Publications by authors named "Amara Nassar-Sheikh Rashid"

12 Publications

  • Page 1 of 1

Population pharmacokinetics of infliximab in children with juvenile idiopathic arthritis.

Ther Drug Monit 2021 Jul 19. Epub 2021 Jul 19.

Department of pediatric immunology, rheumatology and infectious diseases, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands and Zaans Medical Center, Zaandam, the Netherlands Department of pediatric immunology, rheumatology and infectious diseases, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands Hospital Pharmacy, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.

Background: The recommended infliximab (IFX) dose in (pediatric) rheumatology practice is 3-6 mg/kg every 4-8 weeks. Higher dosage regimens (>10 mg/kg) of IFX are effective and safe. To optimize IFX treatment in juvenile idiopathic arthritis (JIA) patients, therapeutic drug monitoring (TDM) might be beneficial. To support routine TDM of IFX and regimen optimization for JIA patients, in-depth knowledge of the pharmacokinetic (PK) variability of IFX is needed. As soon as the optimal therapeutic drug ranges are known, PK model-based simulation can be used to individualize drug dosing recommendations. In this study, a population PK model for IFX is described for JIA patients.

Materials And Methods: Data including IFX trough concentrations and anti-IFX antibodies of 27 pediatric JIA patients on IFX maintenance treatment were retrieved from electronic charts. Three population PK models from the literature were validated for the authors' dataset using the nonlinear-mixed effects modeling program NONMEM. A novel population pharmacokinetic model was developed based on the study data.

Results: A total of 65 blood samples obtained after a median of 32 days following the last IFX infusion (IQR 28-42) were analyzed. The three published models underpredicted the observed trough concentrations. A newly developed one-compartment model best described the data corresponding to IFX serum concentration over time in JIA patients.

Conclusion: This study shows a novel PK model for IFX in JIA patients. The data show that different PK models are needed for different age categories (children or adults) and different diseases.
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http://dx.doi.org/10.1097/FTD.0000000000000914DOI Listing
July 2021

Anti-rituximab antibodies affect pharmacokinetics and pharmacodynamics of rituximab in children with immune-mediated diseases.

Clin Exp Rheumatol 2021 Jun 26. Epub 2021 Jun 26.

Department of Paediatric Immunology, Rheumatology and Infectious diseases, Amsterdam University Medical Centers, Emma Children's Hospital, Amsterdam, The Netherlands.

Objectives: Rituximab (RTX) is a chimeric monoclonal CD20-antibody. Lack of efficacy has been suggested to be related to the presence of anti-drug antibodies (ADA). The aims of this study were to determine if ADA impact the pharmacokinetics (PK) and pharmacodynamics (PD) of RTX in children, whether the formation of ADA differs between various immune-mediated diseases and if it is related to the occurrence of infusion-related reactions (IRR).

Methods: All children <18 years who had received RTX treatment in our centre between December 2006 and February 2020 with known ADA/RTX-levels, were retrospectively included. The presence of ADA was defined as a titre >8 AU/ml.

Results: Of twenty-six children treated with RTX for various immune-mediated diseases, six patients were ADA-positive (23.1%). In all ADA-positive patients, RTX concentrations were undetectable in contrast to ADA-negative patients (median RTX concentration 3.1 μg/ml; IQR 0.57-12.0; p<0.001). Failure of B cell depletion was found in 5/6 ADA-positive and 1/19 ADA-negative patients (p=0.003). In SLE-patients, 50.0% (n=4/8) had developed RTX-ADA. Severe anaphylaxis (n=3) occurred only in the ADA-positive group.

Conclusions: In our cohort of paediatric patients, undetectable RTX concentrations were found in ADA-positive patients, indicative that these ADA have a PK impact. RTX-ADA also seem to affect the PD, as in the majority of these patients, B cell depletion failed. ADA were most present in SLE-patients and anaphylactic reactions occurred only in ADA-positive patients. With this knowledge, a change of drug might be considered in the presence of RTX-ADA.
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June 2021

Reliable detection of subtypes of nailfold capillary haemorrhages in childhood-onset systemic lupus erythematosus.

