Publications by authors named "Matthew D Wood"

91 Publications

Beyond the Cubital Tunnel: Use of Adjunctive Procedures in the Management of Cubital Tunnel Syndrome.

Hand (N Y) 2021 Apr 2:1558944721998022. Epub 2021 Apr 2.

Washington University in St. Louis, MO, USA.

Background: Our management of cubital tunnel syndrome has expanded to involve multiple adjunctive procedures, including supercharged end-to-side anterior interosseous to ulnar nerve transfer, cross-palm nerve grafts from the median to ulnar nerve, and profundus tenodesis. We also perform intraoperative brief electrical stimulation in patients with severe disease. The aims of this study were to evaluate the impact of adjunctive procedures and electrical stimulation on patient outcomes.

Methods: We performed a retrospective review of 136 patients with cubital tunnel syndrome who underwent operative management from 2013 to 2018. A total of 38 patients underwent adjunctive procedure(s), and 33 received electrical stimulation. A historical cohort of patients who underwent cubital tunnel surgery from 2009 to 2011 (n = 87) was used to evaluate the impact of adjunctive procedures. Study outcomes were postoperative improvements in Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores, pinch strength, and patient-reported pain and quality of life.

Results: In propensity score-matched samples, patients who underwent adjunctive procedures had an 11.3-point greater improvement in DASH scores than their matched controls ( = .0342). In addition, patients who received electrical stimulation had significantly improved DASH scores relative to baseline (11.7-point improvement, .0001), whereas their control group did not. However, when compared between treatment arms, there were no significant differences for any study outcome.

Conclusions: Patients who underwent adjunctive procedures experienced greater improvement in postoperative DASH scores than their matched pairs. Additional studies are needed to evaluate the effects of brief electrical stimulation in compression neuropathy.
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http://dx.doi.org/10.1177/1558944721998022DOI Listing
April 2021

The Role of the IL-4 Signaling Pathway in Traumatic Nerve Injuries.

Neurorehabil Neural Repair 2021 Mar 23:15459683211001026. Epub 2021 Mar 23.

Washington University, St Louis, MO, USA.

Following traumatic peripheral nerve injury, adequate restoration of function remains an elusive clinical goal. Recent research highlights the complex role that the immune system plays in both nerve injury and regeneration. Pro-regenerative processes in wounded soft tissues appear to be significantly mediated by cytokines of the type 2 immune response, notably interleukin (IL)-4. While IL-4 signaling has been firmly established as a critical element in general tissue regeneration during wound healing, it has also emerged as a critical process in nerve injury and regeneration. In this context of peripheral nerve injury, endogenous IL-4 signaling has recently been confirmed to influence more than leukocytes, but including also neurons, axons, and Schwann cells. Given the role IL-4 plays in nerve injury and regeneration, exogenous IL-4 and/or compounds targeting this signaling pathway have shown encouraging preliminary results to treat nerve injury or other neuropathy in rodent models. In particular, the exogenous stimulation of the IL-4 signaling pathway appears to promote postinjury neuron survival, axonal regeneration, remyelination, and thereby improved functional recovery. These preclinical data strongly suggest that targeting IL-4 signaling pathways is a promising translational therapy to augment treatment approaches of traumatic nerve injury. However, a better understanding of the type 2 immune response and associated signaling networks functioning within the nerve injury microenvironment is still needed to fully develop this promising therapeutic avenue.
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http://dx.doi.org/10.1177/15459683211001026DOI Listing
March 2021

Editorial Commentary of "Nerve Reconstruction Using Processed Nerve Allograft in the US Military".

Mil Med 2021 Jan 12. Epub 2021 Jan 12.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.

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http://dx.doi.org/10.1093/milmed/usaa497DOI Listing
January 2021

Post-treatment hypermutation in a recurrent diffuse glioma with H3.3 p.G34 Mutation.

Neuropathol Appl Neurobiol 2021 Apr 20;47(3):460-463. Epub 2020 Dec 20.

Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR, USA.

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http://dx.doi.org/10.1111/nan.12679DOI Listing
April 2021

Updates in Pediatric Glioma Pathology.

Surg Pathol Clin 2020 Dec 9;13(4):801-816. Epub 2020 Oct 9.

Department of Pathology, Oregon Health & Science University and Knight Cancer Institute, 3181 Southwest Sam Jackson Park Road, L-113, Portland, OR 97239, USA. Electronic address:

Gliomas are a diverse group of primary central nervous system tumors with astrocytic, oligodendroglial, and/or ependymal features and are an important cause of morbidity/mortality in pediatric patients. Glioma classification relies on integrating tumor histology with key molecular alterations. This approach can help establish a diagnosis, guide treatment, and determine prognosis. New categories of pediatric glioma have been recognized in recent years, due to increasing application of molecular profiling in brain tumors. The aim of this review is to alert pediatric pathologists to emerging diagnostic concepts in pediatric glioma neuropathology, emphasizing the incorporation of molecular features into diagnostic practice.
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http://dx.doi.org/10.1016/j.path.2020.08.006DOI Listing
December 2020

Video-based Learning in Surgery: Establishing Surgeon Engagement and Utilization of Variable-duration Videos.

