Gradient of Tissue Injury after Stroke: Rethinking the Infarct versus Noninfarcted Dichotomy

2020 ◽  
Vol 49 (1) ◽  
pp. 32-38 ◽  
Author(s):  
Felix Ng ◽  
Vijay Venkatraman ◽  
Mark Parsons ◽  
Andrew Bivard ◽  
Gagan Sharma ◽  
...  
Keyword(s):  
Diffusion Tensor ◽  
Tissue Injury ◽  
Ct Perfusion ◽  
Mean Diffusivity ◽  
Brain Regions ◽  
Homologous Region ◽  
Anterior Circulation ◽  
Prospective Longitudinal Study ◽  
Fluid Attenuated Inversion Recovery ◽  
Prospective Longitudinal

Aim: To evaluate the degree of variability in microstructural injury within and adjacent to regions identified as infarcted tissue using diffusion tensor imaging (DTI). Methods: In this prospective longitudinal study, 18 patients presenting within 12 h of anterior circulation acute ischemic stroke who underwent CT perfusion (CTP) at baseline followed by fluid-attenuated inversion recovery (FLAIR) and DTI 1-month were analyzed. Four regions of interest (ROI) corresponding to the severity of hypoperfusion on CTP within and beyond the radiological infarct lesion defined on FLAIR were segmented. Fractional anisotropy (FA) and mean diffusivity (MD) were quantified for each ROI and compared to a mirror homologue in the contralateral hemisphere. Ipsilateral to contralateral FA and MD ratios were compared across ROIs. Results: Lower FA and higher MD values were observed within both the infarct lesion and the peri-infarct tissue compared with their homologous contralateral brain regions (all comparisons p ≤ 0.01). No difference was observed in FA and MD between remote nonhypoperfused tissue and its contralateral homologous region (FA p = 0.42, MD p ≥ 0.99). The magnitude of asymmetry (ipsilateral/contralateral ratios) of FA and MD was greater with increasing severity of hypoperfusion in a dose-response pattern. Asymmetry greatest in the area of infarction with severe hypoperfusion, followed by infarction with moderate hypoperfusion, the peri-infarct hypoperfused tissue, and lastly the remote nonhypoperfused normal tissue (median on clustered quantile regression p ≤ 0.01). Conclusion: A gradient of microstructural injury corresponding to the severity of ischemic insult is present within and beyond conventionally defined infarct boundaries. The traditional dichotomized notion of infarcted versus noninfarcted tissue widely adopted in clinical research and in practice warrants reexamination.

Abstract WP71: Gradient of Tissue Injury on Diffusion Tensor Imaging After Stroke: Rethinking the Infarct vs Non-infarcted Dichotomy

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Felix Ng ◽  
Vijay Venkatraman ◽  
Mark Parsons ◽  
Andrew Bivard ◽  
Gagan Sharma ◽  
...  
Keyword(s):  
Diffusion Tensor Imaging ◽  
Diffusion Tensor ◽  
Tissue Injury ◽  
Ct Perfusion ◽  
Mean Diffusivity ◽  
Brain Regions ◽  
Homologous Region ◽  
Fluid Attenuated Inversion Recovery ◽  
Infarcted Tissue ◽  
Diffusion Tensor Imaging Dti

Objective: To evaluate the degree of variability in microstructural injury within and adjacent to regions identified as infarcted tissue using Diffusion Tensor Imaging (DTI). Methods: Perfusion CT was performed in 18 patients within 12 hours of ischemic stroke onset followed by Fluid-attenuated Inversion recovery (FLAIR) and DTI one month after stroke. Four regions of interest (ROIs) corresponding to the severity of hypoperfusion on CT perfusion within and beyond the radiological infarct lesion defined on FLAIR were segmented. Fractional anisotropy (FA) and mean diffusivity (MD) were quantified for each ROI and compared to a mirror homologue in the contralateral hemisphere. Ipsilateral to contralateral FA and MD ratios were compared across ROIs. Results: Lower FA and higher MD values were observed within both the infarct lesion and the peri-infarct tissue compared with their homologous contralateral brain regions (all comparisons p≤0.01). No difference was observed in FA and MD between remote non-hypoperfused tissue and its contralateral homologous region (FA p=0.42, MD p≥0.99). The magnitude of asymmetry (ipsilateral/contralateral ratios) of FA and MD was greater with increasing severity of hypoperfusion in a dose-response pattern. Asymmetry greatest in the area of infarction with severe hypoperfusion, followed by infarction with moderate hypoperfusion, the peri-infarct hypoperfused tissue and lastly the remote non-hypoperfused normal tissue (median on clustered quantile regression p≤0.01). Conclusion: A gradient of microstructural injury corresponding to the severity of ischemic insult is present within and beyond conventionally-defined infarct boundaries. The traditional dichotomized notion of infarcted versus non-infarcted tissue widely adopted in clinical research and in practice warrants re-examination.

