Publications by authors named "Vanessa Hill"

34 Publications

Executive Summary: Criteria for Critical Care of Infants and Children: PICU Admission, Discharge, and Triage Practice Statement and Levels of Care Guidance.

Pediatrics 2019 10 5;144(4). Epub 2019 Sep 5.

Division of Medical Critical Care, Boston Children's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts.

This is an executive summary of the 2019 update of the 2004 guidelines and levels of care for PICU. Since previous guidelines, there has been a tremendous transformation of Pediatric Critical Care Medicine with advancements in pediatric cardiovascular medicine, transplant, neurology, trauma, and oncology as well as improvements of care in general PICUs. This has led to the evolution of resources and training in the provision of care through the PICU. Outcome and quality research related to admission, transfer, and discharge criteria as well as literature regarding PICU levels of care to include volume, staffing, and structure were reviewed and included in this statement as appropriate. Consequently, the purposes of this significant update are to address the transformation of the field and codify a revised set of guidelines that will enable hospitals, institutions, and individuals in developing the appropriate PICU for their community needs. The target audiences of the practice statement and guidance are broad and include critical care professionals; pediatricians; pediatric subspecialists; pediatric surgeons; pediatric surgical subspecialists; pediatric imaging physicians; and other members of the patient care team such as nurses, therapists, dieticians, pharmacists, social workers, care coordinators, and hospital administrators who make daily administrative and clinical decisions in all PICU levels of care.
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http://dx.doi.org/10.1542/peds.2019-2433DOI Listing
October 2019

Criteria for Critical Care Infants and Children: PICU Admission, Discharge, and Triage Practice Statement and Levels of Care Guidance.

Pediatr Crit Care Med 2019 09;20(9):847-887

Pediatrics and Pediatric Critical Care Medicine, Department of Pediatrics, Mount Sinai Beth Israel and Mount Sinai West Hospitals, New York City, NY.

Objectives: To update the American Academy of Pediatrics and Society of Critical Care Medicine's 2004 Guidelines and levels of care for PICU.

Design: A task force was appointed by the American College of Critical Care Medicine to follow a standardized and systematic review of the literature using an evidence-based approach. The 2004 Admission, Discharge and Triage Guidelines served as the starting point, and searches in Medline (Ovid), Embase (Ovid), and PubMed resulted in 329 articles published from 2004 to 2016. Only 21 pediatric studies evaluating outcomes related to pediatric level of care, specialized PICU, patient volume, or personnel. Of these, 13 studies were large retrospective registry data analyses, six small single-center studies, and two multicenter survey analyses. Limited high-quality evidence was found, and therefore, a modified Delphi process was used. Liaisons from the American Academy of Pediatrics were included in the panel representing critical care, surgical, and hospital medicine expertise for the development of this practice guidance. The title was amended to "practice statement" and "guidance" because Grading of Recommendations, Assessment, Development, and Evaluation methodology was not possible in this administrative work and to align with requirements put forth by the American Academy of Pediatrics.

Methods: The panel consisted of two groups: a voting group and a writing group. The panel used an iterative collaborative approach to formulate statements on the basis of the literature review and common practice of the pediatric critical care bedside experts and administrators on the task force. Statements were then formulated and presented via an online anonymous voting tool to a voting group using a three-cycle interactive forecasting Delphi method. With each cycle of voting, statements were refined on the basis of votes received and on comments. Voting was conducted between the months of January 2017 and March 2017. The consensus was deemed achieved once 80% or higher scores from the voting group were recorded on any given statement or where there was consensus upon review of comments provided by voters. The Voting Panel was required to vote in all three forecasting events for the final evaluation of the data and inclusion in this work. The writing panel developed admission recommendations by level of care on the basis of voting results.

Results: The panel voted on 30 statements, five of which were multicomponent statements addressing characteristics specific to PICU level of care including team structure, technology, education and training, academic pursuits, and indications for transfer to tertiary or quaternary PICU. Of the remaining 25 statements, 17 reached consensus cutoff score. Following a review of the Delphi results and consensus, the recommendations were written.

Conclusions: This practice statement and level of care guidance manuscript addresses important specifications for each PICU level of care, including the team structure and resources, technology and equipment, education and training, quality metrics, admission and discharge criteria, and indications for transfer to a higher level of care. The sparse high-quality evidence led the panel to use a modified Delphi process to seek expert opinion to develop consensus-based recommendations where gaps in the evidence exist. Despite this limitation, the members of the Task Force believe that these recommendations will provide guidance to practitioners in making informed decisions regarding pediatric admission or transfer to the appropriate level of care to achieve best outcomes.
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http://dx.doi.org/10.1097/PCC.0000000000001963DOI Listing
September 2019

Tired and stressed: Examining the need for sleep.

Eur J Neurosci 2020 01 26;51(1):494-508. Epub 2018 Oct 26.

Department of Genetics and Development, Columbia University Medical Center, New York City, New York.

A key feature of circadian rhythms is the sleep/wake cycle. Sleep causes reduced responsiveness to the environment, which puts animals in a particularly vulnerable state; yet sleep has been conserved throughout evolution, indicating that it fulfils a vital purpose. A core function of sleep across species has not been identified, but substantial advances in sleep research have been made in recent years using the genetically tractable model organism, Drosophila melanogaster. This review describes the universality of sleep, the regulation of sleep, and current theories on the function of sleep, highlighting a historical and often overlooked theory called the Free Radical Flux Theory of Sleep. Additionally, we summarize our recent work with short-sleeping Drosophila mutants and other genetic and pharmacological tools for manipulating sleep which supports an antioxidant theory of sleep and demonstrates a bi-directional relationship between sleep and oxidative stress.
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http://dx.doi.org/10.1111/ejn.14197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453762PMC
January 2020

A bidirectional relationship between sleep and oxidative stress in Drosophila.

