Childrens Hospital and Regional Medical Center

Seattle, WA, United States

Childrens Hospital and Regional Medical Center

Seattle, WA, United States
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Moore A.M.,University of Washington | Patel S.,University of Washington | Forsberg K.J.,University of Washington | Wang B.,University of Washington | And 7 more authors.
PLoS ONE | Year: 2013

Emerging antibiotic resistance threatens human health. Gut microbes are an epidemiologically important reservoir of resistance genes (resistome), yet prior studies indicate that the true diversity of gut-associated resistomes has been underestimated. To deeply characterize the pediatric gut-associated resistome, we created metagenomic recombinant libraries in an Escherichia coli host using fecal DNA from 22 healthy infants and children (most without recent antibiotic exposure), and performed functional selections for resistance to 18 antibiotics from eight drug classes. Resistance-conferring DNA fragments were sequenced (Illumina HiSeq 2000), and reads assembled and annotated with the PARFuMS computational pipeline. Resistance to 14 of the 18 antibiotics was found in stools of infants and children. Recovered genes included chloramphenicol acetyltransferases, drug-resistant dihydrofolate reductases, rRNA methyltransferases, transcriptional regulators, multidrug efflux pumps, and every major class of beta-lactamase, aminoglycoside-modifying enzyme, and tetracycline resistance protein. Many resistance-conferring sequences were mobilizable; some had low identity to any known organism, emphasizing cryptic organisms as potentially important resistance reservoirs. We functionally confirmed three novel resistance genes, including a 16S rRNA methylase conferring aminoglycoside resistance, and two tetracyclineresistance proteins nearly identical to a bifidobacterial MFS transporter (B. longum s. longum JDM301). We provide the first report to our knowledge of resistance to folate-synthesis inhibitors conferred by a predicted Nudix hydrolase (part of the folate synthesis pathway). This functional metagenomic survey of gut-associated resistomes, the largest of its kind to date, demonstrates that fecal resistomes of healthy children are far more diverse than previously suspected, that clinically relevant resistance genes are present even without recent selective antibiotic pressure in the human host, and that cryptic gut microbes are an important resistance reservoir. The observed transferability of gut-associated resistance genes to a gram-negative (E. coli) host also suggests that the potential for gut-associated resistomes to threaten human health by mediating antibiotic resistance in pathogens warrants further investigation. © 2013 Moore et al.


Davis S.D.,Indiana University | Ferkol T.W.,University of Washington | Rosenfeld M.,Childrens Hospital and Regional Medical Center | Lee H.-S.,University of South Florida | And 12 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Rationale: The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined. Objectives: To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype. Methods: A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping. Measurements and Main Results: Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA 1 IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/ CA/MTD; n = 40). Median FEV 1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/ CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations. Conclusions: Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/ CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40. Copyright © 2015 by the American Thoracic Society.