Clin Exp Rheumatol 2021 Jun 8. Epub 2021 Jun 8.

Department of Internal Medicine, Ghent University, and Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.

Objectives: In systemic lupus erythematosus (SLE), it is necessary to obtain biomarkers that predict cardiovascular complications due to premature atherosclerosis, which is related to endothelial dysfunction. Nailfold capillary abnormalities might be a biomarker for endothelial dysfunction. In adults and children with SLE, nailfold capillary haemorrhages have shown to be significantly correlated with disease activity. Recently, different subtypes of capillary haemorrhages have been described in childhood-onset SLE (cSLE). The aim of the current study was to assess the inter- and intra-rater reliability of observations of different subtypes of haemorrhages in cSLE patients.

Methods: Five raters blindly evaluated 140 capillaroscopy images from 35 cSLE-patients (diagnosed according to the 2012 SLICC criteria). The images were assessed qualitatively (present or absent) and quantitatively (total number) on four different subtypes of haemorrhages: 1) punctate extravasations, 2) perivascular haemorrhage, 3) large confluent haemorrhage and 4) non-definable. As subgroups 1) and 2) were interpreted as a continuous spectrum, a post-hoc analysis with "merged" (mean) kappa/ICC was additionally calculated as one sub-group.

Results: Qualitative assessment showed a kappa 0.65 (95% CI: 0.60-0.70) for "punctate extravasations and perivascular haemorrhages merged" and a kappa 0.78 (95% CI: 0.72-0.83) for large confluent haemorrhages. For the quantitative assessment, ICC was 0.82 (95% CI: 0.76-0.87) for the "merged groups" and ICC 0.93 (95% CI: 0.91-0.95) for large confluent haemorrhages.

Conclusions: Our study shows that different subtypes of capillary haemorrhages in cSLE-patients could be reliably reproduced by different raters. This confirms our recent observation of perivascular extravasations as a subgroup of capillary haemorrhage in cSLE that might reflect endothelial dysregulation.
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June 2021

Nailfold capillary abnormalities in childhood-onset systemic lupus erythematosus: a cross-sectional study compared with healthy controls.

Lupus 2021 Apr 3;30(5):818-827. Epub 2021 Mar 3.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centers (Amsterdam UMC), University of Amsterdam, Amsterdam, the Netherlands.

Objectives: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients.

Methods: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases.

Results: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001).

Conclusions: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.
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http://dx.doi.org/10.1177/0961203321998750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020305PMC
April 2021

Exploring contrast-enhanced MRI findings of the clinically non-inflamed symptomatic pediatric wrist.

Pediatr Radiol 2020 09 13;50(10):1387-1396. Epub 2020 Jul 13.

Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Academic Medical Center Amsterdam Movement Sciences, University of Amsterdam, Amsterdam, The Netherlands.

Background: Knowledge of the synovial and tenosynovial appearance of the clinically non-arthritic symptomatic juvenile wrist using contrast-enhanced magnetic resonance imaging (MRI) is sparse.

Objectives: To analyze contrast-enhanced MRI findings of the clinically non-inflamed symptomatic pediatric wrist, focusing on the enhancing synovial and tenosynovial membrane. To evaluate the coexistent presence of (teno)synovial enhancement, joint fluid, bony depressions and medullary changes suggestive of bone marrow edema.

Materials And Methods: We included 20 children (15 girls; age range: 7.5-17.6 years) who underwent contrast-enhanced MRI of the wrist, based on initial clinical indication, and eventually turned out to be unaffected by arthritic or orthopedic disorders. Various imaging characteristics of the synovium, tenosynovium, joint fluid, bone tissue and bone marrow were evaluated using existing MRI scoring systems.

Results: In 3/20 (15%) children, mild or moderate-severe synovial enhancement was observed and 2/20 (10%) children showed mild tenosynovial enhancement/thickening. Joint fluid (11/20 children; 55%), bony depressions (20/20 children; 100%) and medullary changes suggestive of bone marrow edema (6/20; 30%) were found in a substantial percentage of children. The most frequently observed combination of coexisting imaging characteristics was bony depressions with ≥2 mm joint fluid, which was found in 7/20 (35%) children. Simultaneous presence of synovial and tenosynovial enhancement/thickening, bony depressions and medullary changes suggestive of bone marrow edema was observed in one child.

