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Clausen, F., Marklund, N. & Hillered, L. (2019). Acute Inflammatory Biomarker Responses to Diffuse Traumatic Brain Injury in the Rat Monitored by a Novel Microdialysis Technique. Journal of Neurotrauma, 36(2), 201-211
Open this publication in new window or tab >>Acute Inflammatory Biomarker Responses to Diffuse Traumatic Brain Injury in the Rat Monitored by a Novel Microdialysis Technique
2019 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 36, no 2, p. 201-211Article in journal (Refereed) Published
Abstract [en]

Neuroinflammation is a major contributor to the progressive brain injury process induced by traumatic brain injury (TBI), and may play an important role in the pathophysiology of axonal injury. The immediate neuroinflammatory cascade cannot be characterized in the human setting. Therefore, we used the midline fluid percussion injury model of diffuse TBI in rats and a novel microdialysis (MD) method providing stable diffusion-driven biomarker sampling. Immediately post-injury, bilateral amphiphilic tri-block polymer coated MD probes (100 kDa cut off membrane) were inserted and perfused with Dextran 500 kDa-supplemented artificial cerebrospinal fluid (CSF) to optimize protein capture. Six hourly samples were analyzed for 27 inflammatory biomarkers (9 chemokines, 13 cytokines, and 5 growth factors) using a commercial multiplex biomarker kit. TBI (n = 6) resulted in a significant increase compared with sham-injured controls (n = 6) for five chemokines (eotaxin/CCL11, fractalkine/CX3CL1, LIX/CXCL5, monocyte chemoattractant protein [MCP]1α/CCL2, macrophage inflammatory protein [MIP]1α /CCL3), 10 cytokines (interleukin [IL]-1α, IL-1β, IL-4, IL-6, IL-10, IL-13, IL-17α, IL-18, interferon [IFN]-γ, tumor necrosis factor [TNF]-α), and four growth factors (epidermal growth factor [EGF], granulocyte-macrophage colony-stimulating factor [GM-CSF], leptin, vascular endothelial growth factor [VEGF]). Therefore, diffuse TBI was associated with an increased level of 18 of the 27 inflammatory biomarkers at one through six time points, during the observation period whereas the remaining 9 biomarkers were unaltered. The study shows that diffuse TBI induces an acute increase in a number of inflammatory biomarkers. The novel MD technique provides stable MD sampling suitable for further studies on the early neuroinflammatory cascade in TBI.

Keywords
diffuse axonal injury, inflammatory biomarkers, MD, rat, TBI
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-378744 (URN)10.1089/neu.2018.5636 (DOI)000459444800003 ()29790398 (PubMedID)
Funder
Swedish Research CouncilVINNOVAErik, Karin och Gösta Selanders Foundation
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Fahlström, A., Tobieson, L., Redebrandt, H. N., Zeberg, H., Bartek, J. J., Bartley, A., . . . Marklund, N. (2019). Differences in neurosurgical treatment of intracerebral haemorrhage: a nation-wide observational study of 578 consecutive patients. Acta Neurochirurgica, 161(5), 955-965
Open this publication in new window or tab >>Differences in neurosurgical treatment of intracerebral haemorrhage: a nation-wide observational study of 578 consecutive patients
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2019 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 5, p. 955-965Article in journal (Refereed) Published
Abstract [en]

Background

Supratentorial intracerebral haemorrhage (ICH) carries an excessive mortality and morbidity. Although surgical ICH treatment can be life-saving, the indications for surgery in larger cohorts of ICH patients are controversial and not well defined. We hypothesised that surgical indications vary substantially among neurosurgical centres in Sweden.

Objective

In this nation-wide retrospective observational study, differences in treatment strategies among all neurosurgical departments in Sweden were evaluated.

Methods

Patient records, neuroimaging and clinical outcome focused on 30-day mortality were collected on each operated ICH patient treated at any of the six neurosurgical centres in Sweden from 1 January 2011 to 31 December 2015.

Results

In total, 578 consecutive surgically treated ICH patients were evaluated. There was a similar incidence of surgical treatment among different neurosurgical catchment areas. Patient selection for surgery was similar among the centres in terms of patient age, pre-operative level of consciousness and co-morbidities, but differed in ICH volume, proportion of deep-seated vs. lobar ICH and pre-operative signs of herniation (p<.05). Post-operative patient management strategies, including the use of ICP-monitoring, CSF-drainage and mechanical ventilation, varied among centres (p<.05). The 30-day mortality ranged between 10 and 28%.

