David C Shyr
Clinical Assistant Professor, Pediatrics - Stem Cell Transplantation
Clinical Focus
- Pediatric Hematology-Oncology
Professional Education
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Board Certification: American Board of Pediatrics, Pediatric Hematology-Oncology (2019)
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Medical Education: Medical College of Wisconsin (2005) WI
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Fellowship: Baylor College of Medicine-Pediatric Hematology/Oncology Fellowship (2012) TX
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Fellowship: Children's Hospital of Orange County Hematology/Oncology Fellowship (2011) CA
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Residency: University of California, San Diego (2008) CA
Clinical Trials
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Stem Cell Transplant From Donors After Alpha Beta Cell Depletion in Children and Young Adults
Recruiting
The purpose of the CliniMACS® TCRαβ-Biotin System and CliniMACS® CD19 is to improve the safety and efficacy of allogeneic HLA-partially matched related or unrelated donors HSCT when no matched donors are available, to treat malignant and nonmalignant disorders for which HSCT is the recommended best available therapy. Initially this device will be used in a single-center, open-label, single-arm, phase II clinical trial to evaluate the efficacy of haploidentical PBSC grafts depleted of TCRα/β+ and CD19+ cells using the CliniMACS® TCRαβ/CD19 System in children and adults with hematological and non-hematological malignancies.
All Publications
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Stem cell transplantation for ALL: you've always got a donor, why not always use it?
Hematology. American Society of Hematology. Education Program
2023; 2023 (1): 84-90
Abstract
Hematopoietic stem cell transplantation (HSCT) represents a consolidated therapeutic strategy for high-risk pediatric acute lymphoblastic leukemia (ALL), offering the potential for curative treatment. This manuscript delves into the debate around the more universal application of HSCT for pediatric ALL in the modern era, considering the ubiquitous availability of suitable donors. In fact, despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, a subset of pediatric patients with ALL with high-risk features or relapse continue to encounter poor prognostic outcomes. For this subgroup of patients, HSCT often remains the only potentially curative measure, leveraging the graft-versus- leukemia effect for long-term disease control. Nevertheless, the procedure's complexity and associated risks have traditionally curtailed its widespread use. However, the scenario is shifting with improvements in HLA matching, availability of alternative donor sources, less toxic conditioning regimens, and improved supportive care protocols. Concurrently, emerging therapies like CD19+ CAR T cells present new considerations for definitive therapy selection in relapsed/ refractory ALL. This article reviews critical current evidence and debates the potential of HSCT as a more universal treatment for ALL, reevaluating traditional treatment stratification in light of the constant availability of stem cell donors.
View details for DOI 10.1182/hematology.2023000423
View details for PubMedID 38066901
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Longitudinal Clinical Data Improves Survival Prediction after Hematopoietic Cell Transplantation Using Machine Learning.
Blood advances
2023
Abstract
Serial prognostic evaluation of patients after allogeneic hematopoietic cell transplantation (alloHCT) might help identify patients at high risk of developing potentially lethal organ dysfunction. Current prediction algorithms are based on models that do not incorporate changes to the patients' clinical condition that occur after alloHCT in the model development, which limits their predictive ability. We developed and validated a robust risk-prediction algorithm to predict short-term and long-term survival after alloHCT in pediatric patients that includes baseline biological variables, as well as changes in the patients' clinical status after alloHCT. The model was developed using clinical data from children and young adults treated at a single academic quaternary-care referral center. The model was created using a randomly split training dataset (70% of the cohort), internally validated (remaining 30% of the cohort from the same center), and then externally validated on patient data from another tertiary-care referral center. Repeated clinical measurements performed from 30 days before alloHCT to 30 days afterwards were extracted from the electronic medical record and incorporated into the model to predict survival at 100 days, 1-year, and 2-years after alloHCT. Of the 738 patients who underwent their first alloHCT at our institution between 2000 and 2020, 517 (70%) were randomly included in the training dataset and 221 (30%) constituted the validation dataset. When compared with models constructed from baseline variables alone, the naïve-Bayes machine learning models incorporating longitudinal data were significantly better at predicting whether patients would be alive or deceased at the given timepoints. This proof-of-concept study demonstrates that unlike traditional prognostic tools that use fixed variables for risk assessment, incorporating dynamic variability using clinical and laboratory data improves the prediction of mortality in patients undergoing alloHCT.
View details for DOI 10.1182/bloodadvances.2023011752
View details for PubMedID 37991991
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Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience.
Advances in radiation oncology
2023; 8 (1): 101071
Abstract
Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center.We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset.Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P = .31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P = .03).Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.
