Publications by authors named "Vegard Hovland"

13 Publications

  • Page 1 of 1

Prevalence of long-term mechanical insufflation-exsufflation in children with neurological conditions: a population-based study.

Dev Med Child Neurol 2021 05 3;63(5):537-544. Epub 2021 Jan 3.

Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.

Aim: To determine the prevalence of long-term mechanical insufflation-exsufflation (MI-E) and concomitant mechanical ventilation in children with neurological conditions, with reported reasons behind the initiation of treatment.

Method: This was a population-based, cross-sectional study using Norwegian national registries and a questionnaire.

Results: In total, 114 of 19 264 children with a neurological condition had an MI-E device. Seventy-three of 103 eligible children (31 females, 42 males), median (min-max) age of 10 years 1 month (1y 5mo-17y 10mo), reported their MI-E treatment initiation. Overall, 76% reported airway clearance as the main reason to start long-term MI-E. A prophylactic use was mainly reported by children with neuromuscular disorders (NMDs). Prevalence and age at initiation differed by diagnosis. In spinal muscular atrophy and muscular dystrophies, MI-E use was reported in 34% and 7% of children, of whom 83% and 57% respectively received ventilator support. One-third of the MI-E users were children with central nervous system (CNS) conditions, such as cerebral palsy and degenerative disorders, and ventilator support was provided in 31%. The overall use of concomitant ventilatory support among the long-term MI-E users was 56%.

Interpretation: The prevalence of MI-E in a neuropaediatric population was 6 per 1000, with two-thirds having NMDs and one-third having conditions of the CNS. The decision to initiate MI-E in children with neurological conditions relies on clinical judgment.

What This Paper Adds: The prevalence and age at initiation of mechanical insufflation/exsufflation (MI-E) differed between diagnoses. MI-E was most commonly used in spinal muscular atrophy, where it generally coincided with ventilatory support. One-third of MI-E devices were given to children with central nervous system conditions, and one-third also received ventilatory support.
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http://dx.doi.org/10.1111/dmcn.14797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048789PMC
May 2021

Shared DNA methylation signatures in childhood allergy: The MeDALL study.

J Allergy Clin Immunol 2021 03 15;147(3):1031-1040. Epub 2020 Dec 15.

Centre for Individualized Infection Medicine, CiiM, a joint venture between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema.

Objective: We sought to identify DNA methylation profiles associated with childhood allergy.

Methods: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses.

Results: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium.

Conclusion: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.
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http://dx.doi.org/10.1016/j.jaci.2020.11.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238013PMC
March 2021

Optimizing expiratory flows during mechanical cough in a pediatric neuromuscular lung model.

Pediatr Pulmonol 2020 02 19;55(2):433-440. Epub 2019 Dec 19.

Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslðo, Norway.

Mechanical insufflation-exsufflation (MI-E) is recommended for subjects of all ages with neuromuscular disorders (NMDs) and weak cough. There is a lack of knowledge on the optimal treatment settings for young children. This study aims to determine the MI-E settings providing high expiratory airflow while using safe inspiratory volumes, and to identify possible limits where the benefit of incrementing the MI-E settings to achieve a higher expiratory airflow, decreased. Using an MI-E device and a lung model imitating a 1-year-old child with NMD, we explored the impact of 120 combinations of MI-E pressure and time settings on maximal expiratory airflow and inspiratory volume. High expiratory airflows were achieved with several pressure and time combinations where the exsufflation pressure, followed by insufflation pressure and time, had the greatest impact. The benefit of incrementing the settings to increase the expiratory airflow leveled off for the insufflation pressure and time, but not for the exsufflation pressure. Given exsufflation pressure of -40 or -50 cmH O and insufflation time longer than 1 second, a plateau in the expiratory airflow curve was present at insufflation pressures from 25 cmH O, whereas a plateau in the inspired volume curve occurred at insufflation pressures from 35 cmH O. The present neuromuscular pediatric lung model study showed that expiratory pressure impacts expiratory airflow more than inspiratory pressure and time. An inspiratory and expiratory pressure set between 20 to 30 and -40 cmH O, respectively, and an inspiratory time longer than 1 second may be considered as a basis when titrating MI-E settings in young children with NMD. The findings must be confirmed in clinical trials.
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http://dx.doi.org/10.1002/ppul.24606DOI Listing
February 2020

DNA methylation in childhood asthma: an epigenome-wide meta-analysis.

Lancet Respir Med 2018 05 26;6(5):379-388. Epub 2018 Feb 26.

ISGlobal, Centre for Research in Environmental Epidemiology, the Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Background: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma.

Methods: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting.

Findings: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects.

Interpretation: Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.

