/EBPα; alpha), C/EBPε (epsilon), and growth factor independent-1 (Gfi-1). We also review granulocyte colony-stimulating factor (G-CSF) receptor-induced signal transduction pathways, their influence on proliferation and differentiation, and the cooperativity of cytokines and chemokines in this process.

Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms.

Hereditary neutropenia is usually caused by heterozygous germline mutations in the ELANE gene encoding neutrophil elastase (NE). How mutations cause disease remains uncertain, but two hypotheses have been proposed. In one, ELANE mutations lead to mislocalization of NE. In the other, ELANE mutations disturb protein folding, inducing an unfolded protein response in the endoplasmic reticulum (ER). In this study, we describe new types of mutations that disrupt the translational start site. At first glance, they should block translation and are incompatible with either the mislocalization or misfolding hypotheses, which require mutant protein for pathogenicity. We find that start-site mutations, instead, force translation from downstream in-frame initiation codons, yielding amino-terminally truncated isoforms lacking ER-localizing (pre) and zymogen-maintaining (pro) sequences, yet retain essential catalytic residues. Patient-derived induced pluripotent stem cells recapitulate hematopoietic and molecular phenotypes. Expression of the amino-terminally deleted isoforms in vitro reduces myeloid cell clonogenic capacity. We define an internal ribosome entry site (IRES) within ELANE and demonstrate that adjacent mutations modulate IRES activity, independently of protein-coding sequence alterations. Some ELANE mutations, therefore, appear to cause neutropenia via the production of amino-terminally deleted NE isoforms rather than by altering the coding sequence of the full-length protein.

Cellular stress pathways in pediatric bone marrow failure syndromes: many roads lead to neutropenia.

The inherited bone marrow failure syndromes, like severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS), provide unique insights into normal and impaired myelopoiesis. The inherited neutropenias are heterogeneous in both clinical presentation and genetic associations, and their causative mechanisms are not well established. SCN, for example, is a genetically heterogeneous syndrome associated with mutations of ELANE, HAX1, GFI1, WAS, G6PC3, or CSF3R. The genetic diversity in SCN, along with congenital neutropenias associated with other genetically defined bone marrow failure syndromes (e.g., SDS), suggests that various pathways may be involved in their pathogenesis. Alternatively, all may lead to a final common pathway of enhanced apoptosis. The pursuit for a more complete understanding of the molecular mechanisms that drive inherited neutropenias remains at the forefront of pediatric translational and basic science investigation. Advances in our understanding of these disorders have greatly increased over the last 10 years concomitant with identification of their genetic lesions. Emerging themes include induction of the unfolded protein response (UPR), defective ribosome assembly, and p53-dependent apoptosis. Additionally, defects in metabolism, disruption of mitochondrial membrane potential, and mislocalization have been found. When perturbed, each of these lead to an intracellular stress that triggers apoptosis in the vulnerable granulocytic precursor.

Pediatric myelodysplastic syndromes: they do exist!

One of the most common hematologic malignancies in adults, myelodysplastic syndrome (MDS) is a heterogenous group of clonal disorders characterized by peripheral cytopenia(s) and normal or hypercellular bone marrow with dysplasia in ≥1 blood cell lineages. MDS frequently evolves to secondary acute myeloid leukemia with poor prognosis. Although uncommon among pediatric hematologic malignancies, both de novo and secondary MDS occur in children and may be the first presentation of an inherited bone marrow failure syndrome. Unlike its adult counterpart, pediatric MDS is more frequently associated with hypocellular bone marrow and monosomy 7. Refractory cytopenia is more typical than refractory anemia, as seen in the elderly. Its recognition and management can be quite challenging and requires the expertise of an experienced hematopathologist. In this review, we describe the epidemiology, genetics, and clinical spectrum of pediatric MDS along with its diagnostic and therapeutic challenges. We also compare and contrast pediatric and adult MDS.

Longitudinal Characterization of Herpes Simplex Virus (HSV) Isolates Acquired From Different Sites in an Immune-Compromised Child: A New HSV Thymidine Kinase Mutation Associated With Resistance.

BACKGROUND: Herpes simplex virus resistance to acyclovir is well described in immune-compromised patients. Management of prolonged infection and recurrences in such patients may be problematic. METHODS: A patient with neuroblastoma developed likely primary herpes gingivostomatitis shortly after starting a course of chemotherapy, with spread to the eye during treatment with acyclovir. Viral isolates were serially obtained from separate sites after treatment was begun and tested for susceptibility to acyclovir and foscarnet by plaque reduction and plating efficiency assays. The thymidine kinase and DNA polymerase genes from each isolate were sequenced. RESULTS: Initial isolates from a throat swab, an oral lesion, and conjunctiva were resistant to acyclovir within 13 days of treatment. Subsequent isolates while on foscarnet were initially acyclovir-susceptible, but reactivation of an acyclovir-resistant isolate was subsequently documented while on acyclovir suppression. Genotypic analysis identified a previously unreported UL23 mutation in some resistant isolates. None of the amino acid changes identified in UL30 were associated with resistance. CONCLUSIONS: Phenotypic and genotypic antiviral resistance of herpes simplex isolates may vary from different compartments and over time in individual immune-compromised hosts, highlighting the importance of obtaining cultures from all sites. Phenotypic resistance testing should be considered for isolates obtained from at-risk patients not responding to first-line therapy. Empiric combination treatment with multiple antivirals could be considered in some situations.