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Tymofiyeva, O., Yuan, J. P., Huang, C.-Y., Connolly, C. G., Henje Blom, E., Xu, D. & Yang, T. T. (2019). Application of machine learning to structural connectome to predict symptom reduction in depressed adolescents with cognitive behavioral therapy (CBT). NeuroImage: Clinical, 23, Article ID 101914.
Open this publication in new window or tab >>Application of machine learning to structural connectome to predict symptom reduction in depressed adolescents with cognitive behavioral therapy (CBT)
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2019 (English)In: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 23, article id 101914Article in journal (Refereed) Published
Abstract [en]

Purpose: Adolescent major depressive disorder (MDD) is a highly prevalent, incapacitating and costly illness. Many depressed teens do not improve with cognitive behavioral therapy (CBT), a first-line treatment for adolescent MDD, and face devastating consequences of increased risk of suicide and many negative health outcomes. "Who will improve with CBT?" is a crucial question that remains unanswered, and treatment planning for adolescent depression remains biologically unguided. The purpose of this study was to utilize machine learning applied to patients' brain imaging data in order to help predict depressive symptom reduction with CBT.

Methods: We applied supervised machine learning to diffusion MRI-based structural connectome data in order to predict symptom reduction in 30 depressed adolescents after three months of CBT. A set of 21 attributes was chosen, including the baseline depression score, age, gender, two global network properties, and node strengths of brain regions previously implicated in depression. The practical and robust J48 pruned tree classifier was utilized with a 10-fold cross-validation.

Results: The classification resulted in an 83% accuracy of predicting depressive symptom reduction. The resulting tree of size seven with only three attributes highlights the role of the right thalamus in predicting depressive symptom reduction with CBT. Additional analysis showed a significant negative correlation between the change in the depressive symptoms and the node strength of the right thalamus.

Conclusions: Our results demonstrate that a machine learning algorithm that exclusively uses structural connectome data and the baseline depression score can predict with a high accuracy depressive symptom reduction in adolescent MDD with CBT. This knowledge can help improve treatment planning for adolescent depression.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Machine learning, Adolescent depression, Diffusion MRI, Connectomics, Brain network, CBT
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-164435 (URN)10.1016/j.nicl.2019.101914 (DOI)000485804400115 ()31491813 (PubMedID)
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved
Blomqvist, I., Henje Blom, E., Hägglöf, B. & Hammarström, A. (2019). Increase of internalized mental health symptoms among adolescents during the last three decades. European Journal of Public Health, 29(5), 925-931
Open this publication in new window or tab >>Increase of internalized mental health symptoms among adolescents during the last three decades
2019 (English)In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 29, no 5, p. 925-931Article in journal (Refereed) Published
Abstract [en]

Background: Previous studies suggest an overall increase of adolescent mental health symptoms globally since the 1980s until today, especially an increase of internalizing symptoms in girls. Due to methodological limitations of these studies, further studies are warranted to obtain a more solid knowledgebase.

Methods: This study was cross-sectional and compared two separate but geographically identical groups of adolescents in a middle-sized industrial municipality in Northern Sweden at two time-points [(i) 1981, n = 1083, (505 girls, 577 boys), response rate 99.7%; (ii) 2014, n = 682, (338 girls, 344 boys), response rate 98.3%]. All students in their last year of compulsory school were included. The same self-report questionnaire, consisting of four sub-scales (functional somatic-, anxiety-, depressive symptoms and conduct problems), was used at both occasions. Data were analyzed with descriptive statistics, two-way ANOVA and general linear model.

Results: Symptoms of anxiety and depression and functional somatic symptoms, increased among both boys and girls from 1981 until 2014 (P < 0.001 for all subscales), and the increase of these symptoms was higher in girls. Conduct problems were significantly higher in boys in 1981 and decreased over time so that in 2014 there was no longer a significant difference between boys and girls regarding conduct problems (P = 0.286).

Conclusion: In this population-based study spanning over 30 years, both girls and boys showed increasing internalizing problems, while conduct problems decreased. To halt this trend, we need a deeper understanding of the impact of the major societal changes that have occurred during the last three decades.

