Biophysical interactions between pancreatic cancer cells and pristine carbon nanotube substrates: Potential application for pancreatic cancer tissue engineering.

Novel synthetic biomaterials able to support direct tissue growth and retain cellular phenotypical properties are promising building blocks for the development of tissue engineering platforms for accurate and fast therapy screening for cancer. The aim of this study is to validate an aligned, pristine multi-walled carbon nanotube (CNT) platform for in vitro studies of pancreatic cancer as a systematic understanding of interactions between cells and these CNT substrates is lacking. Our results demonstrate that our CNT scaffolds-which are easily tuneable to form sheets/fibers-support growth, proliferation, and spatial organization of pancreatic cancer cells, indicating their great potential in cancer tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1637-1644, 2018.

The Next 7 Great Achievements in Pediatric Research.

The "7 Great Achievements in Pediatric Research" campaign noted discoveries in the past 40 years that have improved child and adult health in the United States and around the globe. This article predicts the next 7 great pediatric research advancements, including new immunizations, cancer immunotherapy, genomic discoveries, identification of early antecedents of adult health, impact of specific social-environmental influences on biology and health, quality improvement science, and implementation and dissemination research to reduce global poverty. It is an extraordinary time of new research tools that include electronic health records, technological ability to manage big data and measure "omics," and new functional and structural imaging modalities. These tools will discern mechanisms leading to health and disease with new prevention targets and cures. This article further discusses the challenges and opportunities to accelerate these exciting pediatric research discoveries to improve the lives of children and the adults they will become.

Pediatric Academic Productivity: Pediatric Benchmarks for the h- and g-Indices.

OBJECTIVE: To describe h- and g-indices benchmarks in pediatric subspecialties and general academic pediatrics. Academic productivity is measured increasingly through bibliometrics that derive a statistical enumeration of academic output and impact. The h- and g-indices incorporate the number of publications and citations. Benchmarks for pediatrics have not been reported. STUDY DESIGN: Thirty programs were selected randomly from pediatric residency programs accredited by the Accreditation Council for Graduate Medical Education. The h- and g-indices of department chairs were calculated. For general academic pediatrics, pediatric gastroenterology, and pediatric nephrology, a random sample of 30 programs with fellowships were selected. Within each program, an MD faculty member from each academic rank was selected randomly. Google Scholar via Harzing's Publish or Perish was used to calculate the h-index, g-index, and total manuscripts. Only peer-reviewed and English language publications were included. For Chairs, calculations from Google Scholar were compared with Scopus. RESULTS: For all specialties, the mean h- and g-indices significantly increased with academic rank (all P < .05) with the greatest h-indices among Chairs. The h- and g-indices were not statistically different between specialty groups of the same rank; however, mean rank h-indices had large SDs. The h-index calculation using different bibliographic databases only differed by ±1. CONCLUSION: Mean h-indices increased with academic rank and were not significantly different across the pediatric specialties. Benchmarks for h- and g-indices in pediatrics are provided and may be one measure of academic productivity and impact.

Fetal hemoglobin in sickle cell anemia: a glass half full?

Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia by inhibiting deoxy sickle hemoglobin (HbS) polymerization. The blood concentration of HbF, or the number of cells with detectable HbF (F-cells), does not measure the amount of HbF/F-cell. Even patients with high HbF can have severe disease because HbF is unevenly distributed among F-cells, and some cells might have insufficient concentrations to inhibit HbS polymerization. With mean HbF levels of 5%, 10%, 20%, and 30%, the distribution of HbF/F-cell can greatly vary, even if the mean is constant. For example, with 20% HbF, as few as 1% and as many as 24% of cells can have polymer-inhibiting, or protective, levels of HbF of ∼10 pg; with lower HbF, few or no protected cells can be present. Only when the total HbF concentration is near 30% is it possible for the number of protected cells to approach 70%. Rather than the total number of F-cells or the concentration of HbF in the hemolysate, HbF/F-cell and the proportion of F-cells that have enough HbF to thwart HbS polymerization is the most critical predictor of the likelihood of severe sickle cell disease.

Utilizing electronic health record data to determine the health of the medication process after the relocation of a children's hospital.

UNLABELLED: Hospital relocation is a highly complex undertaking, which has the potential to interrupt operations and poses risks for patients, staff, and providers. Little is known how hospital relocation impacts on workflow and communication. METHODS: Using existing Electronic Health Record (EHR) data we determined time from medication ordering to first dose administration as a proxy for well-being of the medication process during a five months window surrounding the relocation of a 205-bed children's hospital. RESULTS: Overall performance of the medication process has declined slightly. We identified regional (unit) differences with the pediatric intensive care unit, which had the most significant changes to its workflow, experiencing a more than doubling of the time from ordering to medication administration. Overall, there was no significant difference in time-sensitive medication administration times. Evaluating the medication ordering-dispensing-administration process through readily available EHR data demonstrated that the impact of a hospital' s relocation on workflow and communication can be successfully monitored.

