Epigenomic regulation of human T-cell leukemia virus by chromatin-insulator CTCF.

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes an aggressive T-cell malignancy and a variety of inflammatory conditions. The integrated provirus includes a single binding site for the epigenomic insulator, CCCTC-binding protein (CTCF), but its function remains unclear. In the current study, a mutant virus was examined that eliminates the CTCF-binding site. The mutation did not disrupt the kinetics and levels of virus gene expression, or establishment of or reactivation from latency. However, the mutation disrupted the epigenetic barrier function, resulting in enhanced DNA CpG methylation downstream of the CTCF binding site on both strands of the integrated provirus and H3K4Me3, H3K36Me3, and H3K27Me3 chromatin modifications both up- and downstream of the site. A majority of clonal cell lines infected with wild type HTLV-1 exhibited increased plus strand gene expression with CTCF knockdown, while expression in mutant HTLV-1 clonal lines was unaffected. These findings indicate that CTCF binding regulates HTLV-1 gene expression, DNA and histone methylation in an integration site dependent fashion.

Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade.

Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.

Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma.

BACKGROUND: Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo. RESULTS: ATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo. To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo, transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and ß, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2. CONCLUSIONS: These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.

Phototherapy to Prevent Severe Neonatal Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation: Technical Report.

OBJECTIVE: To summarize the principles and application of phototherapy consistent with the current 2022 American Academy of Pediatrics "Clinical Practice Guideline Revision for the Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation." METHODS: Relevant literature was reviewed regarding phototherapy devices in the United States, specifically those that incorporate blue to blue-green light-emitting diode, fluorescent, halogen, or fiberoptic light sources, and their currently marketed indications. RESULTS: The efficacy of phototherapy devices varies widely because of nonstandardized use of light sources and configurations and irradiance meters. In summary, the most effective and safest devices have the following characteristics: (1) incorporation of narrow band blue-to-green light-emitting diode lamps (∼460-490 nm wavelength range; 478 nm optimal) that would best overlap the bilirubin absorption spectrum; (2) emission of irradiance of at least 30 µW/cm2/nm (in term infants); and (3) illumination of the exposed maximal body surface area of an infant (35% to 80%). Furthermore, accurate irradiance measurements should be performed using the appropriate irradiance meter calibrated for the wavelength range delivered by the phototherapy device. CONCLUSIONS: With proper administration of effective phototherapy to an infant without concurrent hemolysis, total serum or plasma bilirubin concentrations will decrease within the first 4 to 6 hours of initiation safely and effectively.

Racial and Ethnic Disparities in Length of Stay for Common Pediatric Diagnoses: Trends From 2016 to 2019.

BACKGROUND AND OBJECTIVES: Inequities in pediatric illness include unequal treatment and outcomes for children of historically marginalized races/ethnicities. Length of stay (LOS) is used to assess health care quality and is associated with higher costs/complications. Studies show LOS disparities for Black and Hispanic children in specific diagnoses, but it is unclear how broadly they exist or how they change over time. We examined the association between race/ethnicity and LOS longitudinally for the most common pediatric inpatient diagnoses. METHODS: We used the 2016 and 2019 Kids' Inpatient Databases. The 10 most frequent diagnoses in 2016 were determined. For each diagnosis in each year, we assessed the association between race and LOS by fitting a generalized linear mixed effects model with a negative binomial distribution, accounting for clustering and confounding. Using descriptive statistics, we compared associations between the 2 years for trends over time. RESULTS: Our analysis included >450 000 admissions and revealed significantly longer LOS for Black, Hispanic, and/or Asian American or Pacific Islander, Native American, and other children in 8 of the 10 diagnoses in 2016, with mixed changes over time. Three new disparities emerged in 2019. The largest disparities were for Black children in most diagnoses. CONCLUSIONS: Kids' Inpatient Database data showed longer LOS for children of historically marginalized race/ethnicity with common pediatric inpatient diagnoses, which largely persisted from 2016 to 2019. There is no plausible biological explanation for these findings, and inequities in social needs, access to care, and quality of care likely contribute. Future directions include further study to understand and address contributing factors.

Adult T-Cell Leukemia-Lymphoma Presenting Concurrently with Myelopathy.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus. Of the approximate ten to twenty million people currently infected worldwide, 4-9% of infected individuals develop adult T-cell leukemia/lymphoma (ATLL) or HTLV-associated myelopathy/tropical spastic paresis (HAM/TSP) in their lifetime. The current report is based on a patient who presented concurrently with CD30+ lymphoma subtype ATLL and HAM/TSP. The patient's ATLL responded to brentuximab-vedotin-based chemotherapy; however, HAM/TSP did not improve. The patient's peripheral blood mononuclear cells were cultured and injected into immunodeficient mice, and the mice developed massive organ involvement and chronic lymphocytic leukemia-subtype ATLL. This case study is novel in the findings of concurrent development of ATLL and HAM/TSP, the response to brentuximab-vedotin chemotherapy, and the use HTLV-1 helix basic zipper protein-targeted probe for RNAscope for diagnosis.