Funding: EU and the Seventh Framework Programme (the MeDALL project).
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http://dx.doi.org/10.1016/S2213-2600(18)30052-3DOI Listing
May 2018

The clinical use of mechanical insufflation-exsufflation in children with neuromuscular disorders in Europe.

Paediatr Respir Rev 2018 Jun 3;27:69-73. Epub 2017 Nov 3.

Centre for Neuromuscular Disorders and Home Mechanical Ventilation, UZ Brussel-Inkendaal, Vlezenbeek, Belgium. Electronic address:

Mechanical insufflation-exsufflation (MI-E) is a strategy to treat pulmonary exacerbations in neuromuscular disorders (NMDs). Pediatric guidelines for optimal setting titration of MI-E are lacking and the settings used in studies vary. Our objective was to assess the actual MI-E settings being used in current clinical treatment of children with NMDs and a survey was sent in July 2016 to European expertise centers. Ten centers from seven countries gave information on MI-E settings for 240 children aged 4 months to 17.8 years (mean 10.5). Settings varied greatly between the centers. Auto mode was used in 71%, triggering of insufflation in 21% and manual mode in 8% of the cases. Mean (SD) time for insufflation (Ti) and exsufflation (Te) were 1.9 (0.5) and 1.8 (0.6) s respectively, both ranging from 1 to 4s. Asymmetric time settings were common (65%). Mean (SD) insufflation (Pi) and exsufflation (Pe) pressures were 32.4 (7.8) and -36.9 (7.4), ranging 10 to 50 and -10 to -60cmHO, respectively. Asymmetric pressures were as common as symmetric. Both Ti, Te, Pi and Pe increased with age (p < 0.001). In conclusion, pediatric MI-E settings in clinical use varied greatly and altered with age, highlighting the need of more studies to improve our knowledge of optimal settings in MI-E in children with NMDs.
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http://dx.doi.org/10.1016/j.prrv.2017.08.003DOI Listing
June 2018

The use of the MeDALL-chip to assess IgE sensitization: a new diagnostic tool for allergic disease?

Pediatr Allergy Immunol 2015 May;26(3):239-246

Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Allergic sensitization is frequently present in asthma and rhinitis, but the role of specific immunoglobulin E (s-IgE) is not always clear. Multiple s-IgE analyses may provide insight into this relationship, thus a microarray chip was developed within the EU-funded MeDALL project. The main objective was to evaluate the performance of the MeDALL-chip compared to ImmunoCAP and skin prick test (SPT) in detecting allergic sensitization in children and secondarily to investigate the association to asthma and allergic rhinitis.

Methods: From the 'Environment and Childhood Asthma Study', 265 children were investigated at 10 and 16 yr of age with clinical examination, interview, SPT, ImmunoCAP, and the MeDALL-chip including 152 allergen components in the analysis.

Results: Allergic sensitization at 10 yr was more frequently detected using the MeDALL-chip (38.1%) compared to the ImmunoCAP (32.8%) (p = 0.034) and SPT (25.5%) (p < 0.001), but no significant difference was seen at 16 yr (MeDALL-chip 49.8%, ImmunoCAP 48.6%, SPT 45.8%). The MeDALL-chip did not differ significantly from the ImmunoCAP or SPT in terms of detecting allergic sensitization in subjects with rhinitis or asthma at 10 or 16 yr.

Conclusion: The prevalence of allergic sensitization increased by all three diagnostic tests from 10 to 16 yr was similar by SPT and ImmunoCAP and significantly higher with the MeDALL-chip at 10 yr. All three tests were comparable for identification of allergic sensitization among children with current rhinitis or asthma.
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http://dx.doi.org/10.1111/pai.12366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597352PMC
May 2015

Lung function trajectories from birth through puberty reflect asthma phenotypes with allergic comorbidity.

J Allergy Clin Immunol 2014 Oct 3;134(4):917-923.e7. Epub 2014 Jul 3.

Department of Paediatrics, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Childhood asthma phenotypes reflecting underlying developmental mechanisms are sought, with little information on asthma phenotypes based on allergic comorbidities.

Objective: We asked whether lung function trajectories from birth to 16 years were associated with asthma phenotypes with comorbid allergic rhinitis and atopic dermatitis.

Methods: Lung function (given as z scores) was measured at birth in 329 subjects in the "Environment and Childhood Asthma" birth cohort study in Oslo by using tidal flow volume loops, and at 10 and 16 years by using spirometry. Asthma phenotypes were classified on the basis of recurrent bronchial obstruction at 0 to 2 years, and asthma from the 2- to 10-year and 10- to 16-year intervals, and by combining asthma, atopic dermatitis, and/or allergic rhinitis from 10 to 16 years, stratifying for allergic sensitization. The reference group included 231 subjects without recurrent bronchial obstruction or asthma.