Mayer-Davis E.J.,University of North Carolina at Chapel Hill | Saydah S.,Centers for Disease Control and Prevention | Imperatore G.,Centers for Disease Control and Prevention | Linder B.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | And 5 more authors.
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Despite concern about an "epidemic," there are limited data on trends in prevalence of either type 1 or type 2 diabetes across US race and ethnic groups. OBJECTIVE: To estimate changes in the prevalence of type 1 and type 2 diabetes in US youth, by sex, age, and race/ethnicity between 2001 and 2009. DESIGN, SETTING, AND PARTICIPANTS: Case patients were ascertained in 4 geographic areas and 1 managed health care plan. The study population was determined by the 2001 and 2009 bridged-race intercensal population estimates for geographic sites and membership counts for the health plan. MAIN OUTCOMES AND MEASURES: Prevalence (per 1000) of physician-diagnosed type 1 diabetes in youth aged 0 through 19 years and type 2 diabetes in youth aged 10 through 19 years. RESULTS: In 2001, 4958 of 3.3 million youth were diagnosed with type 1 diabetes for a prevalence of 1.48 per 1000 (95% CI, 1.44-1.52). In 2009, 6666 of 3.4 million youth were diagnosed with type 1 diabetes for a prevalence of 1.93 per 1000 (95% CI, 1.88-1.97). In 2009, the highest prevalence of type 1 diabetes was 2.55 per 1000 among white youth (95% CI, 2.48-2.62) and the lowest was 0.35 per 1000 in American Indian youth (95% CI, 0.26-0.47) and type 1 diabetes increased between 2001 and 2009 in all sex, age, and race/ethnic subgroups except for those with the lowest prevalence (age 0-4 years and American Indians). Adjusted for completeness of ascertainment, there was a 21.1% (95% CI, 15.6%-27.0%) increase in type 1 diabetes over 8 years. In 2001, 588 of 1.7 million youth were diagnosed with type 2 diabetes for a prevalence of 0.34 per 1000 (95% CI, 0.31-0.37). In 2009, 819 of 1.8 million were diagnosed with type 2 diabetes for a prevalence of 0.46 per 1000 (95% CI, 0.43-0.49). In 2009, the prevalence of type 2 diabetes was 1.20 per 1000 among American Indian youth (95% CI, 0.96-1.51); 1.06 per 1000 among black youth (95% CI, 0.93-1.22); 0.79 per 1000 among Hispanic youth (95% CI, 0.70-0.88); and 0.17 per 1000 among white youth (95% CI, 0.15-0.20). Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians. Adjusted for completeness of ascertainment, there was a 30.5% (95% CI, 17.3%-45.1%) overall increase in type 2 diabetes. CONCLUSIONS AND RELEVANCE: Between 2001 and 2009 in 5 areas of the United States, the prevalence of both type 1 and type 2 diabetes among children and adolescents increased. Further studies are required to determine the causes of these increases. Copyright 2014 American Medical Association. All rights reserved.


Wainwright C.E.,Royal Childrens Hospital | Quittner A.L.,University of Miami | Geller D.E.,Nemours Childrens Clinic | Nakamura C.,3820 Meadows Lane | And 4 more authors.
Journal of Cystic Fibrosis | Year: 2011

Background: Previous aztreonam for inhalation solution (AZLI) studies included patients with cystic fibrosis, Pseudomonas aeruginosa (PA) airway infection, and forced expiratory volume in 1s (FEV1) 25% to 75% predicted. This double-blind, multicenter, randomized, placebo-controlled trial enrolled patients (≥6years) with FEV1>75% predicted. Methods: AZLI 75. mg (n = 76) or placebo (n = 81) was administered 3-times daily for 28. days with a 14-day follow-up. Results: Day 28 treatment effects were 1.8points for CFQ-R-Respiratory Symptoms Scale (95%CI: -2.8, 6.4; p=0.443; primary endpoint); -1.2 for log10 sputum PA colony-forming units (p=0.016; favoring AZLI), and 2.7% for relative FEV1% predicted (p=0.021; favoring AZLI). Treatment effects favoring AZLI were larger for patients with baseline FEV1 <90% predicted compared to ≥90% predicted. AZLI was well-tolerated. Conclusions: Effects on respiratory symptoms were modest; however, FEV1 improvements and bacterial density reductions support a possible role for AZLI in these relatively healthy patients. ClinicalTrials.gov identifier: NCT00712166. © 2011 European Cystic Fibrosis Society.


Fairchok M.P.,U.S. Army | Fairchok M.P.,Childrens Hospital and Regional Medical Center | Martin E.T.,Childrens Hospital and Regional Medical Center | Chambers S.,U.S. Army | And 4 more authors.
Journal of Clinical Virology | Year: 2010

Background: The epidemiology of respiratory tract infections (RTIs) in a daycare cohort has not been explored using molecular techniques. Objectives: (1) Determine the overall incidence of RTIs in a daycare cohort using real-time reverse transcriptase polymerase chain reaction (RT-PCR). (2) Determine the relative incidence and impact of specific respiratory viruses, and characterize and compare clinical features associated with these pathogens. Study design: In this prospective cohort study conducted from February 2006 to April 2008, nasal swabs were obtained from symptomatic children ages 0-30 months enrolled in fulltime daycare.RT-PCR was performed to detect respiratory syncytial virus (RSV), human metapneumovirus (MPV), influenza (Flu) viruses A and B, parainfluenza (PIV), adenovirus (AdV), human coronaviruses (CoV) and rhinovirus (RhV). Symptom diaries were completed for each illness. Results: We followed 119 children (mean age 10 months; range 2-24 months) for 115 child years. The mean annual incidence of RTI per child was 4.2 the first year and 1.2 the second year of the study. At least 1 virus was identified in 67% RTIs. Co-infections were common (27% RTIs), with RhV, CoV, and AdV the most common co-pathogens. PIV was identified in 12% of RTIs with a high incidence of PIV4. The viruses with the greatest impact on our population were RSV, RhV and AdV. Conclusions: Using molecular techniques, viruses were identified in approximately twice as many RTIs as previously reported in a daycare cohort. Infections with newly identified viruses, such as HMPV and CoV subtypes were less frequent and severe than infections with RSV, AdV and RhV. © 2010.