Reviewer Feedback for Abstract Submissions to the Pediatric Academic Societies Meeting: A Pilot Project.

PURPOSE: To describe and evaluate a pilot project to provide reviewer comments to authors who submitted abstracts to the Hospital-based medicine topic area for the Pediatric Academic Societies (PAS) 2021 annual meeting METHODS: Abstract reviewers were encouraged via email to include reviewer comments for authors in their abstract reviews. Unedited comments were emailed to authors shortly after the abstract decision notifications were sent. We quantified the number of reviewers who commented per abstract. Additionally, we surveyed authors and reviewers to evaluate the perceived impact of the pilot project. RESULTS: For 123 abstracts submitted to the Hospital-based medicine topic area, every abstract received comments from at least one reviewer, and a median (IQR) of 4 (3-5) reviewers commented per abstract. The response rates for the author and reviewer surveys were 61/114 (54%) and 54/84 (64%), respectively, and both groups of respondents generally favored the pilot program. The majority of authors (59%) made changes to their project based on the feedback provided and 96% reported that they would like to continue to receive reviewer feedback for future PAS abstract submissions. Reviewers reported spending a mean of 11 minutes reviewing each abstract. Most (85%) felt that they spent the same or slightly more (1%-25%) time reviewing than in prior years. Multiple open-ended comments were provided, largely positive. CONCLUSION: A pilot program to incorporate reviewer feedback into abstract decision notification for a large national research meeting was successful. This approach should be considered for future meetings to enhance this integral component of academic development.

Guidance for Structuring a Pediatric Intermediate Care Unit.

The purpose of this policy statement is to update the 2004 American Academy of Pediatrics clinical report and provide enhanced guidance for institutions, administrators, and providers in the development and operation of a pediatric intermediate care unit (IMCU). Since 2004, there have been significant advances in pediatric medical, surgical, and critical care that have resulted in an evolution in the acuity and complexity of children potentially requiring IMCU admission. A group of 9 clinical experts in pediatric critical care, hospital medicine, intermediate care, and surgery developed a consensus on priority topics requiring updates, reviewed the relevant evidence, and, through a series of virtual meetings, developed the document. The intended audience of this policy statement is broad and includes pediatric critical care professionals, pediatric hospitalists, pediatric surgeons, other pediatric medical and surgical subspecialists, general pediatricians, nurses, social workers, care coordinators, hospital administrators, health care funders, and policymakers, primarily in resource-rich settings. Key priority topics were delineation of core principles for an IMCU, clarification of target populations, staffing recommendations, and payment.

The Future of Inpatient Community Hospital Care: Is There One?

Community hospital inpatient pediatric programs face a variety of challenges including financial instability, variable censuses, difficulty maintaining qualified staff, and a lack of focus for the hospital. With the addition of new payment models, such as bundled payments and global budgets, along with a global pandemic, the future of community hospital pediatric inpatient care is uncertain at best. In this article we summarize the challenges, opportunities, and potential solutions to maintaining high-quality care for hospitalized children in community hospitals.

Targeting NF-κB with Nanotherapy in a Mouse Model of Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive, clonal malignancy of mature T cells caused by human T-cell leukemia virus type 1. Although it is a rare tumor type, it serves as an excellent model of a virus driven process that transforms cells and engenders a highly malignant tumor that is extraordinarily difficult to treat. The viral transcriptional transactivator (Tax) in the HTLV-1 genome directly promotes tumorigenesis, and Tax-induced oncogenesis depends on its ability to constitutively activate NF-κB signaling. Accordingly, we developed and evaluated a nano-delivery system that simultaneously inhibits both canonical (p65) and noncanonical (p100) NF-κB signaling pathways locally in tumors after systemic administration. Our results demonstrate that siRNA is delivered rapidly to ATLL tumors after either i.p. or i.v. injection. The siRNA treatment significantly reduced both p65 and p100 mRNA and protein expression. Anti-NF-κB nanotherapy significantly inhibited tumor growth in two distinct tumor models in mice: a spontaneous Tax-driven tumor model, and a Tax tumor cell transplant model. Moreover, siRNA nanotherapy sensitized late-stage ATLL tumors to the conventional chemotherapeutic agent etoposide, indicating a pleiotropic benefit for localized siRNA nanotherapeutics.

