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While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 (IL7) stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.

Abstract: Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in preclinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, JAK2 inhibitor fedratinib, and JAK1/2 inhibitor ruxolitinib. All 3 drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFN-γ)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, in which perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib, and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, whereas fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent proinflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Glucocorticoids (GCs) are the cornerstone of acute lymphoblastic leukemia (ALL) therapy. Although mutations in NR3C1, which encodes the GC receptor (GR), and other genes involved in GC signaling occur at relapse, additional mechanisms of adaptive GC resistance are uncertain. We transplanted and treated 10 primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with GC dexamethasone (DEX). Multiple distinct relapsed clones from 1 such leukemia (T-ALL 8633) exhibited discrete retroviral integrations that upregulated Jdp2 expression. This leukemia harbored a Kdm6a mutation. In the human T-ALL cell line CCRF-CEM, enforced JDP2 overexpression conferred GC resistance, whereas KDM6A inactivation unexpectedly enhanced GC sensitivity. In the context of KDM6A knockout, JDP2 overexpression induced profound GC resistance, counteracting the sensitization conferred by KDM6A loss. These resistant "double mutant" cells with combined KDM6A loss and JDP2 overexpression exhibited decreased NR3C1 mRNA and GR protein upregulation upon DEX exposure. Analysis of paired samples from 2 patients with KDM6A-mutant T-ALL in a relapsed pediatric ALL cohort revealed a somatic NR3C1 mutation at relapse in 1 patient and a markedly elevated JDP2 expression in the other. Together, these data implicate JDP2 overexpression as a mechanism of adaptive GC resistance in T-ALL, which functionally interacts with KDM6A inactivation., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Familial hemophagocytic lymphohistiocytosis (fHLH) encompasses a group of rare inherited immune dysregulation disorders characterized by loss-of-function mutations in one of several genes involved in the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. The resulting defect in cytotoxicity allows these cells to be appropriately stimulated in response to an antigenic trigger, and also impairs their ability to effectively mediate and terminate the immune response. Consequently, there is sustained lymphocyte activation, resulting in the secretion of excessive amounts of pro-inflammatory cytokines that further activate other cells of the innate and adaptive immune systems. Together, these activated cells and pro-inflammatory cytokines mediate tissue damage that leads to multi-organ failure in the absence of treatment aimed at controlling hyperinflammation. In this article, we review these mechanisms of hyperinflammation in fHLH at the cellular level, focusing primarily on studies performed in murine models of fHLH that have provided insight into how defects in the lymphocyte cytotoxicity pathway mediate rampant and sustained immune dysregulation., Competing Interests: KN receives research funding from Incyte. Incyte was not involved in the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Steen, Nichols and Meyer.)

Glucocorticoid (GC) resistance is a poor prognostic factor in T-cell acute lymphoblastic leukaemia (T-ALL). Interleukin-7 (IL-7) mediates GC resistance via GC-induced upregulation of IL-7 receptor (IL-7R) expression, leading to increased pro-survival signalling. IL-7R reaches the cell surface via the secretory pathway, so we hypothesized that inhibiting the translocation of IL-7R into the secretory pathway would overcome GC resistance. Sec61 is an endoplasmic reticulum (ER) channel that is required for insertion of polypeptides into the ER. Here, we demonstrate that KZR-445, a novel inhibitor of Sec61, potently attenuates the dexamethasone (DEX)-induced increase in cell surface IL-7R and overcomes IL-7-induced DEX resistance., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1 , and RAB27A , all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH., Competing Interests: MH is a consultant for Novartis and Sobi. KN receives research funding from Incyte. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Steen, Hermiston, Nichols and Meyer.)