Fuhrman B.,Children's Hospital of Buffalo | Zimmerman J.,Childrens Hospital and Regional Medical Center
Pediatric Critical Care | Year: 2011

Provide the latest in superior quality care for critically ill children with the full-color, updated 4th Edition of Fuhrman and Zimmerman's Pediatric Critical Care. In print, and now online, Drs. Bradley P. Fuhrman and Jerry J. Zimmerman use a comprehensive, organ-systems approach to help you manage a full range of disease entities. Get up-to-the-minute knowledge of topics such as acute lung injury, multiple organ dysfunction syndrome, and more. Implement new clinical techniques and diagnostic tests, weigh the varying perspectives of six associate editors with expertise in the field, reference 1,000+ illustrations to aid diagnosis, and keep sharp with online access to board-style review questions. This definitive title will ensure that you consistently deliver the very best intensive care to your pediatric patients. Focus on the development, function, and treatment of a wide range of disease entities with the text's clear, logical, organ-system approach. Keep all members of the pediatric ICU team up to date with coverage of topics particularly relevant to their responsibilities. Keep current with the latest developments in palliative care, mass casualty/epidemic disease, acute respiratory failure, non-invasive ventilation, neurocritical care, neuroimaging, hypoxic-ischemic encephalopathy, stroke and intracerebral hemorrhage, systemic inflammatory response syndrome, acute lung injury, multiple organ dysfunction syndrome, and much more. Quickly find the information you need with sections newly reorganized for easier access. Gain the perspectives of six expert associate editors on all the new developments in the field. Understand complex concepts quickly and conclusively with a brand new full-color format and more than 1,000 illustrations. Search the full text, download the image library, and access online board review questions targeting every relevant topic, all at www.expertconsult.com. Fuhrman and Zimmerman's Pediatric Critical Care covers the latest developments in pediatric critical care that improve patient care and survival rates. © 2011 Elsevier Inc. All rights reserved.


Mayer-Davis E.J.,University of North Carolina at Chapel Hill | Dabelea D.,University of Colorado at Denver | Crandell J.L.,University of North Carolina at Chapel Hill | Crume T.,University of Colorado at Denver | And 7 more authors.
Diabetes Care | Year: 2013

OBJECTIVE: To test the novel hypothesis that nutritional factors previously associated with type 1 diabetes etiology or with insulin secretion are prospectively associated with fasting C-peptide (FCP) concentration among youth recently diagnosed with type 1 diabetes. RESEARCH DESIGN ANDMETHODS: Included were 1,316 youth with autoantibody-positive type 1 diabetes who participated in the SEARCH for Diabetes in Youth study (baseline disease duration, 9.9 months; SD, 6.3). Nutritional exposures included breastfeeding and age at introduction of complementary foods, baseline plasma long-chain omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), vitamin D, vitamin E, and, froma baseline food frequency questionnaire, estimated intake of the branched-chain amino acid leucine and total carbohydrate. Multiple linear regression models were conducted to relate each nutritional factor to baseline FCP adjusted for demographics, disease-related factors, and other confounders. Prospective analyses included the subset of participants with preserved b-cell function at baseline (baseline FCP ≥0.23 ng/mL) with additional adjustment for baseline FCP and time (mean follow-up, 24.3 months; SD, 8.2; n = 656). FCP concentration was analyzed as log(FCP). RESULTS: In adjusted prospective analyses, baseline EPA (P = 0.02), EPA plus DHA (P = 0.03), and leucine (P = 0.03) were each associated positively and significantly with FCP at followup. Vitamin D was unexpectedly inversely associated with FCP (P = 0.002). CONCLUSIONS: Increased intake of branched-chain amino acids and long-chain omega-3 fatty acids may support preservation of b-cell function. This represents a new direction for research to improve prognosis for type 1 diabetes. © 2013 by the American Diabetes Association.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 90.00K | Year: 2010