Results: Lung function trajectories differed significantly for asthma comorbidity phenotypes for FEV1, forced expiratory flow at 25% to 75% of forced vital capacity, and FEV1/forced vital capacity (all P < .0001). Significant lung function impairment was observed from birth through 16 years among subjects with asthma, atopic dermatitis, and allergic rhinitis. Lung function trajectories in subjects with asthma at 10 to 16 years or asthma in remission differed significantly for all 3 spirometric values compared with the trajectories in those who never had asthma (P < .0001), but not between asthma groups. Allergic sensitization was not significantly associated with asthma phenotype lung function trajectories.

Conclusions: The trajectory consisting of impaired lung function from birth throughout childhood in children with asthma, atopic dermatitis, and allergic rhinitis appears less likely to be driven by allergic sensitization, and may imply disease onset in utero, with clinical presentation later in childhood.
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http://dx.doi.org/10.1016/j.jaci.2014.05.020DOI Listing
October 2014

Asthma with allergic comorbidities in adolescence is associated with bronchial responsiveness and airways inflammation.

Pediatr Allergy Immunol 2014 Jun;25(4):351-9

Department of Paediatrics, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Childhood asthma frequently has allergic comorbidities. However, there is limited knowledge of the longitudinal development of asthma comorbidites and their association to bronchial hyper-responsiveness (BHR) and airway inflammation markers. We therefore aimed to assess the association between childhood asthma with allergic comorbidities and BHR and fractional exhaled nitric oxide (FE(NO)) and the impact of gender on these associations.

Methods: Based on data from 550 adolescents in the prospective birth cohort 'Environment and Childhood Asthma' study, asthma was defined for the three time periods 0-2, 2-10 and 10-16 years of age, using recurrent bronchial obstruction (rBO) 0-2 years of age as a proxy for early asthma. Asthma comorbidities included atopic dermatitis (AD) and allergic rhinitis (AR) from 10 to 16 years. At age 16 years BHR, assessed by metacholine bronchial challenge, and airway inflammation, assessed by FE(NO), were compared between the groups of asthma with or without the two comorbidities, to a reference group with no never asthma, and subsequently stratified by gender.

Results: Boys with asthma and AR, regardless of AD had significantly more severe BHR and higher FE(NO) than the other asthma phenotypes. Almost half of the children remained in the asthma and AR category from 10 to 16 years, the entire difference being determined by new incident cases from 10 to 16 years.

Conclusions: Asthma phenotypes characterized by allergic comorbidities and AR in particular appears closely associated with BHR and FE(NO), especially among boys.
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http://dx.doi.org/10.1111/pai.12241DOI Listing
June 2014

The significance of early recurrent wheeze for asthma outcomes in late childhood.

Eur Respir J 2013 Apr 16;41(4):838-45. Epub 2012 Aug 16.

Dept of Paediatrics, Oslo University Hospital, Oslo, Norway.

Recurrent early life wheeze is not always asthma, and up to 50% of children are reported to remit. With reports of adult asthma symptom relapse, we assessed the prognosis of recurrent bronchial obstruction (rBO) through adolescence in the Environment and Childhood Asthma (ECA) prospective birth cohort study. The present study is based on data from investigations at ages 2, 10 and 16 years of 550 young people (52% males) attending at 16 years of age. Based on the presence of rBO from 0-2 years, defined as recurrent (at least two episodes) doctor-diagnosed wheeze, and asthma from 2-10 years and 10-16 years, defined as at least two episodes of doctor-diagnosed asthma, symptoms and medication use, prognosis of rBO was assessed. Bronchial hyperresponsiveness (BHR) was diagnosed by a metacholine provocation dose ≤ 8 μmol that caused 20% reduction in the forced expiratory volume in 1 s. At 10-16 years, 34% of the 143 rBO children had asthma. All children with rBO had reduced lung function compared with the never asthmatics. Of the rBO children in remission, 48.4% had asthma symptoms, medication use and/or BHR compared with 26.7% with never asthma (p<0.001). Only 34.3% of rBO children were without asthma symptoms, medication use or BHR by 16 years, possibly indicating future asthma risk.
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http://dx.doi.org/10.1183/09031936.00071512DOI Listing
April 2013

Does bronchial hyperresponsiveness in childhood predict active asthma in adolescence?

Am J Respir Crit Care Med 2012 Sep 12;186(6):493-500. Epub 2012 Jul 12.

Department of Paediatrics, Oslo University Hospital, NO-0407 Oslo, Norway.

Rationale: Bronchial hyperresponsiveness (BHR) is an important, but not specific, asthma characteristic.

Objectives: We aimed to assess the predictive value of BHR tested by methacholine and exercise challenge at age 10 years for active asthma 6 years later.