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by pathologic immune activation in which prompt recognition and initiation of immune suppression is essential for survival. Children with HLH have many overlapping clinical features with critically ill children with sepsis and systemic inflammatory response syndrome (SIRS) in whom alternative therapies are indicated. To determine whether plasma biomarkers could differentiate HLH from other inflammatory conditions and to better define a core inflammatory signature of HLH, concentrations of inflammatory plasma proteins were compared in 40 patients with HLH to 47 pediatric patients with severe sepsis or SIRS. Fifteen of 135 analytes were significantly different in HLH plasma compared with SIRS/sepsis, including increased interferon-γ (IFN-γ)-regulated chemokines CXCL9, CXCL10, and CXCL11. Furthermore, a 2-analyte plasma protein classifier including CXCL9 and interleukin-6 was able to differentiate HLH from SIRS/sepsis. Gene expression in CD8+ T cells and activated monocytes from blood were also enriched for IFN-γ pathway signatures in peripheral blood cells from patients with HLH compared with SIRS/sepsis. This study identifies differential expression of inflammatory proteins as a diagnostic strategy to identify critically ill children with HLH, and comprehensive unbiased analysis of inflammatory plasma proteins and global gene expression demonstrates that IFN-γ signaling is uniquely elevated in HLH. In addition to demonstrating the ability of diagnostic criteria for HLH and sepsis or SIRS to identify groups with distinct inflammatory patterns, results from this study support the potential for prospective evaluation of inflammatory biomarkers to aid in diagnosis of and optimizing therapeutic strategies for children with distinctive hyperinflammatory syndromes., (© 2021 by The American Society of Hematology.)

Background: Over 450,000 individuals are hospitalized with burns annually and roughly 35% are scald burns. Children younger than 5 years of age are at the greatest risk of scald burn injury. Caregiver burn prevention programs have been found to reduce the prevalence of injuries in young children; however, low-income and underserved populations seldomly have access to these programs. The impact of scald burn prevention programs in underserved populations remains unexplored. The objective of the current study was to evaluate the efficacy of a scald burn prevention program at a Level One Pediatric Trauma Center in a low-income, underserved community., Methods: Our hospital developed a one-hour scald burn prevention program for caregivers with children 5 years of age or younger. The program educated caregivers on ways to prevent scald burns and create safeguards in their home. Caregivers completed a pre-post survey to measure their ability to identify hot or cold objects, as well as respond to items about their perceptions of the program's utility, their willingness to share it with others, and the likelihood that they would use the information in the future. Data was analyzed using a paired t-test., Results: Two-hundred and sixty-nine (N = 269) caregivers participated in the program. Before the program, caregivers could identify potentially hot objects 83.17% of the time, and after the program, they were able to identify these items 92.31% of the time: t (268) = 12.46, p < .001, d = 1.07. Additionally, 95% of caregivers indicated that the program was helpful, 99% stated that they were likely to share this information with others, and 100% indicated that they would use the information from the program., Conclusions: Education is a critical component to prevent scald burns. Results indicate that a hospital-led scald burn prevention program can positively impact a caregiver's ability to identify possible scald-burn risks. Providing education to caregivers who typically do not receive this information could lower the prevalence of scald burns not only institutionally, but in communities that are disproportionately impacted by this mechanism of injury., (© 2021. The Author(s).)

Background: Motor vehicle collisions (MVCs) are a significant safety issue in the United States. Young children are disproportionally impacted by car accidents and suffer high rates of injuries and mortality. When used properly, car seats have been found to reduce the severity of injuries. However, individuals from low-income areas often do not have access to education or car seats compared to those in suburban or higher income areas. Therefore, the goal of the present study was to measure the effectiveness of a car seat program in an urban, Level I Pediatric Trauma Center on caregiver car seat knowledge., Methods: Caregivers (N = 200) attended a single, one-hour car seat educational program with a Child Passenger Safety Technician (CPST). The sessions included educational and hands-on components, where caregivers were asked to complete a seven-item pre-post knowledge assessment. For completion of the course, caregivers received a car seat for their child., Results: A paired t-test revealed that the workshop significantly increased caregiver knowledge from pre-post: t (199) = - 12.56, p < .001; d = 1.27. McNemar's Chi-Square analyses displayed that caregivers increased in all knowledge categories (p < .001)., Conclusions: While caregivers in urban areas or in low-income areas may have less access to resources, hospital-led car seat courses can increase knowledge of proper car seat usage in these communities. These findings should be used to establish programs in hospitals in areas where these resources are not readily available to caregivers., (© 2021. The Author(s).)

Competing Interests: The authors have declared that no competing interests exist.