Ann Surg 2020 12;272(6):1012-1019

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO.

Objective: To measure surgeon engagement and preferred video duration in a video-based learning program for nerve surgery.

Background: Educational videos can improve, standardize, and democratize best practices in surgery. To improve care internationally, educators must optimize their videos for learning. However, surgeon engagement and optimal video duration remain undefined.

Methods: A YouTube channel and a video-based learning website, PASSIO Education (passioeducation.com), were examined from 2011 to 2017. We assessed views, geographic location, audience engagement (average percent of video watched), audience retention (percent of viewers at each timepoint), and usage of short (median 7.4, range 4.1-20.3 min) and long (median 17.2, range 6.1-47.7 min) video formats for the same procedures. A survey of PASSIO Education membership examined preferred video duration.

Results: Our 117 nerve surgery videos attained over 3 million views with 69% originating outside of the United States. While YouTube achieved more international exposure, PASSIO Education attained a greater mean engagement of 48.4% (14.3% absolute increase, P < 0.0001). Surveyed surgeons (n = 304) preferred longer videos when preparing for infrequent or difficult cases compared with routine cases (P < 0.0001). Engagement declined with video duration, but audience retention between short and long video formats was correlated (τB = 0.52, P < 0.0001).

Conclusions: For effective spread of best practices, we propose the joint use of YouTube for audience outreach and a surgeon-focused platform to maximize educational value. Optimal video duration is surgeon- and case-dependent and can be addressed through offering multiple video durations and interactive viewing options.
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http://dx.doi.org/10.1097/SLA.0000000000003306DOI Listing
December 2020

Macrophage-Derived Vascular Endothelial Growth Factor-A Is Integral to Neuromuscular Junction Reinnervation after Nerve Injury.

J Neurosci 2020 12 6;40(50):9602-9616. Epub 2020 Nov 6.

Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110-1093

Functional recovery in the end target muscle is a determinant of outcome after peripheral nerve injury. The neuromuscular junction (NMJ) provides the interface between nerve and muscle and includes non-myelinating terminal Schwann cells (tSCs). After nerve injury, tSCs extend cytoplasmic processes between NMJs to guide axon growth and NMJ reinnervation. The mechanisms related to NMJ reinnervation are not known. We used multiple mouse models to investigate the mechanisms of NMJ reinnervation in both sexes, specifically whether macrophage-derived vascular endothelial growth factor-A (Vegf-A) is crucial to establishing NMJ reinnervation at the end target muscle. Both macrophage number and Vegf-A expression increased in end target muscles after nerve injury and repair. In mice with impaired recruitment of macrophages and monocytes (-/- mice), the absence of CD68+ cells (macrophages) in the muscle resulted in diminished muscle function. Using a Vegf-receptor 2 (VegfR2) inhibitor (cabozantinib; CBZ) via oral gavage in wild-type (WT) mice resulted in reduced tSC cytoplasmic process extension and decreased NMJ reinnervation compared with saline controls. Mice with Vegf-A conditionally knocked out in macrophages ( mice) demonstrated a more prolonged detrimental effect on NMJ reinnervation and worse functional muscle recovery. Together, these results show that contributions of the immune system are integral for NMJ reinnervation and functional muscle recovery after nerve injury. This work demonstrates beneficial contributions of a macrophage-mediated response for neuromuscular junction (NMJ) reinnervation following nerve injury and repair. Macrophage recruitment occurred at the NMJ, distant from the nerve injury site, to support functional recovery at the muscle. We have shown hindered terminal Schwann cell (tSC) injury response and NMJ recovery with inhibition of: (1) macrophage recruitment after injury; (2) vascular endothelial growth factor receptor 2 (VegfR2) signaling; and (3) Vegf secretion from macrophages. We conclude that macrophage-derived Vegf is a key component of NMJ recovery after injury. Determining the mechanisms active at the end target muscle after motor nerve injury reveals new therapeutic targets that may translate to improve motor recovery following nerve injury.
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http://dx.doi.org/10.1523/JNEUROSCI.1736-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726545PMC
December 2020

Incidence of Nerve Injury After Extremity Trauma in the United States.

Hand (N Y) 2020 Oct 21:1558944720963895. Epub 2020 Oct 21.

Washington University School of Medicine, St. Louis, MO, USA.

Background: Traumatic peripheral nerve injuries cause chronic pain, disability, and long-term reductions in quality of life. However, their incidence after extremity trauma remains poorly understood.

Methods: The IBM® MarketScan® Commercial Database from 2010 to 2015 was used to identify patients aged 18 to 64 who presented to emergency departments for upper and/or lower extremity traumas. Cumulative incidences were calculated for nerve injuries diagnosed within 2 years of trauma. Cox regression models were developed to evaluate the associations between upper extremity nerve injury and chronic pain, disability, and use of physical therapy or occupational therapy.