The Seattle Childrens Hospital is awarded a grant to conduct two workshops that will address the opportunities offered by cloud computing to confront the task of uncovering scientific knowledge from enormous amounts of data generated by biological research. The workshop goals are responsive to the NSF strategic vision on Cyberinfrastructure Framework for 21st Century Science and Engineering, which challenges the community to develop and sustain the necessary cyberinfrastructure capable of enabling science and engineering in the 21st century. Cloud computing offers an unprecedented opportunity to address the challenges of this data bottleneck and open up a new era in Data-Intensive Science (DIS). The two workshops will bring practitioners in biological informatics together to discuss challenges, opportunities and strategies in order to propose short- and long-term strategies to take on these challenges. There is a significant and very timely potential for widespread applicability in that there are many disciplines that now routinely generate data sets that overwhelm storage and analysis infrastructures. The workshops will showcase not only the communities and their challenges, but, more importantly, address how best to meet those challenges.

The workshops will connect computational, data analysis, and inter-disciplinary research communities, including researchers, analyzers, developers, educators, community and tribal leaders, scientific administrators, and policymakers. This will enable both high-level (strategic) and specific (operational) discussions and developments of the user requirements, user-based evaluations, and standardized development with broad impact beyond the particular community challenges.

Cloud computing can have a major impact at helping four main types of diversity issues and institutions. First, clouds have the potential to allow access to extensive compute resources to research groups from all sizes of institutes, but particularly the small to mid-sized institutes that cannot afford to increase their local compute infrastructure. Similarly, secondly, minority-serving institutes (e.g. Howard University) and, thirdly, gender-serving institutions (e.g. Wellesley College) can take advantage of a common resource to boost their compute capabilities. Fourth, young investigators can have ready access to resources outside of their current support levels while more senior investigators can adapt to the increased need for compute resources in their field.

These workshops will be held in September 19-20, 2010 (Seattle, WA; Seattle Childrens Research Institute) and March 20-21, 2011 (Washington, D.C.; J. Craig Venter Institute). Further information on the workshops and their outcomes will be available via the PIs lab home page at http://kolkerlab.proteinspire.org/.


Patent
Childrens Hospital And Regional Medical Center | Date: 2012-09-28

Disclosed herein are methods of treatment of autoimmune diseases such as systemic lupus erythematosus (SLE) as well as clinical assays for detection of autoimmune disease activity in patients utilizing a PD1 ligand.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: MODULATION | Award Amount: 311.00K | Year: 2009

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
The cerebellum is a large part of the brain that is involved in sensory-motor control and motor learning as well as in cognition. Most scientists consider that motor learning is mediated at two separate sites, the cerebellar cortex and the deep cerebellar nuclei (DCN). All effects of the cerebellar cortex are mediated by Purkinje cell inhibition of DCN neurons. However, our understanding of how cells of the DCN integrate inhibitory input from Purkinje cells with excitatory input from other sources has been impeded by the large spatial separation between these two important cell types in mammals. This project focuses on a special system, the caudal cerebellar lobe of mormyrid fish, where these two cell types are close together. The proximity of these two cell types in the mormyrid cerebellum will allow the PI to record simultaneously from both cell types in an in vitro slice preparation. Such recording will allow the effects of Purkinje cells on their target neurons to be determined precisely. Determination of synaptic dynamics and plasticity at this synapse will advance our understanding of the functional circuitry of the cerebellum. Science teachers and students are intrigued by mormyrid electric fish and the electrical pulses they use to probe the environment and communicate with other fish. Groups of students and teachers from local schools will participate in this project examining these fish and their discharges through hands-on experiments. Such experiments will help stimulate student interest in both the biological and physical sciences. The goal will be to make electric fish part of the science curriculum.

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