Background: Shaken baby syndrome/abusive head trauma (SBS/AHT) is the leading cause of child abuse death. Our institution piloted an evidence-based educational program to increase nurse and caregiver knowledge about SBS/AHT., Methods: Nurses participated in a pretest survey, completed online implementation training, and then were given a posttest survey to determine the change in SBS/AHT knowledge. Once trained, nurses disseminated information to caregivers with children younger than 6 months. Caregivers (N = 87) watched an educational video, reviewed information in a booklet with a nurse, and participated in teach-back related to key points of the intervention in both a hospital and the community setting., Results: Prior to the education, nurses (n = 115) scored 8.03 out of 10.00 on the SBS/AHT assessment. Following the intervention, nurses (n = 120) scored 9.00 out of 10.00 on the assessment, t(233) = -6.61, p < .001. During education, caregivers (n = 69) were able to recall 8.55 out of 12 key educational components. In the community setting, caregivers (n = 18) worked together to recall 12 out of the 12 key components. Caregivers were most likely to recall ways to comfort their crying baby (94%) and why shaking a baby is dangerous (93%)., Conclusion: This pilot study significantly increased nurses' knowledge of SBS/AHT and provided education to caregivers about SBS/AHT.

Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS., (© 2020 by The American Society of Hematology.)

Despite decades of clinical use, mechanisms of glucocorticoid resistance are poorly understood. We treated primary murine T lineage acute lymphoblastic leukemias (T-ALLs) with the glucocorticoid dexamethasone (DEX) alone and in combination with the pan-PI3 kinase inhibitor GDC-0941 and observed a robust response to DEX that was modestly enhanced by GDC-0941. Continuous in vivo treatment invariably resulted in outgrowth of drug-resistant clones, ~30% of which showed markedly reduced glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited low GR protein levels. De novo or preexisting mutations in the gene encoding GR (Nr3c1) occurred in relapsed clones derived from multiple independent parental leukemias. CRISPR/Cas9 gene editing confirmed that loss of GR expression confers DEX resistance. Exposing drug-sensitive T-ALLs to DEX in vivo altered transcript levels of multiple genes, and this response was attenuated in relapsed T-ALLs. These data implicate reduced GR protein expression as a frequent cause of glucocorticoid resistance in T-ALL.

Glucocorticoids (GCs) are a central component of therapy for patients with T cell acute lymphoblastic leukemia (T-ALL), and although resistance to GCs is a strong negative prognostic indicator in T-ALL, the mechanisms of GC resistance remain poorly understood. Using diagnostic samples from patients enrolled in the frontline Children's Oncology Group (COG) T-ALL clinical trial AALL1231, we demonstrated that one-third of primary T-ALLs were resistant to GCs when cells were cultured in the presence of IL-7, a cytokine that is critical for normal T cell function and that plays a well-established role in leukemogenesis. We demonstrated that in these T-ALLs and in distinct populations of normal developing thymocytes, GCs paradoxically induced their own resistance by promoting upregulation of IL-7 receptor (IL-7R) expression. In the presence of IL-7, this augmented downstream signal transduction, resulting in increased STAT5 transcriptional output and upregulation of the prosurvival protein BCL-2. Taken together, we showed that IL-7 mediates an intrinsic and physiologic mechanism of GC resistance in normal thymocyte development that is retained during leukemogenesis in a subset of T-ALLs and is reversible with targeted inhibition of the IL-7R/JAK/STAT5/BCL-2 axis.

Background: Psychiatric and psychosomatic consultation-liaison services (CL) are important providers of diagnosis and treatment for hospital patients with mental comorbidities and psychological burdens., Objective: To perform a systematic review and meta-analysis investigating the effects of CL on depression and anxiety., Methods: Following PRISMA guidelines, a systematic literature search was conducted until 2017. Included were published randomized controlled trials using CL interventions with adults in general hospitals, treatment as usual as control groups, and depression and/or anxiety as outcomes. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Level of integration was assessed using the Standard Framework for Levels of Integrated Healthcare. Meta-analyses were performed using random effects models and meta-regression for moderator effects., Results: We included 38 studies (9,994 patients). Risk of bias was high in 17, unclear in 15, and low in 6 studies. Studies were grouped by type of intervention: brief interventions tailored to the patients (8), interventions based on specific treatment manuals (19), and integrated, collaborative care (11). Studies showed small to medium effects on depression and anxiety. Meta-analyses for depression yielded a small effect (d = -0.19, 95% CI: -0.30 to -0.09) in manual studies and a small effect (d = -0.33, 95% CI: -0.53 to -0.13) in integrated, collaborative care studies, the latter using mostly active control groups with the possibility of traditional consultation., Conclusions: CL can provide a helpful first treatment for symptoms of depression and anxiety. Given that especially depressive symptoms in medically ill patients are long-lasting, the results underline the benefit of integrative approaches that respect the complexity of the illness., (© 2019 S. Karger AG, Basel.)