PLoS Biol 2018 07 12;16(7):e2005206. Epub 2018 Jul 12.

Department of Genetics and Development, Columbia University Medical Center, New York, New York, United States of America.

Although sleep appears to be broadly conserved in animals, the physiological functions of sleep remain unclear. In this study, we sought to identify a physiological defect common to a diverse group of short-sleeping Drosophila mutants, which might provide insight into the function and regulation of sleep. We found that these short-sleeping mutants share a common phenotype of sensitivity to acute oxidative stress, exhibiting shorter survival times than controls. We further showed that increasing sleep in wild-type flies using genetic or pharmacological approaches increases survival after oxidative challenge. Moreover, reducing oxidative stress in the neurons of wild-type flies by overexpression of antioxidant genes reduces the amount of sleep. Together, these results support the hypothesis that a key function of sleep is to defend against oxidative stress and also point to a reciprocal role for reactive oxygen species (ROS) in neurons in the regulation of sleep.
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http://dx.doi.org/10.1371/journal.pbio.2005206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042693PMC
July 2018

Multi-Stakeholder Informed Guidelines for Direct Admission of Children to Hospital.

J Pediatr 2018 07 25;198:273-278.e7. Epub 2018 Apr 25.

Instititute for Healthcare Delivery and Population Science and Department of Medicine, University of Massachusetts Medical School, Springfield, MA; Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA.

Objectives: To develop pediatric direct admission guidelines and prioritize outcomes to evaluate the safety and effectiveness of hospital admission processes.

Study Design: We conducted deliberative discussions at 1 children's hospital and 2 community hospitals, engaging parents of hospitalized children and inpatient, outpatient, and emergency department physicians and nurses to identify shared and dissenting perspectives regarding direct admission processes and outcomes. Discussions were audio-recorded, professionally transcribed, and analyzed using a general inductive approach. We then convened a national panel to prioritize guideline components and outcome measures using a RAND/UCLA Modified Delphi approach.

Results: Forty-eight stakeholders participated in 6 deliberative discussions. Emergent themes related to effective multistakeholder communication, resources needed for high quality direct admissions, written direct admission guidelines, including criteria to identify children appropriate for and inappropriate for direct admission, and families' needs. Building on these themes, Delphi panelists endorsed 71 guideline components as both appropriate and necessary at children's hospitals and community hospitals and 13 outcomes to evaluate hospital admission systems. Guideline components include (1) pre-admission communication, (2) written guidelines, (3) hospital resources to optimize direct admission processes, (4) special considerations for pediatric populations that may be at particular risk of nosocomial infection and/or stress in emergency departments, (5) communication with families referred for direct admission, and (6) quality reviews to evaluate admission systems.

Conclusions: These direct admission guidelines can be adapted by hospitals and health systems to inform hospital admission policies and protocols. Multistakeholder engagement in evaluation of hospital admission processes may improve transitions of care and health system integration.
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http://dx.doi.org/10.1016/j.jpeds.2018.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086373PMC
July 2018

A model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells.

J Cell Biol 2017 03 21;216(3):595-605. Epub 2017 Feb 21.

Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032

Fragile X syndrome, the most common known monogenic cause of autism, results from the loss of FMR1, a conserved, ubiquitously expressed RNA-binding protein. Recent evidence suggests that Fragile X syndrome and other types of autism are associated with immune system defects. We found that mutants exhibit increased sensitivity to bacterial infection and decreased phagocytosis of bacteria by systemic immune cells. Using tissue-specific RNAi-mediated knockdown, we showed that Fmr1 plays a cell-autonomous role in the phagocytosis of bacteria. mutants also exhibit delays in two processes that require phagocytosis by glial cells, the immune cells in the brain: neuronal clearance after injury in adults and the development of the mushroom body, a brain structure required for learning and memory. Delayed neuronal clearance is associated with reduced recruitment of activated glia to the site of injury. These results suggest a previously unrecognized role for Fmr1 in regulating the activation of phagocytic immune cells both in the body and the brain.
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http://dx.doi.org/10.1083/jcb.201607093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350515PMC
March 2017

period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection.

Curr Biol 2016 Jan 31;26(2):184-194. Epub 2015 Dec 31.

Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. Electronic address:

Most metazoans undergo dynamic, circadian-regulated changes in behavior and physiology. Currently, it is unknown how circadian-regulated behavior impacts immunity against infection. Two broad categories of defense against bacterial infection are resistance, control of microbial growth, and tolerance, control of the pathogenic effects of infection. Our study of behaviorally arrhythmic Drosophila circadian period mutants identified a novel link between nutrient intake and tolerance of infection with B. cepacia, a bacterial pathogen of rising importance in hospital-acquired infections. We found that infection tolerance in wild-type animals is stimulated by acute exposure to dietary glucose and amino acids. Glucose-stimulated tolerance was induced by feeding or direct injection; injections revealed a narrow window for glucose-stimulated tolerance. In contrast, amino acids stimulated tolerance only when ingested. We investigated the role of a known amino-acid-sensing pathway, the TOR (Target of Rapamycin) pathway, in immunity. TORC1 is circadian regulated and inhibition of TORC1 decreased resistance, as in vertebrates. Surprisingly, inhibition of the less well-characterized TOR complex 2 (TORC2) dramatically increased survival, through both resistance and tolerance mechanisms. This work suggests that dietary intake on the day of infection by B. cepacia can make a significant difference in long-term survival. We further demonstrate that TOR signaling mediates both resistance and tolerance of infection and identify TORC2 as a novel potential therapeutic target for increasing survival of infection.
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http://dx.doi.org/10.1016/j.cub.2015.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729625PMC
January 2016

Antibiotic Prescribing Patterns Across the Continuum of Care for Children Hospitalized With Community-Acquired Pneumonia.