Improving teaching on an inpatient pediatrics service: a retrospective analysis of a program change.

BACKGROUND: The traditional role of the faculty inpatient attending providing clinical care and effectively teaching residents and medical students is threatened by increasing documentation requirements, pressures to increase clinical productivity, and insufficient funding available for medical education. In order to sustain and improve clinical education on a general pediatric inpatient service, we instituted a comprehensive program change. Our program consisted of creating detailed job descriptions, setting clear expectations, and providing salary support for faculty inpatient attending physicians serving in clinical and educational roles. This study was aimed at assessing the impact of this program change on the learners' perceptions of their faculty attending physicians and learners' experiences on the inpatient rotations. METHODS: We analyzed resident and medical student electronic evaluations of both clinical and teaching faculty attending physician characteristics, as well as resident evaluations of an inpatient rotation experience. We compared the proportions of "superior" ratings versus all other ratings prior to the educational intervention (2005-2006, baseline) with the two subsequent years post intervention (2006-2007, year 1; 2007-2008, year 2). We also compared medical student scores on a comprehensive National Board of Medical Examiners clinical subject examination pre and post intervention. RESULTS: When compared to the baseline year, pediatric residents were more likely to rate as superior the quality of didactic teaching (OR=1.7 [1.0-2.8] year 1; OR=2.0 [1.1-3.5] year 2) and attendings' appeal as a role model (OR=1.9 [1.1-3.3] year 2). Residents were also more likely to rate as superior the quality of feedback and evaluation they received from the attending (OR=2.1 [1.2-3.7] year 1; OR=3.9 [2.2-7.1] year 2). Similar improvements were also noted in medical student evaluations of faculty attendings. Most notably, medical students were significantly more likely to rate feedback on their data gathering and physical examination skills as superior (OR=4.2 [2.0-8.6] year 1; OR=6.4 [3.0-13.6] year 2). CONCLUSIONS: A comprehensive program which includes clear role descriptions along with faculty expectations, as well as salary support for faculty in clinical and educational roles, can improve resident and medical student experiences on a general pediatric inpatient service. The authors provide sufficient detail to replicate this program to other settings.

Child health research funding and policy: imperatives and investments for a healthier world.

Although pediatric research enjoyed significant benefits during the National Institutes of Health (NIH) doubling era, the proportion of the NIH budget devoted to the pediatric-research portfolio has declined overall. In light of this declining support for pediatric biomedical research, the Federation of Pediatric Organizations held a topic symposium at the 2009 Pediatric Academic Societies annual meeting as a forum for discussion of the past and future states of funding, the rationale for directing public funds toward the understanding of child health and disease, and new programs and paradigms for promoting child health research. This report of the symposium is intended to disseminate more broadly the information presented and conclusions discussed to encourage those in the child health research community to exert influence with policy makers to increase the allocation of national funding for this underfunded area.

Pulmonary hypertension and nitric oxide depletion in sickle cell disease.

During the past decade a large body of experimental and clinical studies has focused on the hypothesis that nitric oxide (NO) depletion by plasma hemoglobin in the microcirculation plays a central role in the pathogenesis of many manifestations of sickle cell disease (SCD), particularly pulmonary hypertension. We have carefully examined those studies and believe that the conclusions drawn from them are not adequately supported by the data. We agree that NO depletion may well play a role in the pathophysiology of other hemolytic states such as paroxysmal nocturnal hemoglobinuria, in which plasma hemoglobin concentrations are often at least an order of magnitude greater than in SCD. Accordingly, we conclude that clinical trials in SCD designed to increase the bioavailability of NO or association studies in which SCD clinical manifestations are related to plasma hemoglobin via its surrogates should be viewed with caution.

Patient safety rounds in a pediatric tertiary care center.

BACKGROUND: Patient safety rounds were implemented in a pediatric tertiary care setting. Completed patient safety issues from three years of pediatric patient safety rounds and nine months of pediatric surgical safety rounds were analyzed. Completed issues were categorized into both Modified Vincent and University HealthSystem Consortium (UHC) categorization schemes to compare and contrast their attributes. FINDINGS: From January 2003 through January 2006, there were 159 completed patient safety issues, 148 (93%) from general pediatric safety rounds and 11 (7%) from pediatric surgical safety rounds. Using the UHC classification scheme, 35.8% of the issues were classified as care coordination/records, 27.0% as equipment safety situation/preventive maintenance, 21.4% as equipment/supplies/devices, 3.8% as error related to procedure/ treatment/test, and 3.8% as medication error. In the Modified Vincent classification scheme, 63.5% of the issues were classified as environmental factors, 23.3% as team factors, 6.9% as individual factors, 3.1% as task factors, and 1.9% as patient characteristics. Pediatric safety rounds were well received by both frontline staff and senior executives. DISCUSSION: The use of pediatric safety rounds is a low-cost intervention that helps to partner senior leaders and frontline staff on patient safety and is an effective tool for improving patient safety in a pediatric setting.