Place, publisher, year, edition, pages
Oxford University Press, 2019
Keywords
anxiety, adolescent, conduct disorder, depressive disorders, mental health, time, descriptive statistics, self-report, knowledge bases, medically unexplained symptoms
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-162726 (URN)10.1093/eurpub/ckz028 (DOI)000491248400023 ()30859217 (PubMedID)
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-11-07Bibliographically approved
Dennhag, I., Henje, E. & Nilsson, K. (2019). Parental caregiver burden and recovery of adolescent anorexia nervosa after multi-family therapy. Eating Disorders, 1-17
Open this publication in new window or tab >>Parental caregiver burden and recovery of adolescent anorexia nervosa after multi-family therapy
2019 (English)In: Eating Disorders, ISSN 1064-0266, E-ISSN 1532-530X, p. 1-17Article in journal (Refereed) Epub ahead of print
Abstract [en]

This study investigated whether parental caregiving burden changed during adjunct multi-family therapy of adolescent anorexia nervosa and eating disorders not otherwise specified (EDNOS) and whether caregiver burden at baseline and changes in caregiver burden during treatment were associated with treatment outcome.

Twenty-four females, 13 to 16 years old, and their parents, participated in the study. Caregiver burden was measured with the Eating Disorders Symptom Impact Scale, by mothers (n = 23) and fathers (n = 22). Treatment outcome was measured by adolescent body mass index, level of global functioning and self-rated eating disorder symptoms by the Eating Disorders Examination Questionnaire 4.0.

All patient outcomes improved and overall caregiver burden decreased significantly during treatment. When broken down in aspects of caregiver burden the decrease in parental perceived isolation, was found to be associated with improvement of BMI and Children's Global Assessment Scale. When analyzing fathers and mothers separately, we found that maternal feelings of guilt and paternal perceived burden of dysregulated behaviors at base-line were correlated to treatment outcome. Future studies are needed to clarify the role of caregiver burden as a potential mediator of treatment results.

Place, publisher, year, edition, pages
Routledge, 2019
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-164587 (URN)10.1080/10640266.2019.1678980 (DOI)31617832 (PubMedID)
Funder
Västerbotten County Council, VLL-678611
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24
Yuan, J. P., Henje Blom, E., Flynn, T., Chen, Y., Ho, T. C., Connolly, C. G., . . . Tymofiyeva, O. (2019). Test-retest reliability of graph theoretic metrics in adolescent brains. Brain Connectivity, 9(2), 144-154
Open this publication in new window or tab >>Test-retest reliability of graph theoretic metrics in adolescent brains
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2019 (English)In: Brain Connectivity, ISSN 2158-0014, E-ISSN 2158-0022, Vol. 9, no 2, p. 144-154Article in journal (Refereed) Published
Abstract [en]

Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate: 1) the effects of edge weighting schemes, and 2) the effects of varying interscan periods on graph metrics' test-retest reliability within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count (SC), and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62±1.10yrs) or within the same scanning session (30 minutes apart) (16.65±1.14yrs). The intraclass correlation coefficient (ICC) was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL-weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA-weights are more suited for DTI connectome studies in adolescents.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2019
Keywords
connectome, diffusion tensor imaging (DTI), graph theory, human brain connectivity, diffusion MRI, network, edge weight, test–retest, adolescent brain
National Category
Psychiatry Neurosciences
Identifiers
urn:nbn:se:umu:diva-153625 (URN)10.1089/brain.2018.0580 (DOI)000463269400003 ()30398373 (PubMedID)
Funder
Swedish Research Council, 350-2012-303
Note

Part 2. Special Issue.

Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2019-05-23Bibliographically approved
LeWinn, K. Z., Strigo, I. A., Connolly, C. G., Ho, T. C., Tymofiyeva, O., Sacchet, M. D., . . . Yang, T. T. (2018). An exploratory examination of reappraisal success in depressed adolescents: Preliminary evidence of functional differences in cognitive control brain regions. Journal of Affective Disorders, 240, 155-164
Open this publication in new window or tab >>An exploratory examination of reappraisal success in depressed adolescents: Preliminary evidence of functional differences in cognitive control brain regions
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2018 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 240, p. 155-164Article in journal (Refereed) Published
Abstract [en]

Background: Most neuroimaging studies of adolescent depression employ tasks not designed to engage brain regions necessary for the cognitive control of emotion, which is central to many behavioral therapies for depression. Depressed adults demonstrate less effective activation of these regions and greater amygdala activation during cognitive reappraisal; we examined whether depressed adolescents show similar patterns of brain activation.