Acute lymphoblastic leukemia (ALL) is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations. With the introduction of intensive multi-agent chemotherapeutic regimens, survival rates for ALL have improved dramatically over the past several decades, though survival rates for adult ALL continue to lag behind those of pediatric ALL. Resistance to chemotherapy remains a significant obstacle in the treatment of ALL, and chemoresistance due to molecular alterations within ALL cells have been described. In addition to these cell-intrinsic factors, the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance, and it is now known that stromal cells within the bone marrow microenvironment, through direct cell-cell interactions and through the release of lymphoid-acting soluble factors, contribute to ALL pathogenesis and chemoresistance. This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context., Competing Interests: All authors declare that there are no conflicts of interest., (© The Author(s) 2019.)

Introduction: Autologous cell harvesting and processing devices are designed to facilitate the harvesting of cells using enzymatic and physical disruption techniques to immediately apply non-cultured autologous cell suspension (ACS) to the wound area., Objective: This case report evaluates clinical outcomes following application of cellular suspension with split-thickness skin grafts (STSGs) as an adjunct for definitive closure of burn injuries and donor sites in 2 pediatric patients., Materials and Methods: The cases were performed under a humanitarian use protocol following institutional review board approval at St. Christopher's Hospital for Children (Philadelphia, PA)., Results: The first patient was a 4-year-old girl with partial- and full-thickness (32% total body surface area) burn injuries of her head, trunk, flank, arms, thighs, and feet. The patient was discharged 19 days following ACS treatment. The second patient was an 18-month-old girl with partial- and full-thickness (21% total body surface area) burns involving the bilateral lower extremities. She was discharged 22 days after ACS treatment with widely meshed autograft. Neither patient required additional surgical interventions. All treatment and donor areas for both patients remained uninfected and neither patient experienced any unexpected treatment-related adverse events., Conclusions: These cases are the first of their kind reported in the pediatric population and suggest ACS in conjunction with STSGs can help decrease surgical procedures and expedite healing in pediatric patients with large surface burns.

Background: School nurses play an integral part in prehospital care for life-threatening bleeding in educational environments. This study evaluated the efficacy of Stop the Bleed training for improving school nurses' knowledge, hands-on skill, self-confidence, and belief in school preparedness for responding to a life-threatening bleeding emergency., Method: Sixteen northeastern U.S. public school nurses completed a 1-hour seminar on appropriate life-threatening bleeding intervention with written and hands-on pre- and postassessments. Written assessments measured bleeding control knowledge, self-confidence, and perceptions of school preparedness. Hands-on assessments measured tourniquet application and wound-packing skills., Results: After training, participants scored significantly higher on the written assessment measuring basic bleeding control knowledge. The written postassessment showed significantly higher levels of self-confidence and belief in school preparedness (p ≤ .05, n = 16). Hands-on skill for tourniquet application and wound packing also significantly increased following training (p ≤ .05, n = 16)., Conclusion: The Stop the Bleed training was effective in improving school nurses' basic knowledge about life-threatening bleeding control and improved tourniquet application and wound-packing skills. [J Contin Educ Nurs. 2019;50(11):501-507.]., (Copyright 2019, SLACK Incorporated.)

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy., Competing Interests: The authors have declared that no competing interests exist.