Results: The final cohort consisted of 1 230 362 patients with employer-sponsored health plans. Nerve injuries were diagnosed in 2.6% of upper extremity trauma patients and 1.2% of lower extremity trauma patients. Only 9% and 38% of nerve injuries were diagnosed by the time of emergency department and hospital discharge, respectively. Patients with nerve injuries were more likely to be diagnosed with chronic pain (hazard ratio [HR]: 5.9, 95% confidence interval [CI], 4.3-8.2), use physical therapy services (HR: 10.7, 95% CI, 8.8-13.1), and use occupational therapy services (HR: 19.2, 95% CI, 15.4-24.0) more than 90 days after injury.

Conclusions: The incidence of nerve injury in this national cohort was higher than previously reported. A minority of injuries were diagnosed by emergency department or hospital discharge. These findings may improve practitioner awareness and inform public health interventions for injury prevention.
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http://dx.doi.org/10.1177/1558944720963895DOI Listing
October 2020

Liposomes embedded within fibrin gels facilitate localized macrophage manipulations within nerve.

J Neurosci Methods 2021 Jan 17;348:108981. Epub 2020 Oct 17.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. Electronic address:

Background: Understanding the role of macrophages at discrete spatial locations during nerve regeneration after injury is important. But, methodologies that systemically manipulate macrophages can obscure their roles within discrete spatial locations within nerve.

New Method: Liposomes were embedded within fibrin gels to construct a delivery system that facilitated macrophage-specific manipulations at a sole spatial region, as macrophages accumulated within the fibrin. Clodronate liposomes were characterized for their toxicity to specific cells composing nerve in vitro, then tested for macrophage-specific depletion in vivo. This delivery system using clodronate liposomes was used to repair a mouse sciatic nerve gap to evaluate its efficacy and effects.

Result: Clodronate liposomes showed specific toxicity to macrophages without affecting dorsal root ganglia (DRG)-derived neurons, endothelial cells, or Schwann cells in culture. The delivery system demonstrated sustained release of liposomes for more than 7 days while still retaining liposomes within the fibrin. In vivo, the delivery system demonstrated macrophages were targeted by liposomes, and the use of clodronate liposomes minimized macrophage accumulation within fibrin, while not affecting macrophage accumulation within DRG. Nerve regeneration across the nerve gap repaired using this delivery system was associated with decreased angiogenesis, Schwann cell accumulation, axon growth, and reinnervation of affected muscle.

Comparison With Existing Methods: This delivery system allowed specific perturbation of macrophages locally in nerve. This method could be applicable across species without the need for genetic manipulations or systemic pharmaceuticals.

Conclusion: Liposomes embedded within fibrin gels locally target macrophages at the site of nerve injury, which enables greater precision in conclusions regarding their roles in nerve.
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http://dx.doi.org/10.1016/j.jneumeth.2020.108981DOI Listing
January 2021

Cystic appearance on magnetic resonance imaging in bihormonal growth hormone and prolactin tumors in acromegaly.

Pituitary 2020 Dec;23(6):672-680

Department of Medicine, Oregon Health & Science University, Portland, OR, USA.

Purpose: To investigate demographic, imaging and laboratory characteristics, and treatment outcomes of acromegaly patients who have bihormonal (BA) growth hormone (GH) and prolactin (PRL) immunoreactive adenomas compared to patients who have densely granulated GH adenomas (DGA) and sparsely granulated GH adenomas (SGA).

Methods: Retrospective review of single-center surgically treated acromegaly patients; pathology was analyzed by a single neuropathologist using 2017 WHO criteria. Preoperative magnetic resonance imaging was assessed to evaluate tumor size, cystic component, invasion and T2 signal intensity.

Results: Seventy-seven patients; 19 BA (9 mammosomatotroph and 10 mixed GH and PRL adenomas) were compared with 30 DGA, and 28 SGA. Patients with BA were older than SGA (49.6 vs 38.5 years, p = 0.035), had a higher IGF-1 index (3.3 vs 2.3, p = 0.040) and tumors were less frequently invasive (15.8% vs 57.1%, p = 0.005). BA more frequently had a cystic component on MRI than both SGA and DGA (52.6% vs 14.3%, and 22%, p = 0.005 and 0.033, respectively). When all histological types were combined, biochemical remission postoperatively was more common in non-cystic than cystic tumors (50% vs 22.5%, p = 0.042). Somatostatin receptor ligand response rate was 66.7%, 90.9% and 37.5% in BA, DGA and SGA patients, respectively (p = 0.053).

Conclusion: Imaging characteristics are an increasingly important adenoma behavior determinant. An adenoma cystic component may suggest that a GH adenoma is a BA. Cystic tumors exhibited lower rates of surgical remission in this series; therefore, optimized individual patient treatment is needed, as patients could be candidates for primary medical treatment.
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http://dx.doi.org/10.1007/s11102-020-01075-7DOI Listing
December 2020

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta Neuropathol Commun 2020 08 28;8(1):151. Epub 2020 Aug 28.

