Medical Specialties Commons^™

Mycn Amplification Is Associated With Repressed Cellular Immunity In Neuroblastoma: An In Silico Immunological Analysis Of Target Database, Peng Zhang, Xiaofang Wu, Moushumi Basu, Chen Dong, Pan Zhang, Yang Liu, Anthony D. Sandler

Pediatrics Faculty Publications

Purpose: RNA and DNA sequencing data are traditionally used to discern intrinsic cellular pathways in cancer pathogenesis, their utility for investigating the tumor microenvironment (TME) has not been fully explored. This study explores the use of sequencing data to investigate immunity within the TME.

Experimental design: Here, we use immune cell fraction estimation analysis to determine the immune profiles in the microenvironment of neuroblastoma (NB) based on RNA-seq data in the TARGET database. The correlation between immune cell transcripts and prognosis in pediatric NB is also investigated.

Results: In silico analysis revealed a strong inverse correlation between MYCNamplification and …

Non-Invasive Placental Perfusion Imaging In Pregnancies Complicated By Fetal Heart Disease Using Velocity-Selective Arterial Spin Labeled Mri, Zungho Zun, Greg Zaharchuk, Nickie Niforatos Andescavage, Mary T. Donofrio, Catherine Limperopoulos

Pediatrics Faculty Publications

The placenta is a vital organ for fetal growth and development during pregnancy. Congenital heart disease (CHD) is a leading cause of morbidity and mortality in newborns. Despite the parallel development of the placenta and fetal heart early in pregnancy, very few studies suggested an association between placental dysfunction and fetal CHD. In this study, we report placental perfusion of healthy pregnancies and pregnancies complicated by fetal CHD measured using advanced fetal MRI techniques. We studied forty-eight pregnant women (31 healthy volunteers and 17 with fetal CHD) that underwent fetal MRI during their second or third trimester of pregnancy. Placental …

Disorders Of Metal Metabolism, Carlos Ferreira, William A. Gahl

Pediatrics Faculty Publications

Trace elements are chemical elements needed in minute amounts for normal physiology. Some of the physiologically relevant trace elements include iodine, copper, iron, manganese, zinc, selenium, cobalt and molybdenum. Of these, some are metals, and in particular, transition metals. The different electron shells of an atom carry different energy levels, with those closest to the nucleus being lowest in energy. The number of electrons in the outermost shell determines the reactivity of such an atom. The electron shells are divided in sub-shells, and in particular the third shell has s, p and d sub-shells. Transition metals are strictly defined as …

Toward A Rapid Production Of Multivirus-Specific T Cells Targeting Bkv, Adenovirus, Cmv, And Ebv From Umbilical Cord Blood, Hema Dave, Min Luo, J.W. Blaney, Shabnum Patel, Cecilia Barese, Conrad Russell Cruz, Elizabeth J. Shpall, Catherine M. Bollard, Patrick J. Hanley

Pediatrics Faculty Publications

Umbilical cord blood (CB) has emerged as an effective alternative donor source for hematopoietic stem cell transplantation. Despite this success, the prolonged duration of immune suppression following CB transplantation and the naiveté of CB T cells leave patients susceptible to viral infections. Adoptive transfer of ex vivo-expanded virus-specific T cells from CB is both feasible and safe. However, the manufacturing process of these cells is complicated, lengthy, and labor-intensive. We have now developed a simplified method to manufacture a single culture of polyclonal multivirus-specific cytotoxic T cells in less than 30 days. It eliminates the need for a live virus …

Malignant Peripheral Nerve Sheath Tumors State Of The Science: Leveraging Clinical And Biological Insights Into Effective Therapies., Aerang Kim, Douglas R Stewart, Karlyne M Reilly, David Viskochil, Markku M Miettinen, Brigitte C Widemann

Pediatrics Faculty Publications

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute …

Medical Genetics And Genomic Medicine In The United States. Part 2: Reproductive Genetics, Newborn Screening, Genetic Counseling, Training, And Registries, Debra S. Regier, Carlos Ferreira, Suzanne Hart, Donald Hadley, Maximilian Muenke

Pediatrics Faculty Publications

eview of genetics in the United States with emphasis on the prenatal, metabolic, genetic counseling, and training aspects of the field.