Pediatr Emerg Care 2018 Jan;34(1):e7-e10

Objectives: The aim of this study was to describe the variation in antibiotic prescribing practices for uncomplicated community-acquired pneumonia across the continuum of care for hospitalized pediatric patients to better inform future efforts at standardizing antibiotic therapy throughout a single hospitalization.

Methods: This is a retrospective cohort study involving 4 hospitals caring for children aged 3 months to 18 years, hospitalized between January 1, 2011, and December 31, 2012, with diagnosis of uncomplicated pneumonia and without complex chronic medical conditions.Data collected include antibiotics prescribed before hospitalization, at the emergency department (ED) encounter, during hospitalization, and at hospital discharge.

Results: Six hundred nine children met inclusion criteria, with a mean age of 5.3 years and median length of stay of 2 days. Emergency department providers prescribed narrow-spectrum therapy 27% of the time, whereas discharging providers prescribed narrow-spectrum therapy 56% of the time. Third- and fourth-generation cephalosporins were less often prescribed in the preadmission setting and at discharge but were more often prescribed in the ED and inpatient setting. There was an association between inpatient prescription of broad-spectrum antibiotics when a blood culture was obtained, when broad-spectrum antibiotics were prescribed in the ED, and with increasing length of stay.

Conclusion: Broad-spectrum antibiotic therapy for community-acquired pneumonia, especially third- and fourth-generation cephalosporins, often originates in the ED. When initiated in this setting, it is likely to be continued in the inpatient setting.
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http://dx.doi.org/10.1097/PEC.0000000000000598DOI Listing
January 2018

Use of Intermittent vs Continuous Pulse Oximetry for Nonhypoxemic Infants and Young Children Hospitalized for Bronchiolitis: A Randomized Clinical Trial.

JAMA Pediatr 2015 Oct;169(10):898-904

Department of Pediatrics, Hasbro Children's Hospital, Providence, Rhode Island.

Importance: Clinical practice guidelines for managing infants and children hospitalized for bronchiolitis recommend only obtaining intermittent or "spot check" pulse oximetry readings for those who show clinical improvement. The effect of such monitoring is currently unknown.

Objective: To determine the effect of intermittent vs continuous pulse oximetry monitoring on hospital length of stay among nonhypoxemic infants and young children hospitalized for bronchiolitis.

Design, Setting, And Participants: Randomized, parallel-group, superiority clinical trial of otherwise healthy infants and children 2 years of age or younger hospitalized for bronchiolitis during the period from 2009 to 2014 at 1 of 4 children's hospitals in the United States. Parents or guardians were blinded to allocation assignment until informed consent was obtained; study personnel and outcome assessors were not.

Interventions: Patients were randomly assigned to undergo continuous or intermittent pulse oximetry monitoring (ie, pulse oximetry measurements were obtained along with a scheduled check of vital signs or for clinical suspicion of deterioration) during hospitalization when oxygen saturation levels were 90% or higher.

Main Outcomes And Measures: Length of hospital stay was the primary outcome. Secondary outcome measures included duration of supplemental oxygen use and rate of escalation of care (defined as transfer to an intensive care unit).

Results: A total of 449 infants and young children were screened for inclusion; 288 infants and young children were excluded, resulting in 161 patients who were enrolled in the study (80 patients underwent continuous monitoring, and 81 patients intermittent). The mean length of stay did not differ based on pulse oximetry monitoring strategy (48.9 hours [95% CI, 41.3-56.5 hours] for continuous monitoring vs 46.2 hours [95% CI, 39.1-53.3 hours] for intermittent monitoring; P = .77). The rates of escalation of care and duration of supplemental oxygen use did not differ between groups.

Conclusions And Relevance: Intermittent pulse oximetry monitoring of nonhypoxemic patients with bronchiolitis did not shorten hospital length of stay and was not associated with any difference in rate of escalation of care or use of diagnostic or therapeutic measures. Our results suggest that intermittent pulse oximetry monitoring can be routinely considered in the management of infants and children hospitalized for bronchiolitis who show clinical improvement.

Trial Registration: clinicaltrials.gov Identifier: NCT01014910.
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http://dx.doi.org/10.1001/jamapediatrics.2015.1746DOI Listing
October 2015

Evaluating the use of blood cultures in the management of children hospitalized for community-acquired pneumonia.

PLoS One 2015 6;10(2):e0117462. Epub 2015 Feb 6.

Department of Pediatrics, Rochester Medical Center, Rochester, NY, United States of America.

Background: Blood cultures are often recommended for the evaluation of community-acquired pneumonia (CAP). However, institutions vary in their use of blood cultures, and blood cultures have unclear utility in CAP management in hospitalized children.

Objective: To identify clinical factors associated with obtaining blood cultures in children hospitalized with CAP, and to estimate the association between blood culture obtainment and hospital length of stay (LOS).

Methods: We performed a multicenter retrospective cohort study of children admitted with a diagnosis of CAP to any of four pediatric hospitals in the United States from January 1, 2011-December 31, 2012. Demographics, medical history, diagnostic testing, and clinical outcomes were abstracted via manual chart review. Multivariable logistic regression evaluated patient and clinical factors for associations with obtaining blood cultures. Propensity score-matched Kaplan-Meier analysis compared patients with and without blood cultures for hospital LOS.