View details for DOI 10.1016/j.adro.2022.101071
View details for PubMedID 36483061
View details for PubMedCentralID PMC9723295
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Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience
ADVANCES IN RADIATION ONCOLOGY
2023; 8 (1)
View details for DOI 10.1016/j.adro.2022.101071
View details for Web of Science ID 000876956000001
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Precision Delivery of Steroids as a Rescue Therapy for Gastrointestinal Graft-versus-Host Disease in Pediatric Stem Cell Transplant Recipients
Journal of Clinical Medicine
2023; 12 (4229)
View details for DOI 10.3390/jcm12134229
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Machine Learning Approaches Incorporating High-Dimensional Longitudinal Data Improve the Prediction of Survival after Allogeneic Hematopoietic Cell Transplantation
AMER SOC HEMATOLOGY. 2022
View details for DOI 10.1182/blood-2022-162890
View details for Web of Science ID 000893223200132
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Outcomes Following Treatment for Adenosine Deaminase Deficient Severe Combined Immunodeficiency: A Report from the PIDTC.
Blood
2022
Abstract
Adenosine deaminase (ADA) deficiency causes ~13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 ADA-SCID patients diagnosed between 1982-2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium (PIDTC) SCID studies. Baseline clinical, immunologic, genetic characteristics and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT) (p<0.01). Overall survival (OS) at 5-years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT) (p=0.01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs. 68% if ≥3.5 months, p=0.02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs. 68.2%, p<0.01) and OS (64.7% vs. 82.3%, p=0.02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies ADA-SCID patients soon after birth and before the onset of infections.
View details for DOI 10.1182/blood.2022016196
View details for PubMedID 35671392
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Role of Cytokine Secretion Signatures of Donor-derived T Cells and Recipient Serum Cytokine Profiles as Predictive Biomarkers of Acute Graft-Versus-Host Disease in alpha beta T-cell/CD19 B-cell Depleted Hematopoietic Stem Cell Transplant Pediatric Recipients
WILEY. 2022
View details for Web of Science ID 000788322300433
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Predicting Relapse In Pediatric Patients with Acute Leukemia Undergoing Stem Cell Transplant Using Interpretable Machine Learning-A Proof-of-Concept Study of Applying Machine Learning Beyond "Big Data"
WILEY. 2022
View details for Web of Science ID 000788322300447
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Volumetric modulated arc therapy total body irradiation in pediatric and adolescent/young adult patients undergoing stem cell transplantation: Early outcomes and toxicities.
Pediatric blood & cancer
2022: e29689
Abstract
INTRODUCTION: Total body irradiation (TBI) is an important component of many conditioning regimens for hematopoietic stem cell transplantation (HSCT), most commonly used in pediatric and adolescent/young adult (AYA) patients. We aimed to evaluate outcomes and toxicities among pediatric and AYA patients treated with TBI utilizing volumetric modulated arc therapy total body irradiation (VMAT-TBI).METHODS: We reviewed pediatric and AYA patients treated with VMAT-TBI at our institution from 2019 to 2021. Data on patient and disease characteristics, treatment details, outcomes and toxicities were collected. Overall survival (OS) and relapse-free survival (RFS) were analyzed using the Kaplan-Meier method.RESULTS: Among 38 patients, 16 (42.1%) were treated with myeloablative regimens and 22 (57.9%) with nonmyeloablative regimens. Median age was 7.2 years (range: 1-27) and median follow-up was 8.7 months (range: 1-21). Lungs Dmean was 7.3 ± 0.3Gy for myeloablative regimens (range: 6.8-7.8). Kidneys were spared to average mean dose of 71.4 ± 4.8% of prescription dose. Gonadal sparing was achieved for patients treated for nonmalignant diseases to Dmean of 0.7 ± 0.1Gy. No patient experienced primary graft failure; one (2.6%) experienced secondary graft failure. The most common grade 1-2 acute toxicities were nausea (68.4%) and fatigue (55.3%). Mucositis was the most common grade 3-4 acute toxicity, affecting 39.5% of patients. There were no cases of pneumonitis or nephrotoxicity attributable to TBI.CONCLUSION: VMAT-TBI offers increased ability to spare organs at risk in pediatric and AYA patients undergoing HSCT, with a favorable acute/subacute toxicity profile and excellent disease control.