Conclusion: Several juvenile idiopathic arthritis-relevant MRI characteristics can be observed in the clinically non-inflamed symptomatic pediatric wrist.
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http://dx.doi.org/10.1007/s00247-020-04739-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445206PMC
September 2020

Experiences, perspectives and expectations of adolescents with juvenile idiopathic arthritis regarding future work participation; a qualitative study.

Pediatr Rheumatol Online J 2020 Apr 15;18(1):33. Epub 2020 Apr 15.

Amsterdam UMC, Department Coronel Institute of Occupational Health. Amsterdam Public Health research institute, P.O. Box 22700, Amsterdam, DE, NL-1100, The Netherlands.

Background: Having Juvenile idiopathic Arthritis (JIA) has widespread implications for a person's life. Patients have to deal with recurring arthritis, characterized by pain often accompanied by a loss of energy. Since JIA often persists into adulthood, patients with JIA are likely to encounter difficulties in their working life. We expect that the experiences in school life may be comparable to the barriers and opportunities which patients affected by JIA encounter in adult working life. Therefore, the aim of this study was to elicit the experiences during school life and the perspectives and expectations regarding future work participation of adolescents with JIA.

Methods: This study used individual, semi-structured interviews and followed a predefined interview guide. Participants between 14 and 18 years of age (n = 22) were purposively selected to achieve a broad range of participant characteristics. Open coding was performed, followed by axial coding and selective coding.

Results: Great differences were seen in the support and understanding that adolescents received in dealing with JIA at school, leisure activities and work. Varying approaches were mentioned on how to pursue a desired vocation. Perspectives regarding disclosure varied. Participants wished to be approached like any other healthy adolescent. Expectations regarding work participation were positively expressed.

Conclusion: This study showed that participants often disregarded having JIA when making plans for their future career. Facilitating an open discussion about the possible limitations accompanying JIA with educators and employers might prevent overburden and increase the chance of starting a career which would accommodate the patient with JIA in the near and distant future.
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http://dx.doi.org/10.1186/s12969-020-00429-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158382PMC
April 2020

MRP8/14 and neutrophil elastase for predicting treatment response and occurrence of flare in patients with juvenile idiopathic arthritis.

Rheumatology (Oxford) 2020 09;59(9):2392-2401

Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam.

Objective: To study two neutrophil activation markers, myeloid-related protein (MRP) 8/14 and neutrophil elastase (NE), for their ability to predict treatment response and flare in patients with JIA.

Methods: Using samples from two cohorts (I and II), we determined MRP8/14 and NE levels of 32 (I) and 81 (II) patients with new-onset, DMARD-naïve arthritis and compared patients who responded to treatment (defined as fulfilling ≥ adjusted ACRpedi50 response and/or inactive disease) with non-responders (defined as fulfilling < adjusted ACRpedi50 response and/or active disease) at 6 and 12 months. Secondly, we compared biomarker levels of 54 (I) and 34 (II) patients with clinically inactive disease who did or did not suffer from a flare of arthritis after 6 or 12 months. Receiver operating characteristic analyses were carried out to study the predictive value of MRP8/14 and NE for treatment response and flare.

Results: For both cohorts, baseline MRP8/14 and NE levels for patients who did or did not respond to treatment were not different. Also, MRP8/14 and NE levels were not different in patients who did or did not flare. Receiver operating characteristic analysis of MRP8/14 and NE demonstrated areas under the curve <0.7 in both cohorts.

Conclusion: In our cohorts, MRP8/14 and NE could not predict treatment response. Also, when patients had inactive disease, neither marker could predict flares.
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http://dx.doi.org/10.1093/rheumatology/kez590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449815PMC
September 2020

Capillaroscopy in childhood-onset systemic lupus erythematosus: a first systematic review.

Clin Exp Rheumatol 2020 Mar-Apr;38(2):350-354. Epub 2019 Dec 18.

Department of Rheumatology, Ghent University Hospital; Faculty of Internal Medicine, Ghent University; and Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, Belgium.