Results: Six hundred fourteen charts met inclusion criteria; 390 children had blood cultures obtained. Of children with blood cultures, six (1.5%) were positive for a pathogen and nine (2.3%) grew a contaminant. Factors associated with blood culture obtainment included presenting with symptoms of systemic inflammatory response syndrome (OR 1.78, 95% CI 1.10-2.89), receiving intravenous hydration (OR 3.94, 95% CI 3.22-4.83), receiving antibiotics before admission (OR 1.49, 95% CI 1.17-1.89), hospital admission from the ED (OR 1.65, 95% CI 1.05-2.60), and having health insurance (OR 0.42, 95% CI 0.30-0.60). In propensity score-matched analysis, patients with blood cultures had median 0.8 days longer LOS (2.0 vs 1.2 days, P < .0001) without increased odds of readmission (OR 0.94, 95% CI 0.45-1.97) or death (P = .25).

Conclusions: Obtaining blood cultures in children hospitalized with CAP rarely identifies a causative pathogen and is associated with increased LOS. Our results highlight the need to refine the role of obtaining blood cultures in children hospitalized with CAP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117462PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319887PMC
January 2016

Early cerebral small vessel disease and brain volume, cognition, and gait.

Ann Neurol 2015 Feb;77(2):251-61

Hotchkiss Brain Institute; Department of Clinical Neurosciences; Department of Radiology; Seaman Family Centre, University of Calgary, Calgary, Alberta.

Objective: Decline in cognitive function begins by the 40s, and may be related to future dementia risk. We used data from a community-representative study to determine whether there are age-related differences in simple cognitive and gait tests by the 40s, and whether these differences were associated with covert cerebrovascular disease on magnetic resonance imaging (MRI).

Methods: Between 2010 and 2012, 803 participants aged 40 to 75 years in the Prospective Urban Rural Epidemiological (PURE) study, recruited from prespecified postal code regions centered on 4 Canadian cities, underwent brain MRI and simple tests of cognition and gait as part of a substudy (PURE-MIND).

Results: Mean age was 58 ± 8 years. Linear decreases in performance on the Montreal Cognitive Assessment, Digit Symbol Substitution Test (DSST), and Timed Up and Go test of gait were seen with each age decade from the 40s to the 70s. Silent brain infarcts were observed in 3% of 40- to 49-year-olds, with increasing prevalence up to 18.9% in 70-year-olds. Silent brain infarcts were associated with slower timed gait and lower volume of supratentorial white matter. Higher volume of supratentorial MRI white matter hyperintensity was associated with slower timed gait and worse performance on DSST, and lower volumes of the supratentorial cortex and white matter, and cerebellum.

Interpretation: Covert cerebrovascular disease and its consequences on cognitive and gait performance and brain atrophy are manifest in some clinically asymptomatic persons as early as the 5th decade of life.
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http://dx.doi.org/10.1002/ana.24320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338762PMC
February 2015

Hypotonic versus isotonic fluids in hospitalized children: a systematic review and meta-analysis.

J Pediatr 2014 Jul 28;165(1):163-169.e2. Epub 2014 Feb 28.

Department of Pediatrics, Baylor College of Medicine, San Antonio, TX.

Objective: To determine whether the use of hypotonic vs isotonic maintenance fluids confers an increased risk of hyponatremia in hospitalized children.

Study Design: A search of MEDLINE (1946 to January 2013), the Cochrane Central Registry (1991 to December 2012), Cumulative Index for Nursing and Allied Health Literature (1990 to December 2012), and Pediatric Academic Societies (2000-2012) abstracts was conducted using the terms "hypotonic fluids/saline/solutions" and "isotonic fluids/saline/solutions," and citations were reviewed using a predefined protocol. Data on the primary and secondary outcomes were extracted from original articles by 2 authors independently. Meta-analyses of the primary and secondary outcomes were performed when possible.

Results: A total of 1634 citations were screened. Ten studies (n = 893) identified as independent randomized controlled trials were included. Five studies examined subjects in the intensive care unit setting, including 4 on regular wards and 1 in a mixed setting. In hospitalized children receiving maintenance intravenous fluids, hyponatremia was seen more often in those receiving hypotonic fluids than in those receiving isotonic fluids, with an overall relative risk of 2.37 (95% CI, 1.72-3.26). Receipt of hypotonic fluids was associated with a relative risk of moderate hyponatremia (<130 mmol/L) of 6.1 (95% CI, 2.2-17.3). A subgroup analysis of hypotonic fluids with half-normal saline found a relative risk of hyponatremia of 2.42 (95% CI, 1.32-4.45).

Conclusion: In hospitalized children in intensive care and postoperative settings, the administration of hypotonic maintenance fluids increases the risk of hyponatremia when compared with administration of isotonic fluids. For patients on general wards, insufficient data are available based on the reviewed studies, and individual risk factors must be assessed.
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http://dx.doi.org/10.1016/j.jpeds.2014.01.040DOI Listing
July 2014

Actin dynamics affect mitochondrial quality control and aging in budding yeast.

Curr Biol 2013 Dec 21;23(23):2417-22. Epub 2013 Nov 21.

Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, 630 W. 168(th) Street, New York, NY 10032, USA.

Actin cables of budding yeast are bundles of F-actin that extend from the bud tip or neck to the mother cell tip, serve as tracks for bidirectional cargo transport, and undergo continuous movement from buds toward mother cells [1]. This movement, retrograde actin cable flow (RACF), is similar to retrograde actin flow in lamellipodia, growth cones, immunological synapses, dendritic spines, and filopodia [2-5]. In all cases, actin flow is driven by the push of actin polymerization and assembly at the cell cortex, and myosin-driven pulling forces deeper within the cell [6-10]. Therefore, for movement and inheritance from mothers to buds, mitochondria must "swim upstream" against the opposing force of RACF [11]. We find that increasing RACF rates results in increased fitness of mitochondria inherited by buds and that the increase in mitochondrial fitness leads to extended replicative lifespan and increased cellular healthspan. The sirtuin SIR2 is required for normal RACF and mitochondrial fitness, and increasing RACF rates in sir2Δ cells increases mitochondrial fitness and cellular healthspan but does not affect replicative lifespan. These studies support the model that RACF serves as a filter for segregation of fit from less-fit mitochondria during inheritance, which controls cellular lifespan and healthspan. They also support a role for Sir2p in these processes.
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http://dx.doi.org/10.1016/j.cub.2013.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932488PMC
December 2013

Assessing proxy reports: agreement between children with asthma and their caregivers on quality of life.