Nasopharyngeal Microbiome Diversity Changes Over Time In Children With Asthma, Marcos Pérez-Losada, Lamia Alamri, Keith Crandall, Robert J. Freishtat

Pediatrics Faculty Publications

Background

The nasopharynx is a reservoir for pathogens associated with respiratory illnesses such as asthma. Next-generation sequencing (NGS) has been used to characterize the nasopharyngeal microbiome of infants and adults during health and disease; less is known, however, about the composition and temporal dynamics (i.e., longitudinal variation) of microbiotas from children and adolescents. Here we use NGS technology to characterize the nasopharyngeal microbiomes of asthmatic children and adolescents (6 to 18 years) and determine their stability over time.

Methods

Two nasopharyngeal washes collected 5.5 to 6.5 months apart were taken from 40 children and adolescents with asthma living in the …

Genetic Variation In The Histamine Production, Response, And Degradation Pathway Is Associated With Histamine Pharmacodynamic Response In Children With Asthma, Bridgette L. Jones, Catherine M.T. Sherwin, Xiaoxi Liu, Hongying Dai, Carrie A. Vyhlidal

Pediatrics Faculty Publications

Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma.

Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD …

Necrotizing Fasciitis Secondary To Aeromonas Infection Presenting With Septic Shock, Nikhil Bhatia, Manuel Castro-Borobio, John N. Greene, Sowmya Nanjappa

Pediatrics Faculty Publications

This report describes a case of necrotizing fasciitis presenting with septic shock due to an Aeromonas infection. The patient cut his foot while mowing the lawn and then spent time in a pool with black mold. He began feeling ill and developed swelling and a quarter-sized black area on his right lower extremity. Despite being hemodynamically unstable with systolic blood pressure in the low 70s, the patient was transferred to our facility from outside hospital 100 miles away. Upon arriving to facility, the patient appeared to be septic and the infected area of skin had grown. Irrigation and debridement were …

Predicting Tacrolimus Concentrations In Children Receiving A Heart Transplant Using A Population Pharmacokinetic Model, Joseph E. Rower, Chris Stockmann, Matthew W. Linakis, Shaun S. Kumar, Xiaoxi Liu, E. Kent Korgenski, Catherine M.T. Sherwin, Kimberly M. Molina

Pediatrics Faculty Publications

Objective Immunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual’s future concentrations.

Design, setting and patients Retrospective data from 48 children who received tacrolimus as inpatients at Primary Children’s Hospital in Salt …

Association Between School Performance And Body Mass Index, Megan Rajagopal, Alissa Briggs, Hatim A. Omar

Pediatrics Faculty Publications

The purpose of this paper is to determine the relationship between grade point average and other factors, including: body mass index, exercise habits, and weight perception. Data from School-Based Health Promotion Centers (SBHC) were used for this study. Students in sixth, seventh, and eighth grades were screened at the SBHC for a variety of behaviors and lifestyle characteristics using the Perkins Adolescent Risk Screen (PARS). Data from a total 579 students (281 males and 298 females; 278 sixth graders, 151 seventh graders, and 150 eight graders) were obtained. Of these students, 145 were underweight, with a BMI less than 18.5; …

High Levels Of Iron Supplementation Prevents Neural Tube Defects In The Fpn1(Ffe) Mouse Model., Bethany A Stokes, Julia A Sabatino, Irene E. Zohn

Pediatrics Faculty Publications

BACKGROUND: Periconception maternal nutrition and folate in particular are important factors influencing the incidence of neural tube defects (NTDs). Many but not all NTDs are prevented by folic acid supplementation and there is a pressing need for additional strategies to prevent these birth defects. Other micronutrients such as iron are potential candidates, yet a clear role for iron deficiency in contributing to NTDs is lacking. Our previous studies with the flatiron (ffe) mouse model of Ferroportin1 (Fpn1) deficiency suggest that iron is required for neural tube closure and forebrain development raising the possibility that iron supplementation could prevent NTDs.