Availability of Pediatric Inpatient Services in the United States.

OBJECTIVES: We sought to evaluate trends in pediatric inpatient unit capacity and access and to measure pediatric inpatient unit closures across the United States. METHODS: We performed a retrospective study of 4720 US hospitals using the 2008-2018 American Hospital Association survey. We used linear regression to describe trends in pediatric inpatient unit and PICU capacity. We compared trends in pediatric inpatient days and bed counts by state. We examined changes in access to care by calculating distance to the nearest pediatric inpatient services by census block group. We analyzed hospital characteristics associated with pediatric inpatient unit closure in a survival model. RESULTS: Pediatric inpatient units decreased by 19.1% (34 units per year; 95% confidence interval [CI] 31 to 37), and pediatric inpatient unit beds decreased by 11.8% (407 beds per year; 95% CI 347 to 468). PICU beds increased by 16.0% (66.9 beds per year; 95% CI 53 to 81), primarily at children's hospitals. Rural areas experienced steeper proportional declines in pediatric inpatient unit beds (-26.1% vs -10.0%). Most states experienced decreases in both pediatric inpatient unit beds (median state -18.5%) and pediatric inpatient days (median state -10.0%). Nearly one-quarter of US children experienced an increase in distance to their nearest pediatric inpatient unit. Low-volume pediatric units and those without an associated PICU were at highest risk of closing. CONCLUSIONS: Pediatric inpatient unit capacity is decreasing in the United States. Access to inpatient care is declining for many children, particularly those in rural areas. PICU beds are increasing, primarily at large children's hospitals. Policy and surge planning improvements may be needed to mitigate the effects of these changes.

HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia.

Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models. Humanized mice infected with HTLV-1 developed lymphoproliferative disease and continuous, progressive osteolytic bone lesions. HTLV-1 lacking HBZ displayed only modest delays to lymphoproliferative disease but significantly decreased disease-associated bone loss compared with HTLV-1-infected mice. Gene expression array of acute ATL patient samples demonstrated increased expression of RANKL, a critical regulator of osteoclasts. We found that HBZ regulated RANKL in a c-Fos-dependent manner. Treatment of HTLV-1-infected humanized mice with denosumab, a monoclonal antibody against human RANKL, alleviated bone loss. Using patient-derived xenografts from primary human ATL cells to induce lymphoproliferative disease, we also observed profound tumor-induced bone destruction and increased c-Fos and RANKL gene expression. Together, these data show the critical role of HBZ in driving ATL-associated bone loss through RANKL and identify denosumab as a potential treatment to prevent bone complications in ATL patients.

Inpatient brain MRI for new-onset seizures: utility and cost effectiveness.

Inpatient magnetic resonance imaging for evaluation of new-onset afebrile seizures can extend hospital stay, can add cost, and may not affect acute management. The study was to assess cost and impact on acute management of inpatient brain magnetic resonance imagings performed as part of new-onset seizure evaluation. Retrospective chart review of brain magnetic resonance imagings on pediatric inpatients admitted for new-onset afebrile seizure has been carried out. Seventy-five patients were identified. Seventy-one of the patients (95%) stayed an additional day for the magnetic resonance imaging. Thirteen had abnormal results. No patient had treatment changes based upon the magnetic resonance imaging results. If these magnetic resonance imagings had been done as an outpatient, the savings to the hospital could have been $215,575. Thus, obtaining an inpatient brain magnetic resonance imaging for evaluation of new-onset seizures did not lead to acute changes in management and added to facility costs and length of stay. Scheduling a magnetic resonance imaging as an outpatient could achieve cost savings without compromising care.

Physician's Role in Coordinating Care of Hospitalized Children.

The hospitalization of a child is a stressful event for the child and family. The physician responsible for the admission has an important role in directing the care of the child, communicating with the child's providers (medical and primary caregivers), and advocating for the safety of the child during the hospitalization and transition out of the hospital. These challenges remain constant across the varied facilities in which children are hospitalized. The purpose of this revised clinical report is to update pediatricians about principles to improve the coordination of care and review expectations and practice.

Changes in Urinary Tract Infection Hospitalizations Post 2011 Revised American Academy Pediatrics Guidelines.