Ann Allergy Asthma Immunol 2013 Jul;111(1):14-9

Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

Background: Health-related quality of life (HRQOL) questionnaires are important tools to evaluate health status in children with asthma; however, children with asthma and their caregivers have shown only low to moderate agreement in their responses.

Objective: To analyze the agreement between children with asthma and their caregivers on HRQOL, specifically in the domains of activity limitation, emotional function, and overall quality of life (QOL).

Methods: We enrolled 79 pediatric patients (ages 5-17 years) with asthma (53 with acute asthma and 26 with refractory asthma) and their caregivers. Children completed the Pediatric Asthma Quality of Life Questionnaire, and caregivers completed the Pediatric Asthma Caregiver's Quality of Life Questionnaire (potential score, 1-7; higher scores indicate better QOL). We used paired t test to examine differences in child and caregiver responses, Pearson correlation to describe patterns of agreement, and multivariate analysis to evaluate the effect of sex, age, and ethnicity on differences in child and caregiver responses.

Results: Children with asthma and their caregivers reported similar scores and demonstrated moderate correlation in emotional function and overall QOL. Children reported a significantly better QOL than their caregivers in response to questions about activity limitation (mean score, 4.62 vs 3.49; P < .001). Male children were more likely to differ from their caregivers than females, especially in regard to activity limitation.

Conclusion: Although caregivers of children with asthma can provide useful proxy information about QOL, their responses cannot be substituted for their children's reports regarding activity limitation. Clinicians and researchers should ask both children and their caregivers about asthma-specific QOL.
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http://dx.doi.org/10.1016/j.anai.2013.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744830PMC
July 2013

Mycoplasma pneumoniae in children with acute and refractory asthma.

Ann Allergy Asthma Immunol 2013 May 23;110(5):328-334.e1. Epub 2013 Feb 23.

Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.

Background: The presence of Mycoplasma pneumoniae has been associated with worsening asthma in children. Sensitive assays have been developed to detect M pneumoniae-derived community-acquired respiratory distress syndrome (CARDS) toxin.

Objectives: To identify the frequency and persistence of M pneumoniae detection in respiratory secretions of children with and without asthma and to evaluate antibody responses to M pneumoniae and the impact of M pneumoniae on biological markers, asthma control, and quality of life.

Methods: We enrolled 143 pediatric patients (53 patients with acute asthma, 26 patients with refractory asthma, and 64 healthy controls; age range, 5-17 years) during a 20-month period with 2 to 5 follow-up visits. We detected M pneumoniae using CARDS toxin antigen capture and polymerase chain reaction and P1 adhesin polymerase chain reaction. Immune responses to M pneumoniae were determined by IgG and IgM levels directed against CARDS toxin and P1 adhesin. pH was measured in exhaled breath condensates, and asthma control and quality of life were assessed using the Asthma Control Test and Pediatric Asthma Quality of Life Questionnaire.

Results: M pneumoniae was detected in 64% of patients with acute asthma, 65% with refractory asthma, and 56% of healthy controls. Children with asthma had lower antibody levels to M pneumoniae compared with healthy controls. Exhaled breath condensate pHs and asthma control and quality of life scores were lower in M pneumoniae-positive patients with asthma.

Conclusion: The results suggest that M pneumoniae detection is common in children, M pneumoniae detection is associated with worsening asthma, and children with asthma may have poor humoral immune responses to M pneumoniae.
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http://dx.doi.org/10.1016/j.anai.2013.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703852PMC
May 2013

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis: a systematic review.

Arch Pediatr Adolesc Med 2011 Oct;165(10):951-6

University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.

Objective: To summarize the risk of occult serious bacterial infection in the youngest febrile infants presenting with either clinical bronchiolitis or respiratory syncytial virus infection.

Data Sources: We performed a systematic search of the Medline database for studies reporting rates of serious bacterial infection in infants younger than 90 days with clinical bronchiolitis and/or respiratory syncytial virus infection.

Study Selection: Studies reporting on cultures performed at the time of presentation to care and providing a denominator, ie, total number of each type of culture obtained, were analyzed.

Main Exposure: Admission for bronchiolitis.

Main Outcome Measures: Age-specific rates of urinary tract infection, bacteremia, and meningitis were extracted.

Results: The weighted rate of urinary tract infections in the youngest infants in the 11 studies analyzed was 3.3% (95% confidence interval, 1.9%-5.7%). No case of bacteremia was reported in 8 of 11 studies. No case of meningitis was reported in any of the studies. Summary statistics for meningitis and bacteremia are not provided because of an excess of zero events in these samples.

Conclusions: A screening approach to culturing for serious bacterial infections in febrile infants presenting with bronchiolitis or respiratory syncytial virus infection is very low yield. The rate of urine cultures positive for bacteria remains significant, though asymptomatic bacteriuria may confound these results.
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http://dx.doi.org/10.1001/archpediatrics.2011.155DOI Listing
October 2011

An extremely primitive star in the Galactic halo.

Nature 2011 Aug 31;477(7362):67-9. Epub 2011 Aug 31.

Zentrum für Astronomie der Universität Heidelberg, Landessternwarte, Königstuhl 12, 69117 Heidelberg, Germany.