Objectives: Recently, a systematic review indicated that, compared to healthy controls, adult patients with systemic lupus erythematosus (SLE) show a significantly more abnormal capillary morphology and greater number of haemorrhages in nailfold capillaroscopy and that these capillary changes are associated with disease activity. As yet, no systematic literature evaluation of capillaroscopy in childhood-onset SLE (cSLE) has been performed. Therefore, we aimed to systematically review the literature on nailfold capillary characteristics in cSLE.

Methods: Search terms "SLE or Lupus", "Capillaroscopy" and "Juvenile or Childhood or Paediatric or Child" were used in PubMed, Embase and Web of Science. Capillary findings were evaluated according to the current international consensus-based definitions for analysis of capillaroscopic characteristics from the European League against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases (SG MC/RD).

Results: After screening eighty search hits, six articles were retained, two of which were case-control studies and four case series. For capillary density, no difference was found between cSLE and healthy controls (one study). Differences in capillary diameter, capillary morphology, haemorrhages and semi-quantitative score were inconclusive or non-interpretable. A scleroderma pattern was not detected in the case control studies but was reported in a minority of cSLE patients in 3 out of 4 case series.

Conclusions: Literature on nailfold capillary findings in cSLE is scarce and inconclusive. To evaluate capillary characteristics in cSLE, prospective longitudinal studies are needed. Future studies should use uniform definitions for capillary characteristics and findings should be compared with healthy controls, matched for age and ethnicity. The EULAR SG MC/RD is stepping up to this need.
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April 2020

Consider the wrist: a retrospective study on pediatric connective tissue disease with MRI.

Rheumatol Int 2019 Dec 20;39(12):2095-2101. Epub 2019 Jun 20.

Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam University Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

The aim of this study is to describe the clinical characteristics and MRI findings of the wrist in a cohort of children suffering from connective tissue disease with musculoskeletal involvement. Ten patients with pediatric connective tissue disease [median age 14.7 years (IQR 12.7-16.6 years), 70% female] were identified from a large MRI database. Clinical findings during the disease course were retrospectively obtained from patient charts and findings at the time of MRI were prospectively registered in the MRI database. MRI wrist datasets were evaluated by three readers in consensus for synovitis, tenosynovitis, bone marrow changes, bone erosions and myositis. Patients suffered from connective tissue disease with clinical overlap of subtypes systemic lupus erythematosus, Sjögren syndrome and dermatomyositis. Median onset of disease was at 12.3 years (IQR 7.8-14.8 years). Clinical arthritis activity was scored low (median visual analogue scale physician 19, IQR 7-31). Notwithstanding, extensive inflammatory abnormalities such as synovitis and tenosynovitis were found in the wrist of 7/10 patients. Osteochondral involvement was detected in 3/10 patients. In a small cohort of children with connective tissue disease and musculoskeletal symptoms, severe inflammatory abnormalities of the involved wrist were present in the MRI, while clinical disease scores suggested mild disease activity. Therefore, clinicians should consider the wrist as vulnerable for joint damage and can add MRI as a helpful tool in the management of patients with pediatric connective tissue disease and musculoskeletal involvement.
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http://dx.doi.org/10.1007/s00296-019-04353-1DOI Listing
December 2019

Prolonged time between intravenous contrast administration and image acquisition results in increased synovial thickness at magnetic resonance imaging in patients with juvenile idiopathic arthritis.

Pediatr Radiol 2019 05 1;49(5):638-645. Epub 2019 Feb 1.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.

Background: Post-contrast synovial thickness measurement is necessary for scoring disease activity in juvenile idiopathic arthritis (JIA). However, the timing of post-contrast sequences varies widely among institutions. This variation in timing could influence thickness measurements.

Objective: To measure thickness of the synovial membrane on early and late post-contrast knee magnetic resonance (MR) images of patients with JIA.

