Infant Feeding and Weight Trajectories in the Eat, Sleep, Console Trial: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Infants with neonatal opioid withdrawal syndrome (NOWS) cared for with the Eat, Sleep, Console (ESC) care approach receive less pharmacologic treatment and have shorter hospital stays compared to usual care with the Finnegan Neonatal Abstinence Scoring Tool, but the effects of these approaches on feeding and weight are unknown. Objective: To evaluate feeding practices and weight trajectories in infants cared for with ESC vs usual care. Design, Setting, and Participants: ESC-NOW is a cluster randomized trial of infants with NOWS born at 36 weeks' gestation or later at 26 US hospitals from September 2020 to March 2022. Each site transitioned from usual care to ESC (the study intervention) at a randomized time. Feeding was per site practice and not specified by the intervention. Feeding and weight outcomes were assessed at hospital discharge. Intervention: ESC vs usual care. Main Outcomes and Measures: Outcomes include prospectively identified secondary end points related to feeding and weight. z Scores were used for growth to account for corrected gestational age at the time of measurement. All analyses were intention to treat and adjusted for study design. Maternal/infant characteristics were included in adjusted models. Results: The analyses included 1305 infants (702 in usual care and 603 in ESC; mean [SD] gestational age, 38.6 [1.3] weeks; 655 [50.2%] male and 650 [49.8%] female). Baseline demographic characteristics were similar between groups. The proportion of breastfed infants was higher in the ESC group (52.7% vs 41.7%; absolute difference, 11%; 95% CI, 1.0-20.9). A higher proportion of infants cared for with ESC received exclusive breast milk (15.1% vs 6.7%; absolute difference, 8.4%; 95% CI, 0.9-5.8) or any breast milk (38.8% vs 27.4%; absolute difference, 11.4%; 95% CI, 0.2-23.1) and were directly breastfeeding at discharge (35.2% vs 19.5%; absolute difference, 15.7%; 95% CI, 4.1-27.3). There was no difference in proportion of infants with weight loss greater than 10% or maximum percentage weight loss, although infants cared for with ESC had a lower weight z score on day of life 3 (-1.08 vs -1.01; absolute difference, 0.07; 95% CI, 0.02-0.12). When pharmacologic treatment was added into the model, no breastfeeding outcomes were statistically significant. Conclusions and Relevance: In this study, infants cared for with ESC were more likely to initiate and continue breastfeeding and had no difference in percentage weight loss. The improvement in breastfeeding with ESC may be driven by reduction in pharmacologic treatment and provision of effective nonpharmacologic care. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

Clinical care ratios for allied health practitioners: an update and implications for workforce planning.

ObjectiveClinical care ratios are used to quantify and benchmark the activity of allied health professionals. This study aims to review previous recommendations and identify what variables may influence them.MethodData was collected from the core allied health professions (audiology, nutrition and dietetics, occupational therapy, physiotherapy, podiatry, prosthetics and orthotics, psychology, social work and speech pathology) across eight Australian hospitals. Data for 113 staff who were casual or from smaller professions (audiology, podiatry, prosthetics and orthotics and psychology) were excluded due to insufficient numbers for analysis. The remaining data were analysed according to profession, seniority (tiers 1, 2 and 3) and employment status (permanent versus casual staff). A two-way ANOVA was performed to assess the association of clinical care ratios with tier, profession, employment status and gender.ResultsData from 1246 staff from the five larger professions at participating hospitals were analysed. There were no interactions between profession and gender (P=0.185) or employment status (P=0.412). The relationship between clinical care ratio and profession was modified by tier (interaction term, P=0.014), meaning that differences in clinical care ratios between professions depended on the tier.ConclusionThis research has confirmed that clinical care ratios are a useful tool in workload management and determining staffing levels for allied health professionals. The recommendations from this research provide a starting point that can be finessed with reference to profession, model of care, workforce structure, governance and training requirements. This will lead to increased staff wellbeing and improved patient outcomes.

Influence of Eat, Sleep, and Console on Infants Pharmacologically Treated for Opioid Withdrawal: A Post Hoc Subgroup Analysis of the ESC-NOW Randomized Clinical Trial.