View details for DOI 10.1002/pbc.29689
View details for PubMedID 35373904
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CEDAR Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe Sickle Cell Disease
CELL PRESS. 2022: 379
View details for Web of Science ID 000794043701407
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Combinatorial Cytokine Secretion Signature of Donor-Derived T Cells Infused with the Graft: A New Potential Biomarker of Acute Graft-Versus-Host Disease in.ss t-Cell/CD19 B-Cell Depleted Hematopoietic Stem Cell Transplant Recipients
AMER SOC HEMATOLOGY. 2021
View details for DOI 10.1182/blood-2021-149948
View details for Web of Science ID 000736398806151
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Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD
AMER SOC HEMATOLOGY. 2021: 1864-+
View details for DOI 10.1182/blood-2021-152892
View details for Web of Science ID 000736398807102
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The Determinative Role of Hematopoietic Stem and Progenitor Cell Graft Composition on the Engraftment Kinetics after HSCT
AMER SOC HEMATOLOGY. 2021: 1794-+
View details for DOI 10.1182/blood-2021-149690
View details for Web of Science ID 000736398807032
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Machine Learning Applications in the Diagnosis of Benign and Malignant Hematological Diseases.
Clinical hematology international
2021; 3 (1): 13-20
Abstract
The use of machine learning (ML) and deep learning (DL) methods in hematology includes diagnostic, prognostic, and therapeutic applications. This increase is due to the improved access to ML and DL tools and the expansion of medical data. The utilization of ML remains limited in clinical practice, with some disciplines further along in their adoption, such as radiology and histopathology. In this review, we discuss the current uses of ML in diagnosis in the field of hematology, including image-recognition, laboratory, and genomics-based diagnosis. Additionally, we provide an introduction to the fields of ML and DL, highlighting current trends, limitations, and possible areas of improvement.
View details for DOI 10.2991/chi.k.201130.001
View details for PubMedID 34595462
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Correction to: Infections in Infants with SCID: Isolation, Infection Screening and Prophylaxis in PIDTC Centers.
Journal of clinical immunology
2020
Abstract
A Correction to this paper has been published: https://doi.org/10.1007/s10875-020-00917-0.
View details for DOI 10.1007/s10875-020-00917-0
View details for PubMedID 33274413
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HLA-haplotype loss after TCRalphabeta/CD19-depleted haploidentical HSCT.
Bone marrow transplantation
2020
View details for DOI 10.1038/s41409-020-01081-0
View details for PubMedID 33070150
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Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.
Journal of clinical immunology
2020
Abstract
PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention.METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management.RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p=0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p=0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented.CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS.TRIAL REGISTRATION: NCT01186913.
View details for DOI 10.1007/s10875-020-00865-9
View details for PubMedID 33006109
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Excellent Outcomes Following Hematopoietic Cell Transplantation for Wiskott-Aldrich Syndrome: A PIDTC Report.
Blood
2020
Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. Here we report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers between 2005 and 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs. ≥5 years old at the time of HCT (94% vs. 66%, overall p=0.0008). OS was excellent regardless of donor type even in cord blood recipients (90%). Conditioning intensity did not impact OS, but was associated with donor T-cell and myeloid engraftment post-HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early post-HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) versus low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005 compared to prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution following either myeloablative or busulfan-containing reduced intensity conditioning. (www.clinicaltrials.gov NCT02064933.).
View details for DOI 10.1182/blood.2019002939
View details for PubMedID 32268350
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Experience with Ruxolitinib (Jakafi (R)) As a Salvage Therapy for Graft-Versus-Host Disease in Children and Young Adults
ELSEVIER SCIENCE INC. 2020: S179
View details for Web of Science ID 000516887900261
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Transplantation Outcomes for Children with Severe Combined Immune Deficiency (SCID) Have Improved over Time: A 36-Year Summary Report By the Primary Immune Deficiency Treatment Consortium (PIDTC)
ELSEVIER SCIENCE INC. 2020: S18–S19
View details for Web of Science ID 000516887900020
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Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.
Frontiers in immunology
2020; 11: 239
Abstract
Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.
View details for DOI 10.3389/fimmu.2020.00239
View details for PubMedID 32153572
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SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery
BLOOD
2018; 132 (17): 1737–49
Abstract
The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.
View details for PubMedID 30154114
View details for PubMedCentralID PMC6202916
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Genotype, Phenotype and T Cell Counts at One Year Predict Survival and Long Term Immune Reconstitution after Transplantation in Severe Combined Immune Deficiency (SCID)-The Primary Immune Deficiency Treatment Consortium (PIDTC)
ELSEVIER SCIENCE INC. 2017: S101–S102
View details for Web of Science ID 000540635000101