BACKGROUND: Multiple randomized trials over the past 2 decades have supported oral antimicrobial treatment for urinary tract infection (UTI), and the 2011 revised American Academy Pediatrics guidelines on the management of UTI provide further support for outpatient management. It is unknown whether practice patterns have changed as a result of these developments. OBJECTIVE: To examine temporal trends in UTI hospitalizations between 1997 and 2012 as measured by the Kids' Inpatient Database. DESIGN AND METHODS: The Kid's Inpatient Database was used to analyze trends in UTI hospitalizations between 1997 and 2012. This triennial database is publicly available through the Agency for Healthcare Research and Quality. Hospitalization volume for clinical classification software principal diagnosis category 159 Urinary tract infection was examined for trends across years by age. Changes in length of stay and charges corrected for inflation were also examined. RESULTS: There were significantly fewer weighted UTI hospitalizations in 2012 compared with 1997 to 2009 (48 102 SE ± 1494 in 2009 vs 41 177 SE ± 1467 in 2012, P < .0001). The largest decrease was in 15- to 17-year-old (19.2%) and <1-year-old (18.6%) groups. The length of stay trended down consistently, but charges have increased despite correcting for consumer price index. CONCLUSIONS: Year 2012 represents the first significant decrease in national hospitalization rates for UTI since 1997, a trend that may be explained by the accumulating evidence supporting outpatient management in addition to recommendations from the 2011 American Academy of Pediatrics UTI guidelines.

HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ. Tax, a transcriptional activator, is critical to ATL development, and has been implicated in pathologic osteolysis. HBZ, HTLV-1 basic leucine zipper transcription factor, promotes tumor cell proliferation and disrupts Wnt pathway modulators; however, its role in ATL induced osteolytic bone loss is unknown. To determine if HBZ is sufficient for the development of bone loss, we established a transgenic Granzyme B HBZ (Gzmb-HBZ) mouse model. Lymphoproliferative disease including tumors, enlarged spleens and/or abnormal white cell counts developed in two-thirds of Gzmb-HBZ mice at 18 months. HBZ positive cells were detected in tumors, spleen and bone marrow. Importantly, pathologic bone loss and hypercalcemia were present at 18 months. Bone-acting factors were present in serum and RANKL, PTHrP and DKK1, key mediators of hypercalcemia and bone loss, were upregulated in Gzmb-HBZ T cells. These data demonstrate that Gzmb-HBZ mice model ATL bone disease and express factors that are current therapeutic targets for metastatic and bone resident tumors.

Cholesterol dependence of HTLV-I infection.

Cholesterol-rich plasma membrane microdomains are important for entry of many viruses, including retroviruses. Depletion of cholesterol with 2-hydroxypropyl-beta-cyclodextrin inhibits entry of human T cell leukemia virus type I (HTLV-1) and HTLV-I envelope pseudotyped lentivirus particles. Using a soluble fusion protein of the HTLV-I surface envelope protein with the immunoglobulin Fc domain, the HTLV-I receptor was found to colocalize with a raft-associated marker and to cluster in specific plasma membrane microdomains. Depletion of cholesterol did not alter receptor binding activity, suggesting a requirement for cholesterol in a postbinding virus entry step.

Lessons from pediatrics residency program directors' experiences with work hour limitations in New York State.

PURPOSE: To evaluate the impact of residency work hour limitations on pediatrics residency programs in New York State, and to learn lessons that can be used nationally with the implementation of the Accreditation Council of Graduate Medical Education's similar rules. METHOD: A three-page questionnaire was mailed to all pediatrics residency program directors in New York. The questionnaire assessed methods used to accommodate the work hour limitations and perceptions of the limitations' effects. RESULTS: Twenty-one program directors responded (68%). Only large programs used night floats and night teams to meet work hour requirements. Programs of all sizes and in all settings used cross coverage and sent residents home immediately post call. About half of the programs hired additional nonresident staff, usually nurse practitioners, physician assistants, and/or attendings. The most frequently reported effects were decreases in the amount of time residents spent in inpatient settings, patient continuity in inpatient settings, flexibility of residents' scheduling, and increased logistical work needed to maintain continuity clinic. A summary of advice to other program directors was "be creative" and "be flexible." CONCLUSIONS: New York's pediatrics residency programs used a variety of mechanisms to meet work hour restrictions. Smaller programs had fewer methods available to them to meet such restrictions. Although the logistical work needed to maintain continuity clinic increased greatly, continuity and outpatient settings themselves were not greatly affected by work hour limitations. Inpatient settings were more affected and experienced much more in the way of change.

Introduction to pediatric hospital medicine.

This article provides a brief summary of the past, present, and future of pediatric hospital medicine. In its short history, it already has made an impact on the way pediatrics is practiced and taught. There is no denying Dr. Menna's prescience when he wrote his opinion in 1990. As the field continues to emerge and mature, the current leadership is cognizant of the obstacles ahead and the need to maintain the goal of the well-being of all children. Maintaining that goal means redoubling efforts to maintain contact with primary care providers for continuity of care in and out of the hospital. Only by promoting patient- and family-centered care, inclusive of all providers, can children's health best be served.