Importance: The function-based eat, sleep, console (ESC) care approach substantially reduces the proportion of infants who receive pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). This reduction has led to concerns for increased postnatal opioid exposure in infants who receive pharmacologic treatment. However, the effect of the ESC care approach on hospital outcomes for infants pharmacologically treated for NOWS is currently unknown. Objective: To evaluate differences in opioid exposure and total length of hospital stay (LOS) for pharmacologically treated infants managed with the ESC care approach vs usual care with the Finnegan tool. Design, Setting, and Participants: This post hoc subgroup analysis involved infants pharmacologically treated in ESC-NOW, a stepped-wedge cluster randomized clinical trial conducted at 26 US hospitals. Hospitals maintained pretrial practices for pharmacologic treatment, including opioid type, scheduled opioid dosing, and use of adjuvant medications. Infants were born at 36 weeks' gestation or later, had evidence of antenatal opioid exposure, and received opioid treatment for NOWS between September 2020 and March 2022. Data were analyzed from November 2022 to January 2024. Exposure: Opioid treatment for NOWS and the ESC care approach. Main Outcomes and Measures: For each outcome (total opioid exposure, peak opioid dose, time from birth to initiation of first opioid dose, length of opioid treatment, and LOS), we used generalized linear mixed models to adjust for the stepped-wedge design and maternal and infant characteristics. Results: In the ESC-NOW trial, 463 of 1305 infants were pharmacologically treated (143/603 [23.7%] in the ESC care approach group and 320/702 [45.6%] in the usual care group). Mean total opioid exposure was lower in the ESC care approach group with an absolute difference of 4.1 morphine milligram equivalents per kilogram (MME/kg) (95% CI, 1.3-7.0) when compared with usual care (4.8 MME/kg vs 8.9 MME/kg, respectively; P = .001). Mean time from birth to initiation of pharmacologic treatment was 22.4 hours (95% CI, 7.1-37.7) longer with the ESC care approach vs usual care (75.4 vs 53.0 hours, respectively; P = .002). No significant difference in mean peak opioid dose was observed between groups (ESC care approach, 0.147 MME/kg, vs usual care, 0.126 MME/kg). The mean length of treatment was 6.3 days shorter (95% CI, 3.0-9.6) in the ESC care approach group vs usual care group (11.8 vs 18.1 days, respectively; P < .001), and mean LOS was 6.2 days shorter (95% CI, 3.0-9.4) with the ESC care approach than with usual care (16.7 vs 22.9 days, respectively; P < .001). Conclusion and Relevance: When compared with usual care, the ESC care approach was associated with less opioid exposure and shorter LOS for infants pharmacologically treated for NOWS. The ESC care approach was not associated with a higher peak opioid dose, although pharmacologic treatment was typically initiated later. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

Digital divide or digital exclusion? Do allied health professionals' assumptions drive use of telehealth?

INTRODUCTION: Telehealth use within allied health services currently lacks structure and consistency, ultimately affecting who can, and cannot, access services. This study aimed to investigate the factors influencing allied health professionals' (AHP) selection of consumers and appointments for telehealth. METHODS: This study was conducted across 16 allied health departments from four Australian hospitals. Semi-structured focus groups were conducted with 58 AHPs. Analysis was underpinned by Qualitative Description methodology with inductive coding guided by Braun and Clarke's thematic analysis approach. RESULTS: Six themes were identified that influenced AHPs' evaluation of telehealth suitability and selection of consumers. These included the following: (1) ease, efficiency and comfort of telehealth for clinicians; (2) clear benefits of telehealth for the consumer, yet the consumers were not always given the choice; (3) consumers' technology access and ability; (4) establishing and maintaining effective therapeutic relationships via telehealth; (5) delivering clinically appropriate and effective care via telehealth; and (6) external influences on telehealth service provision. A further theme of 'assumption versus reality' was noted to pervade all six themes. DISCUSSION: Clinicians remain the key decision makers for whether telehealth is offered within allied health services. Ease and efficiency of use is a major driver in AHP's willingness to use telehealth. Assumptions and pre-conceived frames-of-reference often underpin decisions to not offer telehealth and present major barriers to telehealth adoption. The development of evidence-based, decision-support frameworks that engage the consumer and clinician in determining when telehealth is used is required. Services need to actively pursue joint decision-making between the clinician and consumer about service delivery preferences.

Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

Implementation of a Standardized Premedication Bundle to Improve Procedure Success for Nonemergent Neonatal Intubations.

The American Academy of Pediatrics recommends premedication for all nonemergent neonatal intubations, yet there remains significant variation in this practice nationally. We aimed to standardize our unit's premedication practices for improved intubation success and reduced adverse events. Methods: The study workgroup developed educational material and protocol content. Process measures included premedication use, education, and audit form completion. Primary (success on first intubation attempt and adverse event rates) and secondary (trainee success) study outcomes are displayed using statistical process control charts and pre-post cohort comparisons. Results: Forty-seven percent (97/206) of nurses completed educational intervention before protocol release, with an additional 20% (42/206) following a staff reminder. Two hundred sixteen (216) patients were intubated per protocol with 81% (174/216) audit completion. Compared with baseline (n = 158), intubation attempts decreased from 2 (IQR, 1-2) to 1 (IQR, 1-2) (P = 0.03), and success on the first attempt increased from 40% (63/158) to 57% (124/216) (P < 0.01), with a notable improvement in trainee success from less than 1% (1/40) to 43% (31/72) (P < 0.01). The rate of severe and rare adverse events remained stable; however, there was a rise in nonsevere events from 30% (48/158) to 45% (98/216). The tachycardia rate increased with atropine use. There was no change in chest wall rigidity, number of infants unable to extubate following surfactant, or decompensation awaiting medications. Conclusions: Standardizing procedural care delivery reduced intubation attempts and increased the attempt success rate. However, this was accompanied by an increase in the rate of nonsevere adverse events.

Echocardiographic Predictors of Hospital Outcomes in Preterm Neonates with Patent Ductus Arteriosus and Clinical Suspicion of Pulmonary Hypertension.

Background: Preterm neonates often have an echocardiogram performed in the first few days of life for suspicion of pulmonary hypertension and patent ductus arteriosus. The usefulness of this echocardiogram in predicting outcomes in this population are unknown. The objective of this study was to investigate associations between initial echocardiographic assessment and hospital outcomes in preterm neonates with patent ductus arteriosus and clinical suspicion of pulmonary hypertension. Methods: Premature neonates (<37 weeks gestational age) with patent ductus arteriosus and clinical suspicion of pulmonary hypertension born at our institution or transferred within 48 hours of life were included in this single center retrospective study. The primary outcome was in-hospital extracorporeal membrane oxygenation utilization or mortality. Results: 86 patients were included. Median age at echocardiogram was 2 days (interquartile range 1,7), gestational age was 27 weeks (interquartile range 25,32), and birth weight was 878 grams (interquartile range 650,1818). 15 patients (17%) met the primary outcome. Larger patent ductus arteriosus size (p = .03), patent foramen ovale flow that was bidirectional or right to left (p = .047), and right atrial volume (p = .04) were independently associated with the primary outcome. Conclusion: Larger patent ductus arteriosus size, bidirectional or right to left flow at the patent foramen ovale, and lower right atrial volume are independently associated with in-hospital mortality. These findings on the initial echocardiogram of a preterm neonate can be used to risk stratify these patients for elevated risk for in-hospital extracorporeal membrane oxygenation utilization or mortality.

The X-Linked Helicase DDX3X Is Required for Lymphoid Differentiation and MYC-Driven Lymphomagenesis.

The X-linked gene DDX3X encodes an RNA helicase that is mutated at high frequencies in several types of human B-cell lymphoma. Females have two active DDX3X alleles and males carry a DDX3Y homolog on the Y chromosome. We show here that pan-hematopoietic, homozygous deletion of Ddx3x in female mice perturbs erythropoiesis, causing early developmental arrest. However, both hemizygous male and heterozygous female embryos develop normally, suggesting that one Ddx3x allele is sufficient for fetal hematopoietic development in females and that the Ddx3y allele can compensate for the loss of Ddx3x in males. In adult mice, DDX3X deficiency altered hematopoietic progenitors, early lymphoid development, marginal zone and germinal center B cells, and lymphomagenesis in a sex-dependent manner. Loss of both Ddx3x alleles abrogated MYC-driven lymphomagenesis in females, whereas Ddx3x deletion in males did not affect the formation of B-cell lymphoma in both mouse models. Moreover, tumors that appeared in male mice lacking DDX3X showed upregulated expression of DDX3Y, indicating a critical requirement for DDX3 activity for lymphomagenesis. These data reveal sex-specific roles of DDX3X in erythro- and lymphopoiesis as well as in MYC-driven lymphomagenesis. SIGNIFICANCE: The sex-dependent effects of DDX3X deficiency in malignant transformation of B cells and the compensatory role of DDX3Y support inhibition of DDX3 as a treatment strategy for MYC-driven B-cell lymphoma.