Division of Neuropathology, Department of Pathology, University of California, San Francisco, 513 Parnassus Avenue, Health Sciences West 451, San Francisco, CA, 94143, USA.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.
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http://dx.doi.org/10.1186/s40478-020-01027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456392PMC
August 2020

The Effects of Intraoperative Electrical Stimulation on Regeneration and Recovery After Nerve Isograft Repair in a Rat Model.

Hand (N Y) 2020 Jul 15:1558944720939200. Epub 2020 Jul 15.

Washington University in St. Louis, MO, USA.

Therapeutic electrical stimulation (ES) applied to repaired nerve is a promising treatment option to improve regeneration. However, few studies address the impact of ES following nerve graft reconstruction. The purpose of this study was to determine if ES applied to a nerve repair using nerve isograft in a rodent model could improve nerve regeneration and functional recovery. Adult rats were randomized to 2 groups: "ES" and "Control." Rats received a tibial nerve transection that was repaired using a tibial nerve isograft (1.0 cm length), where ES was applied immediately after repair in the applicable group. Nerve was harvested 2 weeks postrepair for immunohistochemical analysis of axon growth and macrophage accumulation. Independently, rats were assessed using walking track and grid-walk analysis for up to 21 weeks. At 2 weeks, more robust axon regeneration and greater macrophage accumulation was observed within the isografts for the ES compared to Control groups. Both walking track and grid-walk analysis revealed that return of functional recovery was accelerated by ES. The ES group demonstrated improved functional recovery over time, as well as improved recovery compared to the Control group at 21 weeks. ES improved early axon regeneration into a nerve isograft and was associated with increased macrophage and beneficial M2 macrophage accumulation within the isograft. ES ultimately improved functional recovery compared to isograft repair alone. This study supports the clinical potential of ES to improve the management of nerve injuries requiring a nerve graft repair.
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http://dx.doi.org/10.1177/1558944720939200DOI Listing
July 2020

Discussion: Functional Outcome after Reconstruction of a Long Nerve Gap in Rabbits Using Optimized Decellularized Nerve Allografts.

Plast Reconstr Surg 2020 06;145(6):1451-1453

From the Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine.

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http://dx.doi.org/10.1097/PRS.0000000000006868DOI Listing
June 2020

The CCL2/CCR2 axis is critical to recruiting macrophages into acellular nerve allograft bridging a nerve gap to promote angiogenesis and regeneration.

Exp Neurol 2020 09 23;331:113363. Epub 2020 May 23.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA. Electronic address:

Acellular nerve allografts (ANAs) are increasingly used to repair nerve gaps following injuries. However, these nerve scaffolds have yet to surpass the regenerative capabilities of cellular nerve autografts; improved understanding of their regenerative mechanisms could improve design. Due to their acellular nature, both angiogenesis and diverse cell recruitment is necessary to repopulate these scaffolds to promote functional regeneration. We determined the contribution of angiogenesis to initial cellular repopulation of ANAs used to repair nerve gaps, as well as the signaling that drives a significant portion of this angiogenesis. Wild-type (WT) mice with nerve gaps repaired using ANAs that were treated with an inhibitor of VEGF receptor signaling severely impaired angiogenesis within ANAs, as well as hampered cell repopulation and axon extension into ANAs. Similarly, systemic depletion of hematogenous-derived macrophages, but not neutrophils, in these mice models severely impeded angiogenesis and subsequent nerve regeneration across ANAs suggesting hematogenous-derived macrophages were major contributors to angiogenesis within ANAs. This finding was reinforced using CCR2 knockout (KO) models. As macrophages represented the majority of CCR2 expressing cells, a CCR2 deficiency impaired angiogenesis and subsequent nerve regeneration across ANAs. Furthermore, an essential role for CCL2 during nerve regeneration across ANAs was identified, as nerves repaired using ANAs had reduced angiogenesis and subsequent nerve regeneration in CCL2 KO vs WT mice. Our data demonstrate the CCL2/CCR2 axis is important for macrophage recruitment, which promotes angiogenesis, cell repopulation, and subsequent nerve regeneration and recovery across ANAs used to repair nerve gaps.
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http://dx.doi.org/10.1016/j.expneurol.2020.113363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484126PMC
September 2020

T cells modulate IL-4 expression by eosinophil recruitment within decellularized scaffolds to repair nerve defects.