The early Universe had a chemical composition consisting of hydrogen, helium and traces of lithium; almost all other elements were subsequently created in stars and supernovae. The mass fraction of elements more massive than helium, Z, is known as 'metallicity'. A number of very metal-poor stars has been found, some of which have a low iron abundance but are rich in carbon, nitrogen and oxygen. For theoretical reasons and because of an observed absence of stars with Z < 1.5 × 10(-5), it has been suggested that low-mass stars cannot form from the primitive interstellar medium until it has been enriched above a critical value of Z, estimated to lie in the range 1.5 × 10(-8) to 1.5 × 10(-6) (ref. 8), although competing theories claiming the contrary do exist. (We use 'low-mass' here to mean a stellar mass of less than 0.8 solar masses, the stars that survive to the present day.) Here we report the chemical composition of a star in the Galactic halo with a very low Z (≤ 6.9 × 10(-7), which is 4.5 × 10(-5) times that of the Sun) and a chemical pattern typical of classical extremely metal-poor stars--that is, without enrichment of carbon, nitrogen and oxygen. This shows that low-mass stars can be formed at very low metallicity, that is, below the critical value of Z. Lithium is not detected, suggesting a low-metallicity extension of the previously observed trend in lithium depletion. Such lithium depletion implies that the stellar material must have experienced temperatures above two million kelvin in its history, given that this is necessary to destroy lithium.
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http://dx.doi.org/10.1038/nature10377DOI Listing
August 2011

Should pediatric hospitalists seek formal subspecialty status?

Hosp Pediatr 2011 Jul;1(1):4-6

University of South Carolina, School of Medicine, Columbia SC.

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http://dx.doi.org/10.1542/hpeds.2011-0021DOI Listing
July 2011

Nebulized hypertonic saline without adjunctive bronchodilators for children with bronchiolitis.

Pediatrics 2010 Sep 16;126(3):e520-5. Epub 2010 Aug 16.

University of Texas Health Science Center at San Antonio, Department of Pediatrics, and Christus Santa Rosa Children's Hospital, 7703 Floyd Curl Dr, MSC 7829, San Antonio, TX 78229, USA.

Objective: The goal was to determine an adverse event rate for nebulized hypertonic saline solution administered without adjunctive bronchodilators for infants with bronchiolitis.

Methods: This was a retrospective cohort study of the use of nebulized 3% saline for children<2 years of age who were hospitalized with the primary diagnosis of bronchiolitis at a single academic medical center. The medical records of study participants were analyzed for the use of nebulized 3% saline solution and any documented adverse events related to this therapy. Other clinical outcomes evaluated included respiratory distress scores, timing of the use of bronchodilators in relation to 3% saline solution, transfer to a higher level of care, and readmission within 72 hours after discharge.

Results: A total of 444 total doses of 3% saline solution were administered, with 377 doses (85%) being administered without adjunctive bronchodilators. Four adverse events occurred with these 377 doses, for a 1.0% adverse event rate (95% confidence interval: 0.3%-2.8%). Adverse events were generally mild. One episode of bronchospasm was documented, for a rate of 0.3% (95% confidence interval: <0.01%-1.6%).

Conclusions: The use of 3% saline solution without adjunctive bronchodilators for inpatients with bronchiolitis had a low rate of adverse events in our center. Additional clinical trials of 3% saline solution in bronchiolitis should evaluate its effectiveness in the absence of adjunctive bronchodilators.
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http://dx.doi.org/10.1542/peds.2009-3105DOI Listing
September 2010

Practical management of asthma.

Pediatr Rev 2009 Oct;30(10):375-85; quiz 385

University of Texas Health Science Center, San Antonio, TX, USA.

Objectives: After completing this article, readers should be able to: 1. Identify the major environmental factors and comorbid conditions that affect asthma. 2. Describe the role of a written asthma action plan in the management of asthma. 3. Know how to assess asthma control and adjust therapy appropriately. 4. Discuss the evaluation and management of the child who has an acute exacerbation of asthma.
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http://dx.doi.org/10.1542/pir.30-10-375DOI Listing
October 2009

Asthma epidemiology, pathophysiology, and initial evaluation.

Pediatr Rev 2009 Sep;30(9):331-5; quiz 335-6

University of Texas Health Science Center at San Antonio, San Antonio, Tex., USA.

The prevalence of asthma and the burden of disease remain high, despite efforts to improve public awareness about and medical management of asthma. Asthma is a disease of airway inflammation that has a variable natural history. Atopy is the most important risk factor for the development of asthma.
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http://dx.doi.org/10.1542/pir.30-9-331DOI Listing
September 2009

Incidence of apnea in infants hospitalized with respiratory syncytial virus bronchiolitis: a systematic review.

J Pediatr 2009 Nov 3;155(5):728-33. Epub 2009 Aug 3.

Department of Pediatrics, Division of Inpatient Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.

Objective: To determine the incidence of apnea in infants hospitalized with respiratory syncytial virus (RSV) bronchiolitis and identify relevant risk factors from the available literature.

Study Design: A systematic search of available databases for studies reporting the rate of apnea in a consecutive cohort of infants hospitalized with RSV infection was performed. The overall incidence of apnea was extracted and analyzed in relation to preterm birth, age, and potentially confounding illnesses.

Results: The incidence of apnea in the study population of 5575 hospitalized patients with RSV ranged from a high of 23.8% to a low of 1.2%. Comparison of the cohort by term and preterm birth revealed an expected excess in apnea incidence in preterms, even in the absence of information about chronologic age. Many studies appeared to be confounded by the inclusion of impaired infants with neuromuscular disorders.

Conclusions: Based on the available data, precisely quantifying the risk of apnea attributable to RSV infection is not possible. Factors intrinsic to the individual infants may account for a significant percentage of the apnea attributed to RSV. Recent studies have found a < 1% incidence of apnea with RSV in previously healthy term infants.
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http://dx.doi.org/10.1016/j.jpeds.2009.04.063DOI Listing
November 2009

X-linked infantile periodic alternating nystagmus.