Materials And Methods: Dynamic contrast-enhanced T1-weighted knee MR images of 53 children with JIA with current or past knee arthritis were used to study synovial thickness at time point 1 (about 1 min) and time point 2 (about 5 min after contrast administration). Two experienced readers, who were blinded for the time point, independently measured synovial thickness at a predefined, marked location in the patellofemoral compartment on randomized images. Synovial thickness at the two time points was compared using the Wilcoxon signed rank test. Repeatibility of the synovial thickness measurements was studied using intraclass correlation coefficients and Bland-Altman plots.

Results: Median synovial thickness of the 53 patients (median age: 13.5 years, 59% female) increased with prolonged post-contrast interval with a synovial thickness of 1.4 mm at time point 1 and a synovial thickness of 1.5 mm at time point 2 (P<0.001). Repeated synovial thickness measurements showed an intraclass correlation coefficient (ICC) of 0.75, P<0.05 for time point 1 and an ICC of 0.91, P<0.05 for time point 2.

Conclusion: Post-contrast synovial membrane thickness measurements are time-dependent. Therefore, standardization of post-contrast image acquisition timing is important to achieve consistent grading of synovial inflammation.
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http://dx.doi.org/10.1007/s00247-018-04332-xDOI Listing
May 2019

Lyme Borreliosis in Children: A Tertiary Referral Hospital-Based Retrospective Analysis.

Pediatr Infect Dis J 2018 02;37(2):e45-e47

Lyme borreliosis (LB) is an endemic disease in adults in Western countries. Although children may also be infected, pediatric studies on LB are scarce. This study aims to estimate the incidence of LB among children with a clinical suspicion for Lyme in a tertiary referral center in the Netherlands. Patient chart data on medical history, clinical signs and symptoms, diagnostic test results and diagnoses were collected using standardized case record forms. Patients were categorized based on clinical and laboratory findings using a modified, previously published classification system. We included 325 children, with a median age of 11.9 years, of whom 61.8% were female. LB was diagnosed in 38 of the referred children (11.7%). However, of the 85 patients who were specifically referred to the Lyme clinic, 28 (32.9%) were diagnosed with LB. Of the specifically referred Lyme-positive patients, 11 (39.3%) had a definitive LB diagnosis. Twelve children had a posttreatment LB syndrome. In line with previous reports in adults, only a small proportion of children referred with a suspicion of LB were diagnosed with definite or probable LB, which illustrates the difficulty in diagnosing LB by the general practitioner or pediatrician in a district hospital.
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http://dx.doi.org/10.1097/INF.0000000000001735DOI Listing
February 2018

Definitions and Outcome Measures in Pediatric Functional Upper Gastrointestinal Tract Disorders: A Systematic Review.

J Pediatr Gastroenterol Nutr 2016 04;62(4):581-7

Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.

Objectives: Functional disorders of the upper gastrointestinal tract are frequently diagnosed in children. Four different clinical entities are addressed by the Rome III committee: functional dyspepsia (FD), cyclic vomiting syndrome (CVS), adolescent rumination syndrome (ARS), and aerophagia. Management of these disorders is often difficult leading to a wide variety in therapeutic interventions. We hypothesize that definitions and outcome measures in these studies are heterogeneous as well. Our aim is to systematically assess how these disorders and outcomes are defined in therapeutic randomized controlled trials (RCTs).

Study Design: CENTRAL, Embase, and MEDLINE/PubMed were searched from inception to February 25, 2015. Search terms were FD, CVS, ARS, and aerophagia. Therapeutic RCTs, or systematic reviews of RCTs, in English language including subjects ages 4 to 18 years (0-18 years for CVS) were evaluated. Quality was assessed using the Delphi list.

Results: A total of 1398 articles were found of which 8 articles were included. Seven concerned FD and 1 concerned CVS. In all of the studies, Rome criteria or similar definitions were used; all the studies however used different outcome measures. Seventy-five percent of the trials were of good methodological quality. Only 57% used validated pain scales.

Conclusions: Different outcome measures are used in therapeutic trials on functional disorders of the upper gastrointestinal tract. There is a clear paucity of trials evaluating different treatment regimens regarding CVS, ARS, and aerophagia. Uniform definitions, outcome measures, and validated instruments are needed to make a comparison between intervention studies possible.
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http://dx.doi.org/10.1097/MPG.0000000000000973DOI Listing
April 2016
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