scholarly journals MRI in acute muscle tears in athletes: can quantitative T2 and DTI predict return to play better than visual assessment?

2020 ◽  
Vol 30 (12) ◽  
pp. 6603-6613
Author(s):  
J. D. Biglands ◽  
A. J. Grainger ◽  
P. Robinson ◽  
S. F. Tanner ◽  
A. L. Tan ◽  
...  
Keyword(s):  
Diffusion Tensor ◽  
Mean Diffusivity ◽  
Quantitative Mri ◽  
Return To Play ◽  
Prospective Longitudinal Study ◽  
Muscle Tear ◽  
Muscle Changes ◽  
Prospective Longitudinal ◽  
And Diffusion ◽  
Mri Measurements

Abstract Objectives To assess the ability of quantitative T2, diffusion tensor imaging (DTI) and radiologist’s scores to detect muscle changes following acute muscle tear in soccer and rugby players. To assess the ability of these parameters to predict return to play times. Methods In this prospective, longitudinal study, 13 male athletes (age 19 to 34 years; mean 25 years) underwent MRI within 1 week of suffering acute muscle tear. Imaging included measurements of T2 and DTI parameters. Images were also assessed using modified Peetrons and British athletics muscle injury classification (BAMIC) scores. Participants returned for a second scan within 1 week of being determined fit to return to play. MRI measurements were compared between visits. Pearson’s correlation between visit 1 measurements and return to play times was assessed. Results There were significant differences between visits in BAMIC scores (Z = − 2.088; p = 0.037), modified Peetrons (Z = − 2.530; p = 0.011) and quantitative MRI measurements; T2, 13.12 ms (95% CI, 4.82 ms, 21.42 ms; p = 0.01); mean diffusivity (0.22 (0.04, 0.39); p = 0.02) and fractional anisotropy (0.07 (0.01, 0.14); p = 0.03). BAMIC scores showed a significant correlation with return to play time (Rs = 0.64; p = 0.02), but modified Peetrons scores and quantitative parameters did not. Conclusions T2 and DTI measurements in muscle can detect changes due to healing following muscle tear. Although BAMIC scores correlated well with return to play times, in this small study, quantitative MRI values did not, suggesting that T2 and DTI measurements are inferior predictors of return to play time compared with visual scoring. Key Points • Muscle changes following acute muscle tear can be measured using T2 and diffusion measurements on MRI. • Measurements of T2 and diffusion using MRI are not as good as a radiologist’s visual report at predicting return to play time after acute muscle tear.

scholarly journals fMRI-guided white matter connectivity in fluid and crystallized cognitive abilities in healthy adults

2020 ◽  
Author(s):  
Yunglin Gazes ◽  
Jayant Sakhardande ◽  
Ashley Mensing ◽  
Qolamreza Razlighi ◽  
Ann Ohkawa ◽  
...  
Keyword(s):  
White Matter ◽  
Episodic Memory ◽  
Diffusion Tensor ◽  
Mean Diffusivity ◽  
Brain Regions ◽  
Long Distance ◽  
White Matter Tracts ◽  
Percent Signal Change ◽  
Signal Change ◽  
Fluid Abilities