Acta Biomater 2020 08 17;112:149-163. Epub 2020 May 17.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Electronic address:

Decellularized nerve, or acellular nerve allografts (ANAs), are an increasingly used alternative to nerve autografts to repair nerve gaps to facilitate regeneration. The adaptive immune system, specifically T cells, plays a role in promoting regeneration upon these ANA scaffolds. However, how T cells promote regeneration across ANAs is not clear. Here, we show that T cells accumulate within ANAs repairing nerve gaps resulting in regulation of cytokine expression within the ANA environment. This in turn ultimately leads to robust nerve regeneration and functional recovery. Nerve regeneration across ANAs and functional recovery in Rag1KO mice was limited compared to wild-type (WT) mice. Prior to appreciable nerve regeneration, ANAs from Rag1KO mice contained fewer eosinophils and reduced IL-4 expression compared to ANAs from WT mice. During this period, both T cells and eosinophils regulated IL-4 expression within ANAs. Eosinophils represented the majority of IL-4 expressing cells within ANAs, while T cells regulated IL-4 expression. Finally, an essential role for IL-4 during nerve regeneration across ANAs was confirmed as nerves repaired using ANAs had reduced regeneration in IL-4 KO mice compared to WT mice. Our data demonstrate T cells regulate the expression of IL-4 within the ANA environment via their effects on eosinophils. STATEMENT OF SIGNIFICANCE: The immune system has been emerging as a critical component for tissue regeneration, especially when regeneration is supported upon biomaterials. The role of T cells, and their roles in the regeneration of nerve repaired with biomaterials, is still unclear. We demonstrated that when nerves are repaired with decellularized nerve scaffolds, T cells contribute to regeneration by regulating cytokines. We focused on their regulation of cytokine IL-4. Unexpectedly, T cells do not produce IL-4, but instead regulate IL-4 by recruiting eosinophils, which are major cellular sources of IL-4 within these scaffolds. Thus, our work demonstrated how IL-4 is regulated in a model biomaterial, and has implications for improving the design of biomaterials and understanding immune responses to biomaterials.
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http://dx.doi.org/10.1016/j.actbio.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416535PMC
August 2020

New in vitro highly cytotoxic platinum and palladium cyanoximates with minimal side effects in vivo.

J Inorg Biochem 2020 07 6;208:111082. Epub 2020 May 6.

Department of Chemistry, Temple Hall 431, Missouri State University, 901 S. National, Springfield, MO 65897, USA. Electronic address:

Several biologically active bivalent Pd and Pt complexes with two structurally similar cyanoxime ligands abbreviated as H(DECO): 2-oximino-2-cyano-N,N'-diethylacetamide, and H(PyrCO): 2-oximino-2-cyan-N-pyrrolidine acetamide were synthesized and characterized using spectroscopic methods, thermal analysis and X-ray crystallography. Structures revealed planar cis-geometry of studied complexes. Freshly obtained Pt(DECO), Pd(DECO), Pt(PyrCO) and Pd(PyrCO) complexes were used in for in vitro cytotoxicity assays using two different etiology human cancer cell lines HeLa and WiDr cells. Investigated compounds showed cytotoxicity levels at or above cisplatin. Pt(DECO) was also tested in vivo in healthy C57BL/6 mice. The complex was administered at three different dosage (0, 7.5, 15 mg/kg, i.p. once/week), over a total period of 8 weeks. No changes were observed in the animal weight in the treated mice compared to the control dextrose-treated group. The levels of erythrocytes, leukocytes, and hemoglobin were within the normal level suggesting low myelotoxicity. Negligible cardiotoxicity was observed from the histological evaluation of the hearts from the treated animals. Results from the tail nerve conduction velocity (NCV) and nerve histomorphometry suggested no impact of Pt(DECO) on peripheral nerves. The complex, however, induced certain hepatotoxicity and lead to the elevation of IL-6, a pro-inflammatory cytokine. Overall, Pt(DECO)2 showed minimal in vivo toxicity, thus presenting a promising candidate for future testing in animal models of cancer.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518941PMC
July 2020

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Authors:
Matthew Clarke Alan Mackay Britta Ismer Jessica C Pickles Ruth G Tatevossian Scott Newman Tejus A Bale Iris Stoler Elisa Izquierdo Sara Temelso Diana M Carvalho Valeria Molinari Anna Burford Louise Howell Alex Virasami Amy R Fairchild Aimee Avery Jane Chalker Mark Kristiansen Kelly Haupfear James D Dalton Wilda Orisme Ji Wen Michael Hubank Kathreena M Kurian Catherine Rowe Mellissa Maybury Stephen Crosier Jeffrey Knipstein Ulrich Schüller Uwe Kordes David E Kram Matija Snuderl Leslie Bridges Andrew J Martin Lawrence J Doey Safa Al-Sarraj Christopher Chandler Bassel Zebian Claire Cairns Rachael Natrajan Jessica K R Boult Simon P Robinson Martin Sill Ira J Dunkel Stephen W Gilheeney Marc K Rosenblum Debbie Hughes Paula Z Proszek Tobey J Macdonald Matthias Preusser Christine Haberler Irene Slavc Roger Packer Ho-Keung Ng Shani Caspi Mara Popović Barbara Faganel Kotnik Matthew D Wood Lissa Baird Monika Ashok Davare David A Solomon Thale Kristin Olsen Petter Brandal Michael Farrell Jane B Cryan Michael Capra Michael Karremann Jens Schittenhelm Martin U Schuhmann Martin Ebinger Winand N M Dinjens Kornelius Kerl Simone Hettmer Torsten Pietsch Felipe Andreiuolo Pablo Hernáiz Driever Andrey Korshunov Lotte Hiddingh Barbara C Worst Dominik Sturm Marc Zuckermann Olaf Witt Tabitha Bloom Clare Mitchell Evelina Miele Giovanna Stefania Colafati Francesca Diomedi-Camassei Simon Bailey Andrew S Moore Timothy E G Hassall Stephen P Lowis Maria Tsoli Mark J Cowley David S Ziegler Matthias A Karajannis Kristian Aquilina Darren R Hargrave Fernando Carceller Lynley V Marshall Andreas von Deimling Christof M Kramm Stefan M Pfister Felix Sahm Suzanne J Baker Angela Mastronuzzi Andrea Carai Maria Vinci David Capper Sergey Popov David W Ellison Thomas S Jacques David T W Jones Chris Jones