Myc-Interacting Zinc Finger Protein 1 (Miz-1) Is Essential to Maintain Homeostasis and Immunocompetence of the B Cell Lineage.

Aging of the immune system is described as a progressive loss of the ability to respond to immunologic stimuli and is commonly referred to as immunosenescence. B cell immunosenescence is characterized by a decreased differentiation rate in the bone marrow and accumulation of antigen-experienced and age-associated B cells in secondary lymphoid organs (SLOs). A specific deletion of the POZ-domain of the transcription factor Miz-1 in pro-B cells, which is known to be involved in bone marrow hematopoiesis, leads to premature aging of the B cell lineage. In mice, this causes a severe reduction in bone marrow-derived B cells with a drastic decrease from the pre-B cell stage on. Further, mature, naïve cells in SLOs are reduced at an early age, while post-activation-associated subpopulations increase prematurely. We propose that Miz-1 interferes at several key regulatory checkpoints, critical during B cell aging, and counteracts a premature loss of immunocompetence. This enables the use of our mouse model to gain further insights into mechanisms of B cell aging and it can significantly contribute to understand molecular causes of impaired adaptive immune responses to counteract loss of immunocompetence and restore a functional immune response in the elderly.

Beyond forced telehealth adoption: A framework to sustain telehealth among allied health services.

INTRODUCTION: As COVID-19 restrictions reduce globally, services will determine what components of care will continue via telehealth. We aimed to determine the clinician, service, and system level factors that influence sustained use of telehealth and develop a framework to enhance sustained use where appropriate. METHODS: This study was conducted across 16 allied health departments over four health service facilities (Brisbane, Australia). It used a multi-method observational study design, involving telehealth service activity data from hospital administrative databases and qualitative interviews with allied health staff (n = 80). Data were integrated and analysed using Greenhalgh's Non-adoption, Abandonment, Scale-up, Spread, and Sustainability framework. RESULTS: Increased telehealth use during the peak COVID period reverted to in-person activity as restrictions eased. Telehealth is unlikely to be sustained without a clear strategy including determination of roles and responsibilities across the organisation. Clinician resistance due to forced adoption remains a key issue. The main motivator for clinicians to use telehealth was improved consumer-centred care. Benefits beyond this are needed to sustain telehealth and improvements are required to make the telehealth experience seamless for providers and recipients. Data were synthesised into a comprehensive framework that can be used as a blueprint for system-wide improvements and service enhancement or redesign. DISCUSSION: Sustainability of telehealth activity beyond the peak COVID period is unlikely without implementation strategies to address consumer, clinician, service, and system factors. The framework can inform how these strategies can be enacted. Whilst developed for allied health disciplines, it is likely applicable to other disciplines.

Targeting MYC: From understanding its biology to drug discovery.

The MYC oncogene is considered to be a high priority target for clinical intervention in cancer patients due to its aberrant activation in more than 50% of human cancers. Direct small molecule inhibition of MYC has traditionally been hampered by its intrinsically disordered nature and lack of both binding site and enzymatic activity. In recent years, however, a number of strategies for indirectly targeting MYC have emerged, guided by the advent of protein structural information and the growing set of computational tools that can be used to accelerate the hit to lead process in medicinal chemistry. In this review, we provide an overview of small molecules developed for clinical applications of these strategies, which include stabilization of the MYC guanine quadruplex, inhibition of BET factor BRD4, and disruption of the MYC:MAX heterodimer. The recent identification of novel targets for indirect MYC inhibition at the protein level is also discussed.

Human-centered design strategies in family and staff preparation for neonatal care.