AbstractThis study examined within-subject differences among three fluid abilities that decline with age: reasoning, episodic memory and processing speed, compared with vocabulary, a crystallized ability that is maintained with age. The data were obtained from the Reference Ability Neural Network (RANN) study from which 221 participants had complete behavioral data for all 12 cognitive tasks, three per ability, along with fMRI and diffusion weighted imaging data. We used fMRI task activation to guide white matter tractography, and generated mean percent signal change in the regions associated with the processing of each ability along with diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), for each cognitive ability. Qualitatively brain regions associated with vocabulary were more localized and lateralized to the left hemisphere whereas the fluid abilities were associated with brain activations that were more distributed across the brain and bilaterally situated. Using continuous age, we observed smaller correlations between MD and age for white matter tracts connecting brain regions associated with the vocabulary ability than that for the fluid abilities, suggesting that vocabulary white matter tracts were better maintained with age. Furthermore, after multiple comparisons correction, the mean percent signal change for the episodic memory showed positive associations with behavioral performance, and the associations between MD and percent signal change differed by age such that, when divided into three age groups to further explore this interaction, only the oldest age group show a significant negative correlation between the two brain measures. Overall, the vocabulary ability may be better maintained with age due to the more localized brain regions involved, which places smaller reliance on long distance white matter tracts for signal transduction. These results support the hypothesis that functional activation and white matter structures underlying the vocabulary ability contribute to the ability’s greater resistance against aging.

Abstract P579: Fluid Attenuated Inversion Recovery Correlates With Time of Onset of Arterial Ischemic Stroke in Childhood

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Dennis Shaw ◽  
Dwight Barry ◽  
Michael G Abraham ◽  
Dana D Cummings ◽  
Mark T MacKay ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Brain Mri ◽  
Inversion Recovery ◽  
Stroke Onset ◽  
Childhood Stroke ◽  
Arterial Ischemic Stroke ◽  
Anterior Circulation ◽  
Increased Risk ◽  
Fluid Attenuated Inversion Recovery ◽  
Highest Density Interval

Background: In adults, time since stroke onset correlates with efficacy and risk of recanalization therapies; beyond this temporal window there is increased risk of adverse events in particular hemorrhage with thrombolysis and decreased benefit of recanalization due to irreversible tissue injury. In adults the appearance of fluid attenuated inversion recovery (FLAIR) signal is a proxy for time, and is typically present by 6 hours. The time to FLAIR signal hyperintensity in childhood stroke is unknown but is of interest with potential utility due to the often greater uncertainty as to timing symptom onset. Methods: Time to FLAIR signal hyperintensity on brain MRI performed on children within 24 hours of stroke onset was studied with logistic regression. Results: A total of 68 MRIs with FLAIR imaging were available from 54 children (27 female), age 0.8 to 17.9 years, median 12.0 years. Seventy-four percent (40/54) of children and 72% (49/68) of scans had anterior circulation stroke. Interquartile range for time to FLAIR presence was 7.8 to 19.1 hours. The 90% probability of FLAIR change was reached at 11.2 hours for all strokes (Figure, dotted line; 80% highest density interval (HDI): 1.2-11.2 hours), and 9.3 hours for anterior circulation only strokes (Figure, solid line; 80% HDI: 3.3-9.3 hours), though nearly all had FLAIR change by 6 hours. FLAIR change was absent in 4 children after 6 hours, two with anterior circulation stroke (16 year-old at 6.1 hours, 10 year-old at 7.0 hours) and 2 with posterior circulation stroke (15 year-old at 7.3 hours, 9 month-old at 18.2 hours). Conclusion: Similar to adults, FLAIR hyperintensity can be used to estimate time since stroke ictus in childhood stroke. Children may have somewhat delayed time to FLAIR signal change compared with adults, suggesting that they may have a longer window for effective recanalization therapies.

ASSOCIATION ASSESSMENT BETWEEN DIFFUSION TENSOR MAGNETIC RESONANCE IMAGING INDICES AND CLINICAL DISABILITIES IN MS PATIENTS

2016 ◽  
Vol 28 (05) ◽  
pp. 1650034 ◽  
Author(s):  
Vania Karami ◽  
Rasoul Mahdavifar Khayati ◽  
S. Massood Nabavi
Keyword(s):  
Magnetic Resonance Imaging ◽  
Black Holes ◽  
Magnetic Resonance ◽  
Diffusion Tensor ◽  
Mean Diffusivity ◽  
Volume Ratio ◽  
The Other ◽  
Resonance Imaging ◽  
Fluid Attenuated Inversion Recovery ◽  
The Impact