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. The genomic landscape of pediatric ALL has been extensively characterized, allowing for the identification of distinct molecular subtypes of this disease. This in turn has facilitated improvements in risk stratification and tailoring of therapy, resulting in dramatic improvements in survival rates over the past several decades. However, despite these improvements, outcomes remain dismal for the ten percent of patients who continue to fail therapy and relapse. Although the genetic landscape of pediatric ALL is well-understood, increasing evidence suggests that genetic alterations alone are insufficient to promote leukemogenesis and the acquisition of chemoresistance that leads to disease relapse. Instead, cooperating epigenetic alterations are now recognized as important contributors to the aberrant gene expression profiles that are characteristic of the molecular subtypes of ALL, and changes in the epigenetic landscape are now thought to underlie the development of chemoresistance and ultimately disease relapse. This review article focuses on the expanding knowledge of the role of the epigenome in ALL pathogenesis, progression, and response to therapy, and highlights preclinical and clinical efforts to target the epigenome as a means of overcoming chemoresistance and improving outcomes for children with ALL., Competing Interests: Both authors declared that there are no conflicts of interest., (© The Author(s) 2019.)

The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis of cancer into improved therapies. Insertional mutagenesis (IM) in mice is a robust strategy for generating malignancies that recapitulate the extensive inter- and intra-tumoral genetic heterogeneity found in advanced human cancers. While the central role of "driver" viral insertions in IM models that aberrantly increase the expression of proto-oncogenes or disrupt tumor suppressors has been appreciated for many years, the contributions of cooperating somatic mutations and large chromosomal alterations to tumorigenesis are largely unknown. Integrated genomic studies of T lineage acute lymphoblastic leukemias (T-ALLs) generated by IM in wild-type (WT) and Kras mutant mice reveal frequent point mutations and other recurrent non-insertional genetic alterations that also occur in human T-ALL. These somatic mutations are sensitive and specific markers for defining clonal dynamics and identifying candidate resistance mechanisms in leukemias that relapse after an initial therapeutic response. Primary cancers initiated by IM and resistant clones that emerge during in vivo treatment close key gaps in existing preclinical models, and are robust platforms for investigating the efficacy of new therapies and for elucidating how drug exposure shapes tumor evolution and patterns of resistance., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Monique Dail, Anneleen Daemen, and Deepak Sampath are employees and shareholders of Genentech. The remaining authors of this manuscript declare no competing interests related to this work.

Introduction: The national Stop the Bleed (STB) campaign was implemented in 2015 to provide hemorrhage control education to non-medical providers to reduce the number of deaths due to uncontrolled hemorrhage. Hands on training limits the availability of this program, and its importance is not known amongst lay providers. This study aimed to evaluate the efficacy of STB training for laypersons on knowledge and skill-based abilities in the workplace setting. We hypothesized such hands on and in-person training would improve performance., Methods: Non-medical potential first responders (PFR; N = 298) participated in STB training comprised of a lecture and hands-on component. PFRs completed a bleeding control knowledge-based pre-and post-assessment. Following the lecture, participants were divided into experimental and control groups during which hands-on practice was manipulated to determine the impact of guided practice on wound packing and tourniquet application. Wound packing and tourniquet application assessments were performed and scores compared between the experimental and control groups., Results: PFRs scored higher on the bleeding control bleeding control knowledge-based post-test (M = 4.63, SD = 1.32) than on the pre-test (M = 3.21, SD = 1.14). Employees in the experimental group (M = 2.93, SD = .26) also scored significantly higher than the control group (M = 1.97, SD = .77) that attempted wound packing without any hands-on training. PFRs in the experimental group scored significantly higher (M = 7.41, SD = .91) than PFRs in the control group (M = 5.99, SD = 1.81) for tourniquet application., Conclusion: Knowledge related to hemorrhage control increased following the STB course. Participants who engaged in hands-on practice for tourniquet and wound packing were more proficient than those who only saw the lecture. We confirm that in person, hands on training is key to the success of lay STB training., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Medical errors are a significant issue in health care that may be avoided through enhanced communication and documentation. This study examines interdisciplinary communication and compliance with trauma standards of care demonstrated through following the implementation of cohorting trauma patients to one medical/surgical unit and instituting daily interdisciplinary trauma patient rounds. Potential benefits include enhanced communication, improved nursing satisfaction, and increased compliance with trauma standards of care demonstrated through documentation, which the literature suggests improves quality of care. Pre- and postcohorting surveys related to safety attitudes, comfort with caring for trauma patients, and the efficacy of cohorting were administered to the nursing staff. As a marker for increased compliance with trauma standards of care, medical records were reviewed for completion of substance abuse screening upon admission and Functional Independence Measure screening at discharge. The results were compared after the cohorting initiative with 2 years prior. The rate of compliance with substance abuse screening increased from an average of 62.5% in 2015 and 2016 to 84% in 2017. Functional Independence Measure compliance increased from an average of 72.5% in 2015 and 2016 to 94% in 2017 following the cohorting intervention. Nursing perceptions of teamwork, safety climate, and staff support significantly improved (p < .05) from pre- to postcohorting surveys. Improvements were noted in comfort with performing tasks associated with caring for trauma patients but were not statistically significant. Cohorting trauma patients to one medical/surgical unit resulted in positive perceptions of professional relationships, improved communication, and compliance with trauma standards of care for documentation.