METHODS: …

Sirt1 Regulates Glial Progenitor Proliferation And Regeneration In White Matter After Neonatal Brain Injury., Beata Jablonska, Marcin Gierdalski, Li-Jin Chew, Teresa Hawley, Mackenzie Catron, Arturo Lichauco, Juan Cabrera-Luque, Tracy Yuen, David Rowitch, Vittorio Gallo

Pediatrics Faculty Publications

Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture …

Population Pharmacokinetics Of Liposomal Amphotericin B In Immunocompromised Children., Jodi M Lestner, Andreas H Groll, Ghaith Aljayyoussi, Nita L Seibel, Aziza Shad, Corina Gonzalez, Lauren V Wood, Paul F Jarosinski, Thomas J Walsh, William W Hope

Pediatrics Faculty Publications

Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg(-1) daily. Samples were taken at baseline and at 0.5- to 2.0-h intervals for 24 h after receipt of the first dose (n = …

Pediatric Emergency Medicine Point-Of-Care Ultrasound: Summary Of The Evidence., Jennifer R Marin, Alyssa M. Abo, Alexander C Arroyo, Stephanie J Doniger, Jason W Fischer, Rachel Rempell, +21 Additional Authors

Pediatrics Faculty Publications

The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers. To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed "how to" and description of individual point-of-care ultrasound examinations. Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting …

The Role Of Stress In Assessing Life Satisfaction And Self-Efficacy Among Prison Officers, Kamilla Bargiel-Matusiewicz, Paulina Stelmachowska, Hatim A. Omar

Pediatrics Faculty Publications

Stress is a major public health concern. It can be observed in all aspects of life, in everyday family life and work life. The focus of this article is work-related stress. Work stress can be observed in any work environment and in all professions. As a complex condition it affects different people in different ways. The study presented in this article was done on a sample of 59 prison officers who volunteered to participate. Among those 59 participants 34 were males and 25 were females aged between 25 to 52. Each participant received a survey to collect general information about …

Photothermal Therapy Improves The Efficacy Of A Mek Inhibitor In Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors., Elizabeth E. Sweeney, Rachel A. Burga, Chaoyang Li, Yuan Zhu, Rohan Fernandes

Pediatrics Faculty Publications

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate …

Dark Blood Late Enhancement Imaging., Peter Kellman, Hui Xue, Laura J. Olivieri, Russell R. Cross, Elena K Grant, Marianna Fontana, Martin Ugander, James C Moon, Michael S Hansen

Pediatrics Faculty Publications

Background

Bright blood late gadolinium enhancement (LGE) imaging typically achieves excellent contrast between infarcted and normal myocardium. However, the contrast between the myocardial infarction (MI) and the blood pool is frequently suboptimal. A large fraction of infarctions caused by coronary artery disease are sub-endocardial and thus adjacent to the blood pool. It is not infrequent that sub-endocardial MIs are difficult to detect or clearly delineate.

Methods

In this present work, an inversion recovery (IR) T2 preparation was combined with single shot steady state free precession imaging and respiratory motion corrected averaging to achieve dark blood LGE images with good signal …

Novel Mutation Of Interferon-Γ Receptor 1 Gene Presenting As Early Life Mycobacterial Bronchial Disease, Maria J. Gutierrez, Neelu Kaira, Alexandra Horwitz, Gustavo Nino

Pediatrics Faculty Publications

Mendelian susceptibility to mycobacterial diseases (MSMD) are a spectrum of inherited disorders characterized by localized or disseminated infections caused by atypical mycobacteria. Interferon-γ receptor 1 (IFNGR1) deficiency was the first identified genetic disorder recognized as MSMD. Mutations in the genes encoding IFNGR1 can be recessive or dominant and cause complete or partial receptor deficiency. We present the case of a 2½-year-old boy with a history of recurrent wheezing, diagnosed with endobronchial mycobacterial infection. Immunological workup revealed a homozygous nonsense mutation in the IFNGR1 gene, a novel mutation predicted in silico to cause complete IFNGR1 deficiency. This case demonstrates that ( …

Standardization Of Postoperative Transitions Of Care To The Pediatric Intensive Care Unit Enhances Efficiency And Handover Comprehensiveness, Anthony Sochet, Ashley Simms, Grace Ye, Nihal Godiwala, Lauren Hebert, Christine O. Corriveau

Pediatrics Faculty Publications

Introduction: To determine the impact of standardization of postoperative transitions of care to the pediatric intensive care unit on handover efficiency and the quality of healthcare data exchange.