Ophthalmic Genet 2005 Jun;26(2):77-84

Department of Ophthalmology, Pittsburgh Eye and Ear Institute, The University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, U.S.A.

Objective: To describe the clinical and electrophysiological characterization of four family members from three generations who have X-linked infantile periodic alternating nystagmus (XIPAN).

Methods: Complete clinical ophthalmological evaluation, pedigree analysis, electroretinograms (ERG), eye movement recordings (EMR), color vision, and fundus photography were performed on all subjects.

Results: Three males in two generations and one female were examined. Clinical examinations showed a jerk/pendular nystagmus with a latent component, strabismus, and a significant refractive error in the three affected males, while the female had only myopic astigmatism. ERG, color contrast, and fundus examinations were normal in all four family members. All four family members showed EMR abnormalities with infantile jerk/dual jerk and pendular nystagmus waveforms. The female had nystagmus present on EMR only and all patients showed (a)periodicity to their nystagmus.

Conclusions: In this family with no other congenital visual sensory system disease, affected males had obvious periodic alternating nystagmus, strabismus, and refractive errors, while the female had clinically "silent" periodic nystagmus that is probably a marker for the carrier state.
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http://dx.doi.org/10.1080/13816810590968014DOI Listing
June 2005

Gaze-dependent and time-restricted visual acuity measures in patients with Infantile Nystagmus Syndrome (INS).

Am J Ophthalmol 2005 Apr;139(4):716-8

Department of Ophthalmology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Purpose: We report a new method of measuring visual function in patients with INS by demonstrating the effects of eccentric gaze and forced time restriction on optotype recognition.

Design: Cross-sectional, comparative case-series.

Methods: No-time-restricted acuity (NTRA) and time-restricted acuity (TRA) for 19 patients and 18 controls were measured at multiple horizontal gaze angles.

Results: INS patients showed a significant lower visual acuity than controls (P < 0.0001). The TRA were significantly decreased in most gaze positions relative to NTRA in INS patients (P = 0.03) while there were no difference among controls. About half of the INS patients showed that their best visual acuity was gaze dependent, matching the preferred head posture in both NRTA and TRA paradigms.

Conclusions: Gaze-dependent visual acuity tested with and without time restriction may be a useful measure of visual function in INS patients and could be used in interventional clinical trials.
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http://dx.doi.org/10.1016/j.ajo.2004.09.069DOI Listing
April 2005

Effects of extraocular muscle surgery on 15 patients with oculo-cutaneous albinism (OCA) and infantile nystagmus syndrome (INS).

Am J Ophthalmol 2004 Dec;138(6):978-87

Department of Ophthalmology, Children's Hospital of Pittsburgh, the Pittsburgh Eye and Ear Institute, Pittsburgh, Pennsylvania 15213, USA.

Purpose: The purpose of this report is to characterize the clinical and electrophysiological effects of extraocular muscle surgery in 15 patients with oculo-cutaneous albinism (OCA) and infantile nystagmus syndrome (INS). Our hypothesis is that surgery on the extraocular muscles of patients with OCA and INS changes their nystagmus and their visual function.

Design: Interventional, prospective, cohort, noncomparative case series.

Methods: All 15 patients had surgery on all four virgin horizontal recti; three for strabismus alone, three for nystagmus alone, five for an eccentric gaze null zone alone, and four for an eccentric gaze null zone plus strabismus. All patients have been followed for at least six months. All 15 patients had the subjective outcome measure of pre- and postoperative binocular best optically corrected acuity (BBOCA). Objective outcome measures included anomalous head posture (AHP) in nine patients, eye movement recording measures of expanded nystagmus acuity function (NAFX) in 10 patients, null zone position (NUZP) and null zone width (NUZW) in 10 patients, and foveation time (FOV) in nine patients.

Results: The results are summarized as follows; BBOCA increased 0.1 LogMar or greater in 14 of 15 patients. In those operated on for an AHP with or without associated strabismus the AHP improved significantly (P < .01 for all). The NAFX, NUZP, NUZW, and FOV measured from eye movement recordings showed persistent, significant increases in all patients (P < .01 for all).

Conclusions: This report adds to the evidence that surgery on the extraocular muscles in patients with INS has independent neurologic and visual results.
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http://dx.doi.org/10.1016/j.ajo.2004.07.029DOI Listing
December 2004

A comparison of epidemiologic and immunologic features of bronchiolitis caused by influenza virus and respiratory syncytial virus.

J Med Virol 2005 Feb;75(2):282-9

Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.

We studied epidemiologic and immunologic factors in infants with bronchiolitis caused by influenza virus. The proportion of these infants who were male and who had an immediate family member with a history of asthma was similar to that of a control group of infants with respiratory syncytial virus (RSV) bronchiolitis. In subjects with influenza virus infection, concentrations of the beta chemokine macrophage inflammatory protein-1alpha (MIP-1alpha), but not other beta chemokines, in nasopharyngeal secretions (NPS) were greater among infants with more severe, hypoxic bronchiolitis than in subjects with mild, nonhypoxic bronchiolitis, or upper respiratory tract infection alone. Quantities of MIP-1alpha were also correlated with lower values of oxygen saturation. These findings point out epidemiologic and immunologic similarities between bronchiolitis caused by influenza and RSV, and suggest that host factors are more important than the nature of the infecting virus in the development of severe forms of bronchiolitis caused by influenza and RSV.
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http://dx.doi.org/10.1002/jmv.20268DOI Listing
February 2005

Towards a therapeutic inhibition of dystrophin exon 23 splicing in mdx mouse muscle induced by antisense oligoribonucleotides (splicomers): target sequence optimisation using oligonucleotide arrays.