Purpose: Diffusion tensor magnetic resonance imaging (DT-MRI) has the ability to gather information on tissue microstructure by using the indices that quantify the anisotropy of water diffusion in tissues. This study was designed to find out the impact of patient clinical disability on diffusion tensor (DT) indices. Method: In this paper, images were generated from the data acquired at 3T among 25 MS patients (mean age [Formula: see text] years old). DT indices including fractional anisotropy (FA), mean diffusivity (MD), relative anisotropy (RA), and volume ratio (VR) of multiple sclerosis (MS) lesions are calculated and the correlation between Kurtzke expanded disability status scale (EDSS) score and the values of DT indices of 25 MS patients lesions are obtained. The correlation comparison procedure is done between the EDSS scores and DT indices in MS lesions attained, respectively, from fluid attenuated inversion recovery (FLAIR) images and black holes of T1-weighted (T1-w) images. Results: EDSS scores and DT indices of MS lesions extracted from the black holes present in T1-w images are more correlated in comparison with those extracted from FLAIR images. It is found that MD has a significant correlation with EDSS in both types of images. The results of FLAIR image processing indicates that any increase in EDSS leads to decreasing FA and RA on one hand and increasing MD and VR on the other hand. The correlation between the identical size of lesions in different parts of brain with EDSS shows that the location of lesion in brain also has a correlation with EDSS. Conclusion: The results showed, MD is the best biomarker of clinical disability between these four DT indices. It is also concluded that the correlation between DT indices of frontal brain lesions and EDSS is higher than the other selected brain parts.

scholarly journals Characteristics of mental health implications and plasma metabolomics in patients recently recovered from COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lian Yang ◽  
Mei Zhou ◽  
Lingli Li ◽  
Ping Luo ◽  
Wenliang Fan ◽  
...  
Keyword(s):  
Mental Health ◽  
Metabolic Profiling ◽  
Diffusion Tensor ◽  
Demographic Data ◽  
Mean Diffusivity ◽  
Brain Regions ◽  
Cerebral White Matter ◽  
Radial Diffusivity ◽  
Amine Metabolism ◽  
Diffusion Tensor Imaging Dti

AbstractThis study aimed to explore the associations between cerebral white matter (WM) alterations, mental health status, and metabolism in recovered COVID-19 patients. We included 28 recovered COVID-19 patients and 27 healthy controls between April 2020 and June 2020. Demographic data, the mental health scores, diffusion-tensor imaging (DTI) data, and plasma metabolomics were collected and compared between the two groups. Tract-based spatial statistics and graph theory approaches were used for DTI data analysis. Untargeted metabolomics analysis of the plasma was performed. Correlation analyses were performed between these characteristics. Recovered COVID-19 patients showed decreased fractional anisotropy, increased mean diffusivity and radial diffusivity values in widespread brain regions, and significantly lower global efficiency, longer shortest path length, and less nodal local efficiency in superior occipital gyrus (all, P < 0.05, Bonferroni corrected). Our results also demonstrated significantly different plasma metabolic profiling in recovered COVID-19 patients even at 3 months after their hospital discharge, which was mainly related to purine pathways, amino acids, lipids, and amine metabolism. Certain regions with cerebral WM alterations in the recovered patients showed significant correlations with different metabolites and the mental health scores. We observed multiple alterations in both WM integrity and plasma metabolomics that may explain the deteriorated mental health of recovered COVID-19 patients. These findings may provide potential biomarkers for the mental health evaluation for the recovered COVID-19 patients and potential targets for novel therapeutics.

scholarly journals Improving spatial normalization of brain diffusion MRI to measure longitudinal changes of tissue microstructure in the cortex and white matter

2019 ◽  
Author(s):  
Florencia Jacobacci ◽  
Jorge Jovicich ◽  
Gonzalo Lerner ◽  
Edson Amaro ◽  
Jorge L. Armony ◽  
...  
Keyword(s):  
White Matter ◽  
Gray Matter ◽  
Repeated Measures ◽  
Statistical Tests ◽  
Mean Diffusivity ◽  
Prospective Longitudinal Study ◽  
Longitudinal Changes ◽  
Diffusion Weighted Images ◽  
Diffusion Weighted ◽  
Prospective Longitudinal