Methods: From a Norwegian birth cohort, 530 children underwent methacholine challenge and exercise-induced bronchoconstriction (EIB) test (n = 478) at 10 years and structured interview and clinical examination at age 16 years. The methacholine dose causing 20% reduction in FEV(1) (PD(20)) and the reduction in FEV(1) (%) after a standardized treadmill test were used for BHR assessment. Active asthma was defined with at least two criteria positive: doctor's diagnosis of asthma, symptoms of asthma, and/or treatment for asthma in the last year.

Measurements And Main Results: PD(20) and EIB at 10 years of age increased the risk of asthma (β = 0.94 [95% confidence interval (CI), 0.92-0.96] per μmol methacholine and β = 1.10 [95% CI, 1.06-1.15] per %, respectively). Separately the tests explained 10 and 7%, respectively, and together 14% of the variation in active asthma 6 years later. The predicted probability for active asthma at the age of 16 years increased with decreasing PD(20) and increasing EIB. The area under the curve (receiver operating characteristic curves) was larger for PD(20) (0.69; 95% CI, 0.62-0.75) than for EIB (0.60; 95% CI, 0.53-0.67).

Conclusions: BHR at 10 years was a significant but modest predictor of active asthma 6 years later, with methacholine challenge being superior to exercise test.
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http://dx.doi.org/10.1164/rccm.201112-2235OCDOI Listing
September 2012

Bronchial hyperresponsiveness decreases through childhood.

Respir Med 2012 Feb 19;106(2):215-22. Epub 2011 Oct 19.

Oslo University Hospital, Department of Paediatrics, Oslo, Norway.

Limited knowledge exists about development of bronchial hyperresponsiveness (BHR) through adolescence. We aimed to assess changes in and risk factors for BHR in adolescence. From a Norwegian birth cohort 517 subjects underwent clinical examinations, structured interviews and methacholine challenges at age 10 and 16. BHR was divided into four categories: no BHR (cumulative methacholine dose required to reduce FEV(1) by 20% (PD(20)) >16 μmol), borderline BHR (PD(20) ≤16 and >8 μmol), mild to moderate BHR (PD(20) ≤8 and >1 μmol), and severe BHR (PD(20) ≤ 1 μmol). Logistic regression analysis was used to assess risk factors and possible confounders. The number of children with PD(20) ≤ 8 decreased from 172 (33%) to 79 (15%) from age 10-16 (p < 0.001). Most children (n = 295, 57%) remained in the same BHR (category) from age 10-16 (50% with no BHR), whereas the majority 182 (82%) of the 222 children who changed BHR category, had decreased severity at age 16. PD(20) ≤ 8 at age 10 was the major risk factor for PD(20) ≤ 8 6 years later (odds ratio 6.3), without significant confounding effect (>25% change) of gender, active rhinitis, active asthma, height, FEV(1)/FVC, or allergic sensitization. BHR decreased overall in severity through adolescence, was stable for the majority of children and only a minority (8%) had increased BHR from age 10 to 16. Mild to moderate and severe BHR at age 10 were major risk factors for PD(20) ≤ 8 at 16 years and not modified by asthma or body size.
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http://dx.doi.org/10.1016/j.rmed.2011.09.013DOI Listing
February 2012

Comparison of four nasal sampling methods for the detection of viral pathogens by RT-PCR-A GA(2)LEN project.

J Virol Methods 2009 Mar 19;156(1-2):102-6. Epub 2008 Dec 19.

Allergy Research Center, 2nd Pediatric Clinic, University of Athens, 41 Fidippidou str., 11527 Athens, Greece.

The aim of this study was to compare the efficacy and patient discomfort between four techniques for obtaining nasal secretions. Nasal secretions from 58 patients with symptoms of a common cold, from three clinical centers (Amsterdam, Lodz, Oslo), were obtained by four different methods: swab, aspirate, brush, and wash. In each patient all four sampling procedures were performed and patient discomfort was evaluated by a visual discomfort scale (scale 1-5) after each procedure. Single pathogen RT-PCRs for Rhinovirus (RV), Influenza virus and Adenovirus, and multiplex real-time PCR for RV, Enterovirus, Influenza virus, Adenovirus, Respiratory Syncytial Virus (RSV), Parainfluenza virus, Coronavirus, Metapneumovirus, Bocavirus and Parechovirus were performed in all samples. A specific viral cause of respiratory tract infection was determined in 48 patients (83%). In these, the detection rate for any virus was 88% (wash), 79% (aspirate), 77% (swab) and 74% (brush). The degree of discomfort reported was 2.54 for swabs, 2.63 for washes, 2.68 for aspirates and 3.61 for brushings. Nasal washes yielded the highest rate of viral detection without excessive patient discomfort. In contrast, nasal brushes produced the lowest detection rates and demonstrated the highest level of discomfort.
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http://dx.doi.org/10.1016/j.jviromet.2008.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112903PMC
March 2009
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