Conclusions

Although indications for surgical treatment of ICH in the six Swedish neurosurgical centres were homogenous with regard to age and pre-operative level of consciousness, important differences in ICH volume, proportion of deep-seated haemorrhages and pre-operative signs of herniation were observed, and there was a substantial variability in post-operative management. The present results reflect the need for refined evidence-based guidelines for surgical management of ICH.

Keywords
Intracerebral haemorrhage, Surgery, Guidelines, Craniotomy, External ventricular drain, Intraventricular haemorrhage
National Category
Neurology Surgery
Identifiers
urn:nbn:se:uu:diva-383508 (URN)10.1007/s00701-019-03853-0 (DOI)000465840200018 ()30877470 (PubMedID)
Available from: 2019-05-17 Created: 2019-05-17 Last updated: 2019-05-17Bibliographically approved
Kononenko, O., Watanabe, H., Stålhandske, L., Zarelius, A., Clausen, F., Yakovleva, T., . . . Marklund, N. (2019). Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord. Restorative Neurology and Neuroscience, 37(2), 87-96
Open this publication in new window or tab >>Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord
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2019 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 37, no 2, p. 87-96Article in journal (Refereed) Published
Abstract [en]

Background/Objectives: Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf and Gap43 neuroplasticity genes in lumbar spinal cord.

Approach/Methods: Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n=8). Absolute expression levels of Tgfb1, c-Fos, Bdnf, and Gapd43 genes were measured by droplet digital PCR in ipsi- and contralesional, dorsal and ventral quadrants of the L4 and L5 spinal cord. The neuronal activity marker c-Fos was analysed by immunohistochemistry in the dorsal L4 and L5 segments. The contra- vs. ipsilesional expression pattern was examined as the asymmetry index, AI.

Results: The Tgfb1 mRNA levels were significantly higher in the CCI vs. sham-injured rats, and in the contra- vs. ipsilesional dorsal domains in the CCI group. The number of c-Fos-positive cells was elevated in the L4 and L5 segments; and on the contralesional compared to the ipsilesional side in the CCI group. The c-Fos AI in the dorsal laminae was significantly increased by CCI.

Conclusions: The results support the hypothesis that focal TBI induces plastic alterations in the lumbar spinal cord that may contribute to either motor recovery or maladaptive motor responses.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Traumatic brain injury, Tgfb1, c-Fos, spinal cord, plasticity
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-383037 (URN)10.3233/RNN-180882 (DOI)000464944000001 ()30856132 (PubMedID)
Funder
Swedish Research CouncilSwedish Institute
Note

De tre första författarna delar förstaförfattarskapet.

de två sista författarna delar sistaförfattarskapet.

Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-05-08Bibliographically approved
Abu Hamdeh, S., Marklund, N., Lewén, A., Howells, T., Raininko, R., Wikström, J. & Enblad, P. (2019). Intracranial pressure elevations in diffuse axonal injury: association with nonhemorrhagic MR lesions in central mesencephalic structures. Journal of Neurosurgery, 131(2), 604-611
Open this publication in new window or tab >>Intracranial pressure elevations in diffuse axonal injury: association with nonhemorrhagic MR lesions in central mesencephalic structures
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2019 (English)In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 131, no 2, p. 604-611Article in journal (Refereed) Published
Abstract [en]

Objective: Increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) with diffuse axonal injury (DAI) is not well defined. This study investigated the occurrence of increased ICP and whether clinical factors and lesion localization on MRI were associated with increased ICP in patients with DAI.

Methods: Fifty-two patients with severe TBI (median age 24 years, range 9–61 years), who had undergone ICP monitoring and had DAI on MRI, as determined using T2*-weighted gradient echo, susceptibility-weighted imaging, and diffusion-weighted imaging (DWI) sequences, were enrolled. The proportion of good monitoring time (GMT) with ICP > 20 mm Hg during the first 120 hours postinjury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression.