Cancer Discov 2020 Jul 1;10(7):942-963. Epub 2020 Apr 1.

Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1030DOI Listing
July 2020

Design-Based stereology and binary image histomorphometry in nerve assessment.

J Neurosci Methods 2020 04 15;336:108635. Epub 2020 Feb 15.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address:

Background: Stereology and histomorphometry are widely used by investigators to quantify nerve characteristics in normal and pathological states, including nerve injury and regeneration. While these methods of analysis are complementary, no study to date has systematically compared both approaches in peripheral nerve. This study investigated the reliability of design-based stereology versus semi-automated binary imaging histomorphometry for assessing healthy peripheral nerve characteristics.

New Method: Stereological analysis was compared to histomorphometry with binary image analysis on uninjured sciatic nerves to determine nerve fiber number, nerve area, neural density, and fiber distribution.

Results: Sciatic nerves were harvested from 6 male Lewis rats, aged 8-12 weeks for comprehensive analysis of 6 nerve specimens. From each animal, sciatic nerve specimens were fixed, stained, and sectioned for analysis by light and electron microscopy. Both histomorphometry and stereological peripheral nerve analyses were performed on all specimens by two blinded and independent investigators who quantified nerve fiber count, fiber width, density, and related distribution parameters.

Comparison With Existing Methods: Histomorphometry and stereological analysis provided similar outcomes in nerve fiber number and total nerve area. However, the light microscopy, but not electron microscopy, stereological analysis yielded higher nerve fiber area compared to histomorphometry or manual measurement.

Conclusion: Both methods measure similar fiber number and overall nerve fiber area; however, stereology with light microscopy quantified higher fiber area. Histomorphometry optimizes throughput and comprehensive analysis but requires user thresholding.
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http://dx.doi.org/10.1016/j.jneumeth.2020.108635DOI Listing
April 2020

Advances in the repair of segmental nerve injuries and trends in reconstruction.

Muscle Nerve 2020 06 13;61(6):726-739. Epub 2020 Jan 13.

Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.

Despite advances in surgery, the reconstruction of segmental nerve injuries continues to pose challenges. In this review, current neurobiology regarding regeneration across a nerve defect is discussed in detail. Recent findings include the complex roles of nonneuronal cells in nerve defect regeneration, such as the role of the innate immune system in angiogenesis and how Schwann cells migrate within the defect. Clinically, the repair of nerve defects is still best served by using nerve autografts with the exception of small, noncritical sensory nerve defects, which can be repaired using autograft alternatives, such as processed or acellular nerve allografts. Given current clinical limits for when alternatives can be used, advanced solutions to repair nerve defects demonstrated in animals are highlighted. These highlights include alternatives designed with novel topology and materials, delivery of drugs specifically known to accelerate axon growth, and greater attention to the role of the immune system.
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http://dx.doi.org/10.1002/mus.26797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230025PMC
June 2020

Arteriovenous Malformation Presenting as Symptomatic, Enlarging and Contrast-Enhancing Mass 12 Years After Being Treated with Embolization and Radiotherapy.

World Neurosurg 2020 Feb 16;134:45-49. Epub 2019 Oct 16.

Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA. Electronic address:

Background: Gross total resection of arteriovenous malformations (AVMs) of the central nervous system confirmed by formal angiography is accepted as a cure for patients. In some cases, this may not be possible. Even though in these cases other treatment modalities such as endovascular embolization and radiotherapy can be used, long-term follow-up is lacking in the literature.

Case Description: Here we report a case of a 57-year-old woman with history of a right-sided parieto-occipital/periatrial AVM, initially treated with a combination of endovascular embolization and radiotherapy.

Conclusions: The patient subsequently presented (12 years later) with a symptomatic, enlarging, contrast-enhancing mass at the same location that was angiographically occult but ultimately proven to be an AVM on a background of reactive changes on pathology.
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http://dx.doi.org/10.1016/j.wneu.2019.10.055DOI Listing
February 2020

Imaging in the repair of peripheral nerve injury.

Nanomedicine (Lond) 2019 10 15;14(20):2659-2677. Epub 2019 Oct 15.

Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA.