Methods: We collected functional magnetic resonance imaging (fMRI) data during cognitive reappraisal in 41 adolescents with major depressive disorder (MDD) and 34 matched controls (ages 13-17). We examined group differences in (1) activations associated with reappraisal and reappraisal success (i.e., negative affect reduction during reappraisal) using whole brain and amygdala region-of-interest analyses, and (2) functional connectivity of regions from the group-by-reappraisal success interaction.

Results: We found no significant group differences in whole brain or amygdala analyses during reappraisal. In the group-by-reappraisal success interaction, activations in the left dorsomedial prefrontal cortex (dmPFC) and left dorsolateral PFC (dlPFC) were associated with reappraisal success in healthy controls but not depressed adolescents. Depressed adolescents demonstrated reduced connectivity between the left dmPFC and the anterior insula/inferior frontal gyri bilaterally (AI/IFG) and between left dlPFC and left AI/IFG.

Limitations: Our results should be considered exploratory given our less conservative statistical threshold in the group-by-reappraisal interaction.

Conclusions: We find preliminary evidence that depressed adolescents engage cognitive control regions less efficiently than healthy controls, suggesting delayed maturation of regulatory prefrontal cortex regions; more research is needed to determine whether cognitive therapies improve functioning of these regions in depressed youth.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Depression, Adolescence, Cognitive reappraisal, FMRI, Emotion regulation
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-151515 (URN)10.1016/j.jad.2018.07.020 (DOI)000442074600020 ()30071419 (PubMedID)
Available from: 2018-09-12 Created: 2018-09-12 Last updated: 2018-09-12Bibliographically approved
Tymofiyeva, O., Henje Blom, E., Ho, T. C., Connolly, C. G., Lindqvist, D., Wolkowitz, O. M., . . . Yang, T. T. (2018). High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression. Journal of Affective Disorders, 232, 283-290
Open this publication in new window or tab >>High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression
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2018 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 232, p. 283-290Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Adolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group.

METHODS: The first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents.

RESULTS: There were no diagnosis-specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto-occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn.

LIMITATIONS: Undifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations.

CONCLUSIONS: The results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2018
Keywords
Adolescent depression, Anxiety, Brain connectivity, DTI, MRI, Mitochondrial DNA
National Category
Psychiatry Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-146327 (URN)10.1016/j.jad.2018.02.024 (DOI)000428033000038 ()29500956 (PubMedID)
Available from: 2018-04-05 Created: 2018-04-05 Last updated: 2018-06-09Bibliographically approved
diva2:1105196
Open this publication in new window or tab >>DTI-based connectome analysis of adolescents with major depressive disorder reveals hypoconnectivity of the right caudate
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2017 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 207, p. 18-25Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Adolescence is a vulnerable period for the onset of major depressive disorder (MDD). While some studies have shown white matter alterations in adolescent MDD, there is still a gap in understanding how the brain is affected at a network level.

METHODS: We compared diffusion tensor imaging (DTI)-based brain networks in a cohort of 57 adolescents with MDD and 41 well-matched healthy controls who completed self-reports of depression symptoms and stressful life events. Using atlas-based brain regions as network nodes and tractography streamline count or mean fractional anisotropy (FA) as edge weights, we examined weighted local and global network properties and performed Network-Based Statistic (NBS) analysis.

RESULTS: While there were no significant group differences in the global network properties, the FA-weighted node strength of the right caudate was significantly lower in depressed adolescents and correlated positively with age across both groups. The NBS analysis revealed a cluster of lower FA-based connectivity in depressed subjects centered on the right caudate, including connections to frontal gyri, insula, and anterior cingulate. Within this cluster, the most robust difference between groups was the connection between the right caudate and middle frontal gyrus. This connection showed a significant diagnosis by stress interaction and a negative correlation with total stress in depressed adolescents.

LIMITATIONS: Use of DTI-based tractography, one atlas-based parcellation, and FA values to characterize brain networks represent this study's limitations.