Results: All patients had episodes of ICP > 20 mm Hg. The mean proportion of GMT with ICP > 20 mm Hg was 5%, and 27% of the patients (14/52) spent more than 5% of GMT with ICP > 20 mm Hg. The Glasgow Coma Scale motor score at admission (p = 0.04) and lesions on DWI sequences in the substantia nigra and mesencephalic tegmentum (SN-T, p = 0.001) were associated with the proportion of GMT with ICP > 20 mm Hg. In multivariable linear regression, lesions on DWI sequences in SN-T (8% of GMT with ICP > 20 mm Hg, 95% CI 3%–13%, p = 0.004) and young age (−0.2% of GMT with ICP > 20 mm Hg, 95% CI −0.07% to −0.3%, p = 0.002) were associated with increased ICP.

Conclusions: Increased ICP occurs in approximately one-third of patients with severe TBI who have DAI. Age and lesions on DWI sequences in the central mesencephalon (i.e., SN-T) are associated with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in patients with DAI.

Abbreviations: ADC = apparent diffusion coefficient; CPP = cerebral perfusion pressure; DAI = diffuse axonal injury; DWI = diffusion-weighted imaging; EVD = external ventricular drain; GCS = Glasgow Coma Scale; GMT = good monitoring time; GOSE = Glasgow Outcome Scale–Extended; ICC = intraclass correlation coefficient; ICP = intracranial pressure; MAP = mean arterial blood pressure; NICU = neurointensive care unit; SN-T = substantia nigra and mesencephalic tegmentum; SWI = susceptibility-weighted imaging; TBI = traumatic brain injury; T2*GRE = T2*-weighted gradient echo.

Keywords
diffuse axonal injury, MRI, elevated ICP, intracranial pressure, TBI, traumatic brain injury, diffusion-weighted imaging, trauma
National Category
Neurology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-362207 (URN)10.3171/2018.4.JNS18185 (DOI)000478642100036 ()30215559 (PubMedID)
Note

Correction in: JOURNAL OF NEUROSURGERY, Volume: 131, Issue: 2, Pages: 637-638, DOI: 10.3171/2018.10.JNS18185a

Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2019-10-18Bibliographically approved
Wang, C., Iashchishyn, I. A., Kara, J., Fodera, V., Vetri, V., Sancataldo, G., . . . Morozova-Roche, L. A. (2019). Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model. Neuroscience Letters, 699, 199-205
Open this publication in new window or tab >>Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model
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2019 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 699, p. 199-205Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer's and Parkinson's. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer's as demonstrated recently in the human brain tissues. Here by using immunohistochemistry in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post- TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochemistry we have shown that S100A9 was produced by both neuronal and microglial cells. However, A beta peptide deposits characteristic for Alzheimer's disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously observed in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and atomic force microscopy we demonstrated that in vitro S100A9 self- assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temperature and reduction/oxidation, which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2019
Keywords
Alzheimer's disease, Amyloid, Neuroinflammation, Oligomerization, S100A9, Traumatic brain injury
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-383165 (URN)10.1016/j.neulet.2019.02.012 (DOI)000465055200032 ()30753908 (PubMedID)
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically approved
Watanabe, H., Zhang, M., Sarkisyan, D., Kononenko, O., Clausen, F., Iakovleva, T., . . . Bakalkin, G. (2018). Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A79-A79
Open this publication in new window or tab >>Asymmetric Hindlimb Motor Response To Focal Traumatic Brain Injury Is Controlled By Side-Specific Opioid Mechanism
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A79-A79Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Therapeutics / Drug Discovery, Rehabilitation, Receptor Mediated / Signaling, Neuropathology
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-363881 (URN)000441527400221 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Abu Hamdeh, S., Virhammar, J., Sehlin, D., Alafuzoff, I., Cesarini, K. G. & Marklund, N. (2018). Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus. Journal of Neurosurgery, 1-9
Open this publication in new window or tab >>Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus
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2018 (English)In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, p. 1-9Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aβ) reflect the propensity of cortical Aβ aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment. METHODS Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aβ40, Aβ42, and neurotoxic Aβ oligomers/protofibrils, associated with Aβ aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aβ species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale. RESULTS The brain tissue levels of Aβ42 were negatively correlated with CSF Aβ42 (Spearman's r = -0.53, p < 0.05). The Aβ40, Aβ42, and Aβ oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aβ aggregates (p < 0.05). The preoperative CSF Aβ42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aβ aggregates and high brain tissue Aβ42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05). CONCLUSIONS Brain tissue measurements of soluble Aβ species are feasible. Since high Aβ42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aβ species may be associated with the clinical response to shunt treatment.