Pulsed-dosing with oral sodium phenylbutyrate increases hemoglobin F in a patient with sickle cell anemia.

Increasing hemoglobin F (HbF) appears to be beneficial for patients with sickle cell anemia. We previously demonstrated that daily, oral sodium phenylbutyrate (OSPB) induces HbF synthesis in pediatric and adult patients with hemoglobin SS (HbSS). The high doses and need for daily therapy, however, have limited its use. Here, we report a patient treated with pulsed-dosing of OSPB for over 3 years. This patient developed a modest, but sustained elevation in HbF over the course of therapy without side effects. Although larger studies are needed, this case demonstrates that pulsed-dosing with OSPB enhances HbF synthesis.

Role of cyclic nucleotides in fetal hemoglobin induction in cultured CD34+ cells.

OBJECTIVE: In vivo, several drugs have been shown to increase fetal hemoglobin (HbF), including 5-azacytidine (AZA), sodium butyrate (SB), and hydroxyurea (HU). Studies in K562 cells suggest that cyclic guanosine monophosphate (cGMP) is required for HbF induction; however, the role of cyclic nucleotides in HbF induction in primary erythroid cultures has not been established. METHODS: CD34-selected peripheral blood monocytes cultured in a semi-solid serum-free system that mimics in vivo F-cell production are utilized to explore the role of cyclic adenosine monophosphate (cAMP) and cGMP in HbF induction in response to HU, AZA, and SB. RESULTS: In serum-free CD34 cultures, HU, SB, and AZA all markedly stimulate FNRBC production up to 30-fold, associated with induction of gamma-globin mRNA and total HbF protein. Guanylate cyclase inhibition results in only minimal blunting of HbF induction by each agent. In contrast, adenylate cyclase inhibition markedly reduces HU, SB, and AZA-mediated FNRBC induction and gamma-globin mRNA induction. The adenylate cyclase activator forskolin modestly induces FNRBC production and augments the action of standard induction agents. HU, AZA, and SB, however, fail to significantly stimulate adenylate cyclase themselves. CONCLUSIONS: In human CD34(+) cultures, cAMP production is required for full induction of HbF by HU, SB, and AZA, while perturbation of cGMP production has only minimal effects. These findings are in marked contrast to data in K562 cells where cGMP production is critical for HbF induction while cAMP stimulation blunts HbF response, and suggest that these agents may share a common induction pathway.

Hospitalization rates and costs of care of patients with sickle-cell anemia in the state of Maryland in the era of hydroxyurea.

The multicenter study of hydroxyurea (MSH) in sickle-cell anemia (SCA) demonstrated that patients treated with hydroxyurea (HU) had a 44% decrease in hospitalizations when compared with those taking placebo. A subsequent study looking at the cost-effectiveness of HU showed that decreased hospitalizations for painful crisis accounted for the majority of cost savings in those taking HU. The purpose of this study was to examine whether the expected decrease in hospital utilization occurred after the approval of HU in Maryland. We used data collected by the Maryland Health Services Cost Review Commission to obtain SCA discharge data for Maryland from FY1995 through FY2003. We also reviewed the inpatient and outpatient charts of all adults with SCA admitted to a large university hospital during 2003. Hospitalization rates for adults with SCA in Maryland have increased significantly since approval of HU. While the total costs of inpatient care in Maryland are estimated to have increased by 31% above inflation from 1995 to 2003, the costs of inpatient care for adult SCA patients has increased by almost 60% above inflation. By comparison, there has been no significant increase in the pediatric hospitalization rate. We found that 70% of patients in one hospital who were appropriate candidates for HU were not taking the medication. Hospital utilization among adults with SCA has increased significantly. There are likely many factors that have played a role in this increase. One factor that appears to be involved is the underutilization of HU.

Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms.

Optimal reexpression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of aza-CR. Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders. Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation. Gene demethylation correlated with the area under the aza-CR plasma concentration-time curve. Administration of both drugs was associated with induction of acetylation of histones H3 and H4. This study provides the first demonstration that molecular mechanisms responsible for responses to DNA methyltransferase/histone deacetylase inhibitor combinations may include reversal of aberrant epigenetic gene silencing. The promising percentage of major hematologic responses justifies the testing of such combinations in prospective randomized trials.