Methods: This was a prospective, pre–post observational study after standardization of postoperative transitions in a 44-bed pediatric intensive care unit in a 313-bed tertiary care pediatric hospital from April to July 2015. Standardization was completed using a multidisciplinary handover checklist. Primary outcomes were efficiency expressed as mean handover duration and the comprehensiveness of healthcare data exchange.

Results: Forty-seven postoperative transitions were observed of which 23 were preintervention and 24 were postintervention. After …

Native T1 Values Identify Myocardial Changes And Stratify Disease Severity In Patients With Duchenne Muscular Dystrophy., Laura J. Olivieri, Peter Kellman, Robert J. Mccarter, Russell R. Cross, Michael S. Hansen, Christopher F. Spurney

Pediatrics Faculty Publications

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked, inherited disorder causing dilated cardiomyopathy with variable onset and progression. Currently we lack objective markers of the effect of therapies targeted towards preventing progression of subclinical cardiac disease. Thus, our aim was to compare the ability of native T1 and extracellular volume (ECV) measurements to differentiate risk of myocardial disease in DMD and controls.

METHODS: Twenty boys with DMD and 16 age/gender-matched controls without history predisposing to cardiac fibrosis, but with a clinical indication for cardiovascular magnetic resonance (CMR) evaluation, underwent CMR with contrast. Data points collected include left ventricular ejection fraction …

Age-Related Effect Of Viral-Induced Wheezing In Severe Prematurity, Geovanny F. Perez, Amisha Jain, Bassem Kurdi, Rosemary Megalaa, Krishna Pancham, Shehlanoor Huseni, Natalia Isaza, Carlos E. Rodriguez-Martinez, Mary C. Rose, Dinesh Pillai, Gustavo Nino

Pediatrics Faculty Publications

Abstract: Premature children are prone to severe viral respiratory infections in early life, but the age at which susceptibility peaks and disappears for each pathogen is unclear. Methods: A retrospective analysis was performed of the age distribution and clinical features of acute viral respiratory infections in full-term and premature children, aged zero to seven years. Results: The study comprised of a total of 630 hospitalizations (n = 580 children). Sixty-seven percent of these hospitalizations occurred in children born full-term (> 37 weeks), 12% in preterm (32–37 weeks) and 21% in severely premature children (< 32 weeks). The most common viruses identified were rhinovirus (RV; 60%) and respiratory syncytial virus (RSV; 17%). Age-distribution analysis of each virus identified that severely premature children had a higher relative frequency of RV and RSV in their first three years, relative to preterm or full-term children. Additionally, the probability of RV- or RSV-induced wheezing was higher overall in severely premature children less than three years old. Conclusions: Our results indicate that the …

A Proteogenomic Approach To Understanding Myc Function In Metastatic Medulloblastoma Tumors., Jerome A Staal, Yanxin Pei, Brian R. Rood

Pediatrics Faculty Publications

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite …

Long-Term Biocompatibility, Imaging Appearance And Tissue Effects Associated With Delivery Of A Novel Radiopaque Embolization Bead For Image-Guided Therapy, Karun Sharma, Zainab Bascal, Hugh Kilpatrick, Koorosh Ashrafi, Sean L. Willis, Matthew R. Dreher, Andrew L. Lewis