OBJECTIVE: This paper describes human-centered design strategies used to develop solutions for neonatal intensive care unit (NICU) patients, families, and staff in preparation for transition from an open bay (OB) NICU to a single-family room (SFR) NICU. HUMAN-CENTERED DESIGN: Through a series of user group meetings, an interdisciplinary team of NICU families, administrators, providers, nurses, and other care team members (CTMs) collaborated with design professionals to create and carry out their vision for the new NICU. This process, which spanned the design, construction, and transition planning phases of the project, enabled stakeholders at the Medical University of South Carolina in Charleston, South Carolina (USA) to seek solutions for integrating patient and family-centered care into the fabric of its new facility and to redesign the care experience. RESULT: From this work, new opportunities for family and staff engagement emerged. CONCLUSIONS: Continuous end-user involvement led to targeted preparation for neonatal care.

Strengthening teamwork capability in allied health: implementation of a team development program in a metropolitan health service.

Objective Collaborative practice is critical to optimising patient outcomes in contemporary healthcare settings. Evidence suggests interprofessional learning is an effective way to develop teamwork capabilities, yet these skills are traditionally developed in professional silos, or not at all. This study evaluated the implementation of a team development program, the Team Management Systems (TMS) program, for allied health staff within a large metropolitan health service. Methods A mixed-methods audit-quality improvement study was conducted, using Kirkpatrick's four-level evaluation model to structure evaluation of the program. Semistructured questionnaire and workforce survey data were retrieved immediately, 6 months and 1-2 years after training and applied to each level of the model (Reaction, Learning, Behaviour, Results). Results In all, 886 staff participated in the TMS program from 2014 to 2018. High satisfaction with the program was observed. Knowledge of what constitutes effective teamwork improved significantly (P=0.008) in TMS participants compared with a matched untrained cohort. Participants reported positive behaviour change and continued engagement with TMS principles 6 months after training. Perceived impact of the program on patient and/or organisational outcomes was evident, although less compelling than the changes to knowledge and behaviour. Conclusions The TMS program yielded positive effects on staff satisfaction, knowledge, team dynamics and team behaviours. These findings demonstrate the significant value of such initiatives to enhance the capability and effectiveness of interdisciplinary healthcare teams. What is known about the topic? Complex conditions, increasing comorbidities, specialisation and scarcity of resources mean healthcare workers need to work effectively in teams to achieve quality, safe, person centred patient care. There is some evidence of the effect of teamwork initiatives on knowledge or behaviour in specific clinical specialities, single services or single professions, but limited research is available regarding the effects of teamwork programs across multiple professions, including allied health professions, and on patient and organisational outcomes. What does this paper add? This paper describes the effect of a large-scale teamwork program implemented across multiple professions, including enablers and barriers. It presents outcomes at all four levels of Kirkpatrick's evaluation model, including the less studied behaviour and results levels. What are the implications for practitioners? This paper supports health service leaders to consider developing and implementing interprofessional teamwork programs to foster essential teamwork capabilities. Learning together about teamwork, across professional silos, will lead to collaborative, patient-centred care, which leads to safe, quality patient outcomes.

Acute Kidney Injury Guidelines Are Associated With Improved Recognition and Follow-up for Neonatal Patients.

BACKGROUND: Studies demonstrate that neonatal acute kidney injury (AKI) is associated with increased morbidity and mortality. Acute kidney injury survivors are at risk for renal dysfunction and chronic kidney disease and require long-term follow-up. PURPOSE: To maximize identification of AKI and ensure referral, we created guidelines for diagnosis, evaluation, and management of AKI. METHODS/SEARCH STRATEGY: Retrospective cohort study of neonatal intensive care unit patients treated before guideline implementation (cohort 1; n = 175) and after (cohort 2; n = 52). Outcome measures included AKI incidence, documented diagnosis, and pediatric nephrology consultation. Statistical methods included t tests, Fisher exact tests, and Wilcoxon rank sum tests. FINDINGS/RESULTS: We found 68 AKI episodes in 52 patients in cohort 1 and 15 episodes in 12 patients in cohort 2. Diagnosis and documentation of AKI improved after guideline implementation (C1:24/68 [35%], C2: 12/15 [80%]; P = .003) as did pediatric nephrology consultation (C1:12/68 [18%]; C2: 12/15 [80%]; P < .001) and outpatient referral (C1: 3/47 [6%], C2:5/8 [63%]; P < .01). IMPLICATIONS FOR PRACTICE: Neonatal AKI guideline implementation was associated with improvements in recognition, diagnosis, and inpatient and outpatient nephrology consultation. Early recognition and diagnosis along with specialist referral may improve outcomes among neonatal AKI survivors, ensuring appropriate future monitoring and long-term follow-up. IMPLICATIONS FOR RESEARCH: Future research should continue to determine the long-term implications of early diagnosis of AKI and appropriate subspecialty care with follow-up.