ABSTRACTBackgroundFractional anisotropy (FA) and mean diffusivity (MD) are frequently used to evaluate longitudinal changes in white matter microstructure. Recently, there has been a growing interest in identifying experience-dependent plasticity in gray matter using MD. Improving registration has thus become a major goal to enhance the detection of subtle longitudinal changes in cortical microstructure.PurposeTo optimize normalization to improve registration in gray matter and reduce variability associated with multi-session registrations.Study TypeProspective longitudinal studySubjectsTwenty-one healthy subjects (18-31 years old) underwent 9 magnetic resonance imaging (MRI) scanning sessions each.Field Strength/Sequence3.0T, diffusion-weighted multiband-accelerated sequence, MP2RAGE sequence.AssessmentDiffusion-weighted images were registered to standard space using different pipelines that varied in the features used for normalization, namely the non-linear registration algorithm (FSL vs ANTs), the registration target (FA-based vs T1-based templates), and the use of intermediate individual (FA-based or T1-based) targets. We compared the across-session test-retest reproducibility error from these normalization approaches for FA and MD in white and gray matters.Statistical TestsReproducibility errors were compared using a repeated-measures analysis of variance with pipeline as within-subject factor.ResultsThe registration of FA data to the FMRIB58 FA atlas using ANTs yielded lower reproducibility errors in white matter (p<0.0001) with respect to FSL. Moreover, using the MNI152 T1 template as the target of registration resulted in lower reproducibility errors for MD (p<0.0001), whereas the FMRIB58 FA template performed better for FA (p<0.0001). Finally, the use of an intermediate individual template improved reproducibility when registration of the FA images to the MNI152-T1 was carried out within modality (FA-FA) (p<0.05), but not via a T1-based individual template.Data ConclusionA normalization approach using ANTs to register FA images to the MNI152 T1 template via an individual FA template minimized test-retest reproducibility errors both for gray and white matter.

scholarly journals Diffusion tensor imaging revealed different pathological processes of white matter hyperintensities

2019 ◽  
Author(s):  
Zhigang Min ◽  
Hairong Shan ◽  
Long Xu ◽  
Daihai Yuan ◽  
Xuexia Sheng ◽  
...  
Keyword(s):  
Diffusion Tensor Imaging ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Diffusion Tensor ◽  
Mean Diffusivity ◽  
Brain Regions ◽  
Periventricular White Matter ◽  
Frontal Horn ◽  
Fazekas Scale ◽  
Normal White Matter

Abstract Background The purpose of this study was to verify the pathological heterogeneity of white matter hyperintensities (WMHs). We compared diffusion tensor imaging (DTI) metrics within different brain regions using identical grading protocols, and subsequently investigated the microstructural changes in these areas as the WMH progressed. Methods Seventy-three patients with WMH and 18 healthy controls who received DTI were included in this study. We measured fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA), and radial diffusivity (DR) of periventricular and deep WMH in six brain regions and grouped these measures according to the Fazekas scale. We then compared the DTI metrics of different regions with the same Fazekas scale grade. Results Significantly lower FA values (all p<0.001), and higher MD (all p<0.001) and DR values (all p<0.001) were associated with WMH observed within the periventricular white matter around the frontal horn (pFH) and the frontal lateral ventricle (pFLV) compared to other regions with the same Fazekas grades. However, in the normal white matter of the pFH and pFLV, FA was not significantly lower than all other regions. Furthermore, in these areas, MD, DA, and DR were not significantly higher than in all other regions. Conclusion Distinct pathological processes occurred within frontal periventricular WMH and other regions; these processes may represent the effects of severe demyelination within the frontal periventricular white matter.

The heritability of amyloid burden in older adults: the Older Australian Twins Study

2021 ◽  
pp. jnnp-2021-326677
Author(s):  
Rebecca Koncz ◽  
Anbupalam Thalamuthu ◽  
Wei Wen ◽  
Vibeke S Catts ◽  
Vincent Dore ◽  
...  
Keyword(s):  
Older Adults ◽  
Diffusion Tensor ◽  
Genetic Correlations ◽  
Mean Diffusivity ◽  
Brain Regions ◽  
White Matter Hyperintensity ◽  
Amyloid Pet ◽  
Amyloid Burden ◽  
Environmental Correlations ◽  
Pet Scans