Keywords
AD = Alzheimer’s disease, Alzheimer’s disease, Aβ = amyloid beta, Aβ oligomers, ELISA = enzyme-linked immunosorbent assay, HPtau = hyperphosphorylated tau protein, LOD = limit of detection, LP = lumboperitoneal, MMSE = Mini-Mental State Examination, VP = ventriculoperitoneal, amyloid-β, hydrocephalus, iNPH, iNPH = idiopathic normal pressure hydrocephalus
National Category
Neurology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-342227 (URN)10.3171/2017.7.JNS171005 (DOI)000454604000014 ()29350601 (PubMedID)
Funder
The Swedish Brain Foundation
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2019-12-06Bibliographically approved
Vedung, F., Hanni, S., Tegner, Y., Johansson, J. & Marklund, N. (2018). CONCUSSION INCIDENCE IN SWEDISH ELITE SOCCER. Paper presented at 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA. Journal of Neurotrauma, 35(16), A270-A270
Open this publication in new window or tab >>CONCUSSION INCIDENCE IN SWEDISH ELITE SOCCER
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2018 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A270-A270Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
Rehabilitation, Concussion / mTBI
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-363880 (URN)000441527400721 ()
Conference
3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, AUG 11-16, 2018, Toronto, CANADA
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Thelin, E. P., Helmy, A., Nelson, D. W. & Marklund, N. (2018). Editorial: Monitoring Pathophysiology in the injured Brain. Frontiers in Neurology, 9, Article ID 193.
Open this publication in new window or tab >>Editorial: Monitoring Pathophysiology in the injured Brain
2018 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 193Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
traumatic brain injury, subarachnoid hemorrhage, monitoring, biomarkers, neurocritical care
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-356893 (URN)10.3389/fneur.2018.00193 (DOI)000428278500001 ()
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Baunsgaard, C. B., Nissen, U. V., Brust, A. K., Frotzler, A., Ribeill, C., Kalke, Y.-B., . . . Biering-Sorensen, F. (2018). Exoskeleton Gait Training After Spinal Cord Injury: An Exploratory Study on Secondary Health Conditions. Journal of Rehabilitation Medicine, 50(9), 806-813
Open this publication in new window or tab >>Exoskeleton Gait Training After Spinal Cord Injury: An Exploratory Study on Secondary Health Conditions
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2018 (English)In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 50, no 9, p. 806-813Article in journal (Refereed) Published
Abstract [en]

Objective: To explore changes in pain, spasticity, range of motion, activities of daily living, bowel and lower urinary tract function and quality of life of individuals with spinal cord injury following robotic exoskeleton gait training.

Design: Prospective, observational, open-label multicentre study. Methods: Three training sessions per week for 8 weeks using an Ekso GT robotic exoskeleton (Ekso Bionics). Included were individuals with recent (<1 year) or chronic (>1 year) injury, paraplegia and tetraplegia, complete and incomplete injury, men and women.

Results: Fifty-two participants completed the training protocol. Pain was reported by 52% of participants during the week prior to training and 17% during training, but no change occurred longitudinally. Spasticity decreased after a training session compared with before the training session (p< 0.001), but not longitudinally. Chronically injured participants increased Spinal Cord Independence Measure (SCIM III) from 73 to 74 (p= 0.008) and improved life satisfaction (p= 0.036) over 8 weeks of training. Recently injured participants increased SCIM III from 62 to 70 (p<0.001), but no significant change occurred in life satisfaction. Range of motion, bowel and lower urinary function did not change over time.

Conclusion: Training seemed not to provoke new pain. Spasticity decreased after a single training session. SCIM III and quality of life increased longitudinally for subsets of participants.

Place, publisher, year, edition, pages
FOUNDATION REHABILITATION INFORMATION, 2018
Keywords
exoskeleton, spinal cord injury, rehabilitation, pain, spasticity, SCIM III
National Category
Other Medical Sciences not elsewhere specified Neurosciences
Identifiers
urn:nbn:se:uu:diva-369113 (URN)10.2340/16501977-2372 (DOI)000447771700005 ()30183055 (PubMedID)
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9797-5626

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