Surgical intervention followed by physical therapy remains the major way to repair damaged nerves and restore function. Imaging constitutes promising, yet underutilized, approaches to improve surgical and postoperative techniques. Dedicated methods for imaging nerve regeneration will potentially provide surgical guidance, enable recovery monitoring and postrepair intervention, elucidate failure mechanisms and optimize preclinical procedures. Herein, we present an outline of promising innovations in imaging-based tracking of peripheral nerve regeneration. We emphasize optical imaging because of its cost, versatility, relatively low toxicity and sensitivity. We discuss the use of targeted probes and contrast agents (small molecules and nanoparticles) to facilitate nerve regeneration imaging and the engineering of grafts that could be used to track nerve repair. We also discuss how new imaging methods might overcome the most significant challenges in nerve injury treatment.
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http://dx.doi.org/10.2217/nnm-2019-0115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886568PMC
October 2019

A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy.

Neuropathology 2019 Oct 21;39(5):389-393. Epub 2019 Aug 21.

Department of Pathology, Oregon Health & Science University, Portland, Oregon, USA.

Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy.
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http://dx.doi.org/10.1111/neup.12586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852525PMC
October 2019

Comparing electrical stimulation and tacrolimus (FK506) to enhance treating nerve injuries.

Muscle Nerve 2019 11 21;60(5):629-636. Epub 2019 Aug 21.

Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, Missouri.

Introduction: Neuroenhancing therapies are desired because repair of nerve injuries can fail to achieve recovery. We compared two neuroenhancing therapies, electrical stimulation (ES) and systemic tacrolimus (FK506), for their capabilities to enhance regeneration in the context of a rat model.

Methods: Rats were randomized to four groups: ES 0.5 mA, ES 2.0 mA, FK506, and repair alone. All groups underwent tibial nerve transection and repair, and outcomes were assessed by using twice per week walking track analysis, cold allodynia response, relative muscle mass, and nerve histology.

Results: Electrical stimulation and FK506 groups demonstrated improved functional recovery and myelinated axon counts distal to the repair compared with repair alone. Electrical stimulation provided improvements in nerve regeneration that were not different from optimized FK506 systemic administration.

Discussion: Providing ES after nerve repair improved regeneration and recovery in rats, with minimal differences in therapeutic efficacy to FK506, further demonstrating its clinical potential to improve management of nerve injuries.
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http://dx.doi.org/10.1002/mus.26659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083518PMC
November 2019

An unusual recurrent high-grade glioneuronal tumor with MAP2K1 mutation and CDKN2A/B homozygous deletion.

Acta Neuropathol Commun 2019 07 9;7(1):110. Epub 2019 Jul 9.

Department of Pathology, Oregon Health & Science University, Mail Code L-113, 3181 SW Sam Jackson Park Road, Portland, OR, 97202, USA.

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http://dx.doi.org/10.1186/s40478-019-0763-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617605PMC
July 2019

Neuroma Management: Capping Nerve Injuries With an Acellular Nerve Allograft Can Limit Axon Regeneration.

Hand (N Y) 2021 Mar 29;16(2):157-163. Epub 2019 May 29.

Washington University School of Medicine, St. Louis, MO, USA.

Management of painful neuromas continues to challenge clinicians. Controlling axon growth to prevent neuroma has gained considerable traction. A logical extension of this idea is to therefore develop an approach to control and arrest axon growth. Given the limits in axonal regeneration across acellular nerve allografts (ANAs), these constructs could provide a means to reliably terminate axon regeneration from an injured nerve. The purpose of this study was to determine if attaching an ANA to an injured nerve could provide a means to control and limit axon regeneration in a predictable manner. Twenty (20) adult rats received a sciatic nerve transection, where only the proximal nerve was repaired using an ANA of variable length (0.5, 2.5, and 5.0 cm) or left unrepaired (control). The nerves were harvested 5 weeks post-operatively for gross and histomorphometric analysis. The extent of myelinated axons in regenerated tissue was quantified. At 5 weeks, limited axon regeneration within the ANAs was observed. All lengths of ANAs lead to reduced myelinated axon numbers in the most terminal tissue region compared to untreated injured nerve ( = .002). Additionally, ANA length 2.5 cm or greater did not contain any axons at the most terminal tissue region. This study demonstrates a proof of concept that ANAs attached to the proximal end of an injured nerve can limit axon growth in a controlled manner. Furthermore, the extent of axon growth from the injured nerve into the ANA is dependent on the ANA length.
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http://dx.doi.org/10.1177/1558944719849115DOI Listing
March 2021

The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration.

Exp Neurol 2019 08 11;318:216-231. Epub 2019 May 11.

Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Repair of traumatic nerve injuries can require graft material to bridge the defect. The use of alternatives to bridge the defect, such as acellular nerve allografts (ANAs), is becoming more common and desired. Although ANAs support axon regeneration across short defects (<3 cm), axon regeneration across longer defects (>3 cm) is limited. It is unclear why alternatives, including ANAs, are functionally limited by length. After repairing Lewis rat nerve defects using short (2 cm) or long (4 cm) ANAs, we showed that long ANAs have severely reduced axon regeneration across the grafts and contain Schwann cells with a unique phenotype. But additionally, we found that long ANAs have disrupted angiogenesis and altered leukocyte infiltration compared to short ANAs as early as 2 weeks after repair. In particular, long ANAs contained fewer T cells compared to short ANAs. These outcomes were accompanied with reduced expression of select cytokines, including IFN-γ and IL-4, within long versus short ANAs. T cells within ANAs did not express elevated levels of IL-4, but expressed elevated levels of IFN-γ. We also directly assessed the contribution of T cells to regeneration across nerve grafts using athymic rats. Interestingly, T cell deficiency had minimal impact on axon regeneration across nerve defects repaired using isografts. Conversely, T cell deficiency reduced axon regeneration across nerve defects repaired using ANAs. Our data demonstrate that T cells contribute to nerve regeneration across ANAs and suggest that reduced T cells accumulation within long ANAs could contribute to limiting axon regeneration across these long ANAs.
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http://dx.doi.org/10.1016/j.expneurol.2019.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605105PMC
August 2019

Applications of molecular neuro-oncology - a review of diffuse glioma integrated diagnosis and emerging molecular entities.

Diagn Pathol 2019 Apr 9;14(1):29. Epub 2019 Apr 9.

Knight Diagnostic Laboratories and Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA.

Insights into the molecular underpinnings of primary central nervous system tumors have radically changed the approach to tumor diagnosis and classification. Diagnostic emphasis has shifted from the morphology of a tumor under the microscope to an integrated approach based on morphologic and molecular features, including gene mutations, chromosomal copy number alterations, and gene rearrangements. In 2016, the World Health Organization provided guidelines for making an integrated diagnosis that incorporates both morphologic and molecular features in a subset of brain tumors. The integrated diagnosis now applies to infiltrating gliomas, a category that includes diffusely infiltrating astrocytoma grades II, III, and IV, and oligodendroglioma, grades II and III, thereby encompassing the most common primary intra-axial central nervous system tumors. Other neoplasms such as medulloblastoma, embryonal tumor with multilayered rosettes, certain supratentorial ependymomas, and atypical teratoid/rhabdoid tumor are also eligible for integrated diagnosis, which can sometimes be aided by characteristic immunohistochemical markers. Since 2016, advances in molecular neuro-oncology have resulted in periodic updates and clarifications to the integrated diagnostic approach. These advances reflect expanding knowledge on the molecular pathology of brain tumors, but raise a challenge in rapidly incorporating new molecular findings into diagnostic practice. This review provides a background on the molecular characteristics of primary brain tumors, emphasizing the molecular basis for classification of infiltrating gliomas, the most common entities that are eligible for an integrated diagnosis. We then discuss entities within the diffuse gliomas that do not receive an integrated diagnosis by WHO 2016 criteria, but have distinctive molecular features that are important to recognize because their clinical behavior can influence clinical management and prognosis. Particular attention is given to the histone H3 G34R/G34V mutant astrocytomas, an entity to consider when faced with an infiltrating glioma in the cerebral hemisphere of children and young adults, and to the group of histologically lower grade diffuse astrocytic gliomas with molecular features of glioblastoma, an important category of tumors to recognize due to their aggressive clinical behavior.
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http://dx.doi.org/10.1186/s13000-019-0802-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457044PMC
April 2019

Cerebral amyloidoma: A mimicker of granulomatous disease on brain MRI.

J Neuroradiol 2019 09 7;46(5):336-339. Epub 2019 Mar 7.

University of California San Francisco, Department of Pathology, Division of Neuropathology, San Francisco, CA 94143 USA.

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http://dx.doi.org/10.1016/j.neurad.2019.02.009DOI Listing
September 2019

Co-evolution of physical and social sciences in synthetic biology.

Crit Rev Biotechnol 2019 May 6;39(3):351-365. Epub 2019 Feb 6.

b US Army Engineer Research and Development Center , Vicksburg , MS , USA.

Emerging technologies research often covers various perspectives in disciplines and research areas ranging from hard sciences, engineering, policymaking, and sociology. However, the interrelationship between these different disciplinary domains, particularly the physical and social sciences, often occurs many years after a technology has matured and moved towards commercialization. Synthetic biology may serve an exception to this idea, where, since 2000, the physical and the social sciences communities have increasingly framed their research in response to various perspectives in biological engineering, risk assessment needs, governance challenges, and the social implications that the technology may incur. This paper reviews a broad collection of synthetic biology literature from 2000-2016, and demonstrates how the co-development of physical and social science communities has grown throughout synthetic biology's earliest stages of development. Further, this paper indicates that future co-development of synthetic biology scholarship will assist with significant challenges of the technology's risk assessment, governance, and public engagement needs, where an interdisciplinary approach is necessary to foster sustainable, risk-informed, and societally beneficial technological advances moving forward.
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http://dx.doi.org/10.1080/07388551.2019.1566203DOI Listing
May 2019