ObjectiveTo determine the proportional genetic contribution to the variability of cerebral β-amyloid load in older adults using the classic twin design.MethodsParticipants (n=206) comprising 61 monozygotic (MZ) twin pairs (68 (55.74%) females; mean age (SD): 71.98 (6.43) years), and 42 dizygotic (DZ) twin pairs (56 (66.67%) females; mean age: 71.14 (5.15) years) were drawn from the Older Australian Twins Study. Participants underwent detailed clinical and neuropsychological evaluations, as well as MRI, diffusion tensor imaging (DTI) and amyloid PET scans. Fifty-eight participants (17 MZ pairs, 12 DZ pairs) had PET scans with 11Carbon-Pittsburgh Compound B, and 148 participants (44 MZ pairs, 30 DZ pairs) with 18Fluorine-NAV4694. Cortical amyloid burden was quantified using the centiloid scale globally, as well as the standardised uptake value ratio (SUVR) globally and in specific brain regions. Small vessel disease (SVD) was quantified using total white matter hyperintensity volume on MRI, and peak width of skeletonised mean diffusivity on DTI. Heritability (h2) and genetic correlations were measured with structural equation modelling under the best fit model, controlling for age, sex, tracer and scanner.ResultsThe heritability of global amyloid burden was moderate (0.41 using SUVR; 0.52 using the centiloid scale) and ranged from 0.20 to 0.54 across different brain regions. There were no significant genetic or environmental correlations between global amyloid burden and markers of SVD.ConclusionAmyloid deposition, the hallmark early feature of Alzheimer’s disease, is under moderate genetic influence, suggesting a major environmental contribution that may be amenable to intervention.

scholarly journals Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e042093
Author(s):  
Neil Samuel Nyholm Graham ◽  
Karl A Zimmerman ◽  
Guido Bertolini ◽  
Sandra Magnoni ◽  
Mauro Oddo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Longitudinal Study ◽  
Brain Injury ◽  
Diffusion Tensor ◽  
Axonal Injury ◽  
Ethics Committee ◽  
Cerebral Microdialysis ◽  
Prospective Longitudinal Study ◽  
Neuroimaging Biomarkers ◽  
Prospective Longitudinal

Introduction and aimsTraumatic brain injury (TBI) often results in persistent disability, due particularly to cognitive impairments. Outcomes remain difficult to predict but appear to relate to axonal injury. Several new approaches involving fluid and neuroimaging biomarkers show promise to sensitively quantify axonal injury. By assessing these longitudinally in a large cohort, we aim both to improve our understanding of the pathophysiology of TBI, and provide better tools to predict clinical outcome.Methods and analysisBIOmarkers of AXonal injury after TBI is a prospective longitudinal study of fluid and neuroimaging biomarkers of axonal injury after moderate-to-severe TBI, currently being conducted across multiple European centres. We will provide a detailed characterisation of axonal injury after TBI, using fluid (such as plasma/microdialysate neurofilament light) and neuroimaging biomarkers (including diffusion tensor MRI), which will then be related to detailed clinical, cognitive and functional outcome measures. We aim to recruit at least 250 patients, including 40 with cerebral microdialysis performed, with serial assessments performed twice in the first 10 days after injury, subacutely at 10 days to 6 weeks, at 6 and 12 months after injury.Ethics and disseminationThe relevant ethical approvals have been granted by the following ethics committees: in London, by the Camberwell St Giles Research Ethics Committee; in Policlinico (Milan), by the Comitato Etico Milano Area 2; in Niguarda (Milan), by the Comitato Etico Milano Area 3; in Careggi (Florence), by the Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana, Sezione area vasta centro; in Trento, by the Trento Comitato Etico per le Sperimentazioni Cliniche, Azienda Provinciale per i Servizi Sanitari della Provincia autonoma di Trento; in Lausanne, by the Commission cantonale d’éthique de la recherche sur l’être humain; in Ljubljana, by the National Medical Ethics Committee at the Ministry of Health of the Republic of Slovenia. The study findings will be disseminated to patients, healthcare professionals, academics and policy-makers including through presentation at conferences and peer-reviewed publications. Data will be shared with approved researchers to provide further insights for patient benefit.Trial registration numberNCT03534154.

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