J Gene Med 2004 Oct;6(10):1149-58

Centre for Biomedical Science, School of Biological Sciences, Royal Holloway-University of London, Egham TW20 0EX, UK.

Background: The activity of synthetic antisense oligonucleotides (splicomers) designed to block pre-mRNA splicing at specific exons has been demonstrated in a number of model systems, including constitutively spliced exons in mouse dystrophin RNA. Splicomer reagents directed to Duchenne muscular dystrophy (DMD) RNAs might thus circumvent nonsense or frame-shifting mutations, leading to therapeutic expression of partially functional dystrophin, as occurs in the milder, allelic (Becker) form of the disease (BMD).

Methods: Functional and hybridisation array screens have been used to select optimised splicomers directed to exon 23 of dystrophin mRNA which carries a nonsense mutation in the mdx mouse. Splicomers were transfected into cultured primary muscle cells, and dystrophin mRNA assessed for exon exclusion. Splicomers were also administered to the muscles of mdx mice.

Results: Oligonucleotide array analyses with dystrophin pre-mRNA probes revealed strong and highly specific hybridisation patterns spanning the exon 23/intron 23 boundary, indicating an open secondary structure conformation in this region of the RNA. Functional screening of splicomer arrays by direct analysis of exon 23 RNA splicing in mdx muscle cultures identified a subset of biologically active reagents which target sequence elements associated with the 5' splice site region of dystrophin intron 23; splicomer-mediated exclusion of exon 23 was specific and dose-responsive up to a level exceeding 50% of dystrophin mRNA, and Western blotting demonstrated de novo expression of dystrophin protein at 2-5% of wild-type levels. Direct intramuscular administration of optimised splicomer reagents in vivo resulted in the reappearance of sarcolemmal dystrophin immunoreactivity in > 30% of muscle fibres in the mdx mouse

Conclusions: These results suggest that correctly designed splicomers may have direct therapeutic value in vivo, not only for DMD, but also for a range of other genetic disorders.
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http://dx.doi.org/10.1002/jgm.603DOI Listing
October 2004

Prevalence of diurnal voiding symptoms and difficult arousal from sleep in children with nocturnal enuresis.

J Urol 2004 Jul;172(1):311-6

Division of Pediatric Nephrology, Schneider Children's Hospital at North Shore and North Shore University Hospital, Manhasset, New York 11030, USA.

Purpose: We analyzed the relative contribution of detrusor instability and difficult arousal from sleep in the genesis of nocturnal enuresis (NE), and evaluate a clinical feature that may prospectively help differentiate patients with monosymptomatic NE (mono NE) from those with diurnal voiding symptoms (DVSs) of urgency and urge incontinence associated with NE (NE + DVSs).

Materials And Methods: Patients referred for voiding problems and 627 controls were evaluated for NE, DVSs, nocturia and arousal from sleep on a scale of 1 to 8. Patients were categorized into 3 groups-mono NE of primary or secondary onset (200, boys 71%, girls 29%), primary or secondary NE + DVSs (329, boys 43%, girls 57%) and isolated DVSs (146, boys 21%, girls 79%).

Results: DVSs were noted in 49% of boys and 76% of girls with NE, although 40% of patients or parents did not complain of DVSs. The DVSs were elicited on detailed interrogation or on finding evidence of urinary incontinence on perineal examination. While one-third of controls and patients with isolated DVSs manifested nocturia at least twice a month, only 6% of bedwetters did so. Difficult arousal from sleep (scores 6 to 8) was more prevalent in patients with NE (59%) than controls (20%) or patients with isolated DVSs (5%), and in patients with mono NE and primary NE than in NE + DVSs or secondary NE, with reverse prevalence for nocturia. Easy sleep arousal (scores 1 to 3) was noted in 65% of patients with secondary NE + DVSs vs up to 6% of other NE subgroups. Compared to patients with mono NE, those with NE + DVSs had a higher prevalence of urinary tract infection (UTI), encopresis, psychosocial/learning problems, and family history of UTI and DVSs, ie problems associated with detrusor instability.

Conclusions: DVSs accompany NE in two-thirds of patients but can be missed during a cursory history. Difficult sleep arousal seems to have a major role in primary mono NE, and detrusor instability in secondary NE + DVSs. In patients with NE a history of frequent nocturia, easy sleep arousal, UTI, encopresis, psychosocial learning problems or family history of UTI and DVSs should raise the suspicion for associated undisclosed DVSs.
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http://dx.doi.org/10.1097/01.ju.0000132363.36007.49DOI Listing
July 2004

Production of interferon gamma in respiratory syncytial virus infection of humans is not associated with interleukins 12 and 18.

J Med Virol 2004 Jun;73(2):289-94

Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.

In order to understand early events in the immune response to respiratory syncytial virus (RSV) infection, we studied the presence of various chemokines and cytokines in respiratory secretions of human infants with RSV infection. Interferon gamma (IFNgamma) was present in 30/39 (76.9%) subjects tested, but the IFNgamma-inducing cytokines interleukin (IL)12 and IL18 were detectable in 6/40 (15%) and 11/38 (28.9%) subjects, respectively. Quantities of IL12 and IL18 did not correlate with those of IFNgamma. IL18, but neither IFNgamma nor IL12 was found in significantly greater concentrations in subjects with mild, nonhypoxic forms of bronchiolitis than in those with upper respiratory illness alone or hypoxic bronchiolitis. The findings suggest that IFNgamma may be induced independently of the activities of IL12 and IL18 during RSV infection. Immune responses characterized by relatively greater release of IL18 may be associated with milder forms of bronchiolitis.
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http://dx.doi.org/10.1002/jmv.20089DOI Listing
June 2004