Objective: Burnout is a process of physical and emotional exhaustion that often results in clinical depression. Detailed descriptions and evaluations of specialized psychosomatic treatment are rare. This pilot study investigates the feasibility of inpatient and day hospital treatment of patients with burnout syndrome. Additionally, we present results of an initial, noncontrolled, pre-post-evaluation of changes in symptoms and individual work-related risk factors for burnout., Methods: Sixty-four consecutive patients with burnout syndrome were assessed before and after specialized multimodal treatment using a clinical symptom checklist (ICD-10 Symptom Rating) and burnout-specific instruments (Maslach Burnout Inventory, Occupational Stress & Coping Inventory)., Results: Patients' average age was 45 (range 23 to 61), 70% were currently employed, 24% in managerial positions or self-employed, and 89% diagnosed with an affective disorder. The average length of time off work due to illness in the past year was 13 weeks. Treatment lasted five weeks on average. After treatment, depression (p < 0.001; effect size d = 0.79), emotional exhaustion (p = 0.001; d = 0.41), and the subjective significance of work (p = 0.001; d = 0.36) decreased, while emotional distancing (p < 0.001; d = 0.56), balance and mental stability (p < 0.001; d = 0.38) and life satisfaction (p < 0.001; d = 0.37) increased. Clinical significance was determined using the Reliable Change Index., Conclusions: The treatment program described here is well accepted by patients with severe burnout. It contributes to positive changes in symptoms and work-related risk factors. Controlled studies are necessary to establish treatment efficacy.

Background: When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca(2+)-ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β1-adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes., Methods and Results: Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β1-selective), metoprolol+doxazosin (β1/α1), or carvedilol (β1/β2/α1). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β1-adrenergic signaling., Conclusions: In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal-adult paradigm but may be because of reversal of gene expression controlled by a β1-adrenergic receptor gene network., Clinical Trial Registration: URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992., (© 2015 American Heart Association, Inc.)

Adiponectin is an insulin sensitizing fat cell (FC) hormone whose levels are related to adipose tissue (AT) mass and depot distribution. We hypothesized that the nature of AT expansion (hypertrophy vs. hyperplasia) contributes to obesity-related reductions in serum adiponectin and that this effect is influenced by the regional distribution of AT to subcutaneous (S) and visceral (V) depots. Thirteen obese subjects provided paired AT biopsies. Serum total and high molecular weight (HMW) adiponectin levels were determined by ELISA. Secretion was quantified following 24-h explant culture. FC size, number, % large, and % small FC were determined by microscopic analysis. Secretion of total adiponectin was highest by SAT (P = 0.008) and correlated more strongly with serum adiponectin (total: P = 0.015, r = 0.77; HMW: P = 0.005, r = 0.83) than did secretion by VAT (P = 0.05, r = 0.66 for both). FC size was greatest in SAT and correlated negatively with both serum (total: P = 0.01, r = -0.74; HMW: P = 0.03, r = -0.69) and secreted (total: P = 0.05, r = -0.72; HMW: P = 0.02, r = -0.87) adiponectin. The % small FC in SAT correlated positively with both serum (total: P = 0.006, r = 0.87; HMW: P = 0.009, r = 0.79) and secreted (total: P = 0.03, r = 0.75; HMW: P = 0.01, r = 0.92) adiponectin. VAT FC size correlated negatively with serum HMW adiponectin (P = 0.01, r = -0.76) but not with any measure of secretion. VAT had the greatest % small FC, which related positively to serum HMW (P = 0.004, r = 0.81) and to secreted total adiponectin (P = 0.02, r = 0.78). These studies indicate that differences in fat cell size and depot distribution of AT expansion are important influences on adiponectin in obesity.