Pediatrics Faculty Publications

The objective of this study was to undertake a comprehensive long-term biocompatibility and imaging assessment of a new intrinsically radiopaque bead (LC Bead LUMI™) for use in transarterial embolization. The sterilized device and its extracts were subjected to the raft of ISO10993 biocompatibility tests that demonstrated safety with respect to cytotoxicity, mutagenicity, blood contact, irritation, sensitization, systemic toxicity and tissue reaction. Intra-arterial administration was performed in a swine model of hepatic arterial embolization in which 0.22–1 mL of sedimented bead volume was administered to the targeted lobe(s) of the liver. The beads could be visualized during the embolization procedure with …

Glycemic Variability Predicts Inflammation In Adolescents With Type 1 Diabetes, Robert P. Hoffman, Amanda S. Dye, Hong Huang, John A. Bauer

Pediatrics Faculty Publications

Background: Adolescents with type 1 diabetes (T1D) have increased risk of cardiovascular disease as well as elevations in biomarkers of systemic inflammation, plasma protein oxidation and vascular endothelial injury. It is unclear whether hyperglycemia itself, or variations in blood glucose are predictors of these abnormalities.

Methods: This study was designed to determine the relationship of inflammatory (C-reactive protein, CRP), oxidative (total anti-oxidative capacity, TAOC) and endothelial injury (soluble intracellular adhesion molecule 1, sICAM1) markers to glycemic control measures from 3 days of continuous glucose monitoring (CGM) and to hemoglobin A_1c (HbA_1c), and HbA_1c×duration area under …

A Novel Adaptation Of A Parent-Child Observational Assessment Tool For Appraisals And Coping In Children Exposed To Acute Trauma, Meghan L. Marsac, Nancy Kassam-Adams

Pediatrics Faculty Publications

Background: Millions of children worldwide are exposed to acute potentially traumatic events (PTEs) annually. Many children and their families experience significant emotional distress and/or functional impairment following PTEs. While current research has begun to highlight a role for early appraisals and coping in promoting or preventing full recovery from PTEs, the exact nature of the relationships among appraisals, coping, and traumatic stress reactions as well as how appraisals and coping behaviors are influenced by the child's environment (e.g., parents) remains unclear; assessment tools that reach beyond self-report are needed to improve this understanding.

Objective: The objective of the current study …

Airway Secretory Micrornaome Changes During Rhinovirus Infection In Early Childhood, Maria J. Gutierrez, Jose L. Gomez, Geovanny F. Perez, Krishna Pancham, Stephanie Val, Dinesh K. Pillai, Mamta Giri, Sarah Ferrante, Robert Freishtat, Mary C. Rose, Diego Preciado, Gustavo Nino

Pediatrics Faculty Publications

Background Innate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV) to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood.

Methods Nasal airway secretions were obtained from …

Airway Secretory Micrornaome Changes During Rhinovirus Infection In Early Childhood., M. Gutierrez, J. Gomez, Geovanny Perez, Krishna Pancham, Dinesh K. Pillai, M. Giri, S. Ferrante, Robert J. Freishtat, Mary C. Rose, Diego A. Preciado, Gustavo Nino

Pediatrics Faculty Publications

BACKGROUND:

Innate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV) to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood.

METHODS:

Nasal airway secretions were obtained from …

Improving Human Papillomavirus Immunization Rates In Kentucky, Nneka S. Udechukwu, Paul Duffin, Alissa Briggs, Hatim A. Omar

Pediatrics Faculty Publications

No abstract provided.

Primary Health Care: Potential Home For Family-Focused Preventive Interventions, Laurel K Leslie, Christopher J Mehus, J David Hawkins, Thomas Boat, Mary Ann Mccabe, Shari Barkin, Ellen C Perrin, Carol W Metzler, And 4 Others

Pediatrics Faculty Publications

Family-focused prevention programs have been shown to effectively reduce a range of negative behavioral health outcomes but have had limited reach. Three key barriers must be overcome to expand the reach of family-focused prevention programs and thereby achieve a significant public health impact. These barriers are (1) current social norms and perceptions of parenting programs; (2) concerns about the expertise and legitimacy of sponsoring organizations to offer parenting advice; and (3) a paucity of stable, sustainable funding mechanisms. Primary healthcare settings are well positioned to overcome these barriers. Recent changes within health care make primary care settings an increasingly favorable …