Investigation of a Common Clinical Approach to Poor Growth in Preterm Infants.

OBJECTIVE: This study aimed to determine the effect of elevated energy intake with medium-chain triglyceride (MCT) oil or formula powder on growth velocity and weight z-score in very low birth weight infants receiving human milk and human milk fortifier. STUDY DESIGN: This was a cohort study of infants exposed to MCT oil or formula powder for at least 7 days. Mean 7-day change in growth velocity and weight z-scores were compared pre- and postintervention. RESULTS: Forty-three infants received increased energy with either MCT oil or formula powder. Infants receiving MCT oil were more preterm and had a lower birth weight. When evaluating 7-day changes pre- and postintervention, growth velocity increased from 10.0 g/kg/day to 19.8 g/kg/day, and change in weight Z-score increased from -0.24 to 0.05. CONCLUSION: This clinical approach using MCT oil or formula powder for additional energy was associated with improved, at least short-term, growth velocity and weight z-score trajectory.

Deletion of the Miz-1 POZ Domain Increases Efficacy of Cytarabine Treatment in T- and B-ALL/Lymphoma Mouse Models.

Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer that mainly affects children. Relapse rates are high and toxic chemotherapies that block DNA replication and induce DNA damage lead to health problems later in life, underlining the need for improved therapies. MYC is a transcription factor that is hyperactive in a large proportion of cancers including leukemia but is difficult to target in therapy. We show that ablation of the function of the BTB/POZ domain factor Zbtb17 (Miz-1), an important cofactor of c-Myc, significantly delayed T- and B-ALL/lymphoma in mice and interfered with the oncogenic transcriptional activity of c-Myc. Leukemic cells that still emerged in this system activated DNA replication pathways that could be targeted by current chemotherapeutic drugs such as cytarabine. Acute ablation of the Miz-1 POZ domain enhanced the effect of cytarabine treatment. The combined treatment was effective in both Eµ-Myc and Notch ICN-driven leukemia models and prolonged survival of tumor-bearing animals by accelerating apoptosis of leukemic cells. These observations suggest that targeting MIZ-1 could render current ALL chemotherapies more effective, with a better outcome for patients. SIGNIFICANCE: Ablation of the POZ domain of Miz-1 perturbs its interaction with c-MYC and delays the generation of T- and B-cell leukemias and lymphomas.

The Effect of Atorvastatin on Vascular Function and Structure in Young Adult Survivors of Childhood Cancer: A Randomized, Placebo-Controlled Pilot Clinical Trial.

Purpose: Many adult survivors of childhood cancer are at high-risk of developing cardiovascular disease. Cancer therapy may cause damage to the vascular endothelium, thereby initiating atherosclerosis. Atorvastatin has been shown to improve endothelial function independent of reducing cholesterol, as well as reduce/slow arterial stiffness and thickening, yet has never been studied in childhood cancer survivors (CCS). Methods: Twenty-seven young adult (age 26.8 ± 6.2 years) survivors of childhood acute lymphoblastic leukemia or Non-Hodgkin's lymphoma were randomly assigned (1:1) 40 mg/day of atorvastatin or placebo for 6 months. Brachial artery flow-mediated dilation (FMD), small artery reactive hyperemia index (RHI), arterial stiffness, and carotid artery elasticity/thickness were assessed. Results: Fifteen participants completed the trial. No significant treatment effect for any vascular outcomes was observed at 6 months; however, a significant decrease in peak FMD (-3.0 [95% confidence interval [CI]: -5.3, -0.7]) and a trending significant decrease in RHI (-0.3 [95% CI: -0.62, 0.01]) was observed in the placebo group, resulting in a trend toward a treatment effects (p < 0.10). No effect on arterial stiffness, carotid arterial elasticity, or thickness was observed. Conclusion: Six months of atorvastatin treatment did not improve endothelial function or arterial stiffness in young adult CCS. While a trend toward an improvement in endothelial function was present, findings should be interpreted with caution owing to the small number of evaluable participants and subsequent lack of sufficient power. Further research in a larger sample size is needed to fully elucidate the effects of atorvastatin on vascular function. Trial registered at clinicaltrials.gov as NCT01733953.

Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative disease in mice.

Growth factor independent 1 (Gfi1) controls myeloid differentiation by regulating gene expression and limits the activation of p53 by facilitating its de-methylation at Lysine 372. In human myeloid leukemia, low GFI1 levels correlate with an inferior prognosis. Here, we show that knockdown (KD) of Gfi1 in mice causes a fatal myeloproliferative disease (MPN) that could progress to leukemia after additional mutations. Both KO and KD mice accumulate myeloid cells that show signs of metabolic stress and high levels of reactive oxygen species. However, only KO cells have elevated levels of Lysine 372 methylated p53. This suggests that in contrast to absence of GFI1, KD of GFI1 leads to the accumulation of myeloid cells because sufficient amount of GFI1 is present to impede p53-mediated cell death, leading to a fatal MPN. The combination of myeloid accumulation and the ability to counteract p53 activity under metabolic stress could explain the role of reduced GF1 expression in human myeloid leukemia.

Maternal Epidural Steroids to Prevent Neonatal Exposure to Hyperthermia and Inflammation.

BACKGROUND: Epidural analgesia is associated with a fourfold increased rate of intrapartum fever. The likely pathophysiology is a noninfectious maternal inflammatory activation. Safe interventions to reduce maternal and neonatal exposures to intrapartum fever and inflammation are needed. OBJECTIVE: The purpose of this study was to determine if prophylactic epidural steroids decrease fetal exposure to hyperthermia and inflammatory cytokines following epidural analgesia. STUDY DESIGN: This is a randomized, double-blinded, placebo controlled trial. Term nulliparous women requesting epidural analgesia received 80 mg methylprednisolone or preservative-free normal saline via the epidural catheter at placement. The primary outcome was maternal temperature >100.4°F. Secondary outcomes included fetal exposure to inflammation as assessed by cord blood interleukin-6 (IL-6) levels and rates of funisitis. Power analysis estimated a sample size requirement of 276, but new Food and Drug Administration (FDA) recommendations advising a black box warning on epidural steroids resulted in early study termination. RESULTS: A total of 116 subjects were enrolled: 58 treatments and 58 placebos. There was no difference in the rate of maternal intrapartum fever or cord blood IL-6 levels between treatment arms. No complications listed in the FDA warning occurred. CONCLUSION: Prophylactic epidural methylprednisolone was not effective in reducing intrapartum fever or neonatal inflammation following epidural analgesia. Alternate mechanisms and preventative strategies should be considered.

Cytomegalovirus-Induced Hemophagocytic Lymphohistiocytosis in an Extreme Preterm Infant: Recognition and Therapy Leading to Recovery.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that can be triggered by cytomegalovirus, a relatively common infectious exposure to neonates. The clinical presentation is common to many acute illnesses seen in extreme premature infants; however, there are key clinical and laboratory findings that can lead to the diagnosis. PURPOSE: We present a case of an extreme premature infant of 25 weeks' gestation who developed cytomegalovirus-induced HLH. Using the current published protocols that are used in pediatric cancer can be adapted for use in a premature infant, which led to remission of HLH and eventual discharge from the neonatal intensive care unit. IMPLICATIONS FOR PRACTICE: There are published treatment protocols used in pediatric oncology that when initiated early can lead to favorable outcomes and remission in even the most fragile neonates. IMPLICATIONS FOR RESEARCH: Additional studies are needed on the pharmacokinetics, dosing, and side effects on medications used for treatment of HLH in preterm infants. Additional research is needed to improve the clinician's ability to reach the diagnosis as well as define treatment strategies that provide optimal outcomes.