CONCLUSIONS: Our results allowed us to suggest caudate-centric models of dysfunctional processes underlying adolescent depression, which might guide future studies and help better understand and treat this disorder.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
MRI, Adolescence, Brain, Depression, Diffusion, Tractography, Connectomics, Graph theory, Neural network, Caudate
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-135695 (URN)10.1016/j.jad.2016.09.013 (DOI)000389088600003 ()27673479 (PubMedID)
Available from: 2017-06-02 Created: 2017-06-02 Last updated: 2018-06-09Bibliographically approved
Blom, E. H., Tymofiyeva, O., Chesney, M. A., Ho, T. C., Moran, P., Connolly, C. G., . . . Yang, T. T. (2017). Feasibility and Preliminary Efficacy of a Novel RDoC-Based Treatment Program for Adolescent Depression: "Training for Awareness Resilience and Action" (TARA)-A Pilot Study. Frontiers in Psychiatry, 7, Article ID 208.
Open this publication in new window or tab >>Feasibility and Preliminary Efficacy of a Novel RDoC-Based Treatment Program for Adolescent Depression: "Training for Awareness Resilience and Action" (TARA)-A Pilot Study
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2017 (English)In: Frontiers in Psychiatry, ISSN 1664-0640, E-ISSN 1664-0640, Vol. 7, article id 208Article in journal (Refereed) Published
Abstract [en]

Background: The novel group treatment program Training for Awareness, Resilience, and Action (TARA) was developed to target specific mechanisms based on neuroscience findings in adolescent depression and framed within the National Institute of Mental Health Research Domain Criteria. TARA contains training of autonomic and emotional self-regulation, interoceptive awareness, relational skills, and value-based committed action.

Methods: We performed a single-arm trial to test the feasibility and preliminary efficacy of TARA in reducing depression and anxiety levels and assessed whether the specific targeted domains of function reflected the hypothesized symptom change. Twenty-six adolescents (14–18 years old, 7 males and 19 females) participated in the 12-week group program. Assessment was performed before (T0), immediately after (T1), and 3 months after the end of TARA (T2).

Results: Significant improvement was seen in depression symptoms (Reynolds Adolescent Depression Scale Second Edition) between T0–T1 (t-value = −3.56, p = 0.002, CI = −6.64, −1.77) and T0–T2 (t-value = −4.17, p < 0.001, CI = −11.20, −3.75) and anxiety symptoms (Multidimensional Anxiety Scale for Children) between T0–T1 (t-value = −2.26, p = 0.033, CI = −4.61, −0.21) and T0–T2 (t-value = −3.06, p = 0.006, 95% confidence interval = −9.02, −1.73). Significant improvements in psychological flexibility, sleep, and mindfulness skills were also found between T0 and T2.

Limitations: The sample size was small without a control condition. The pilot design did not allow for testing the hypothesized brain changes and effect of TARA on relevant systemic biomarkers.

Conclusion: TARA is feasible in a sample of clinically depressed and/or anxious adolescents and preliminary efficacy was demonstrated by reduced depression and anxiety symptoms. The specific symptom and behavioral outcomes corresponded well with the hypothesized mechanisms of change.

Keywords
adolescent depression, Research Domain Criteria (RDoC), non-pharmacological, novel treatment velopment, emotion regulation, autonomic regulation, mindfulness-based, yoga-based
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-132027 (URN)10.3389/fpsyt.2016.00208 (DOI)000391853900001 ()
Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2018-06-09Bibliographically approved
Connolly, C. G., Ho, T. C., Henje Blom, E., LeWinn, K. Z., Sacchet, M. D., Tymofiyeva, O., . . . Yang, T. T. (2017). Resting-state functional connectivity of the amygdala and longitudinal changes in depression severity in adolescent depression. Journal of Affective Disorders, 207, 86-94
Open this publication in new window or tab >>Resting-state functional connectivity of the amygdala and longitudinal changes in depression severity in adolescent depression
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2017 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 207, p. 86-94Article in journal (Refereed) Published
Abstract [en]

Background: The incidence of major depressive disorder (MDD) rises during adolescence, yet the neural mechanisms of MDD during this key developmental period are unclear. Altered amygdala resting-state functional connectivity (RSFC) has been associated with both adolescent and adult MDD, as well as symptom improvement in response to treatment in adults. However, no study to date has examined whether amygdala RSFC is associated with changes in depressive symptom severity in adolescents.

Method: We examined group differences in amygdala RSFC between medication-naïve depressed adolescents (N=48) and well-matched healthy controls (N=53) cross-sectionally. We then longitudinally examined whether baseline amygdala RSFC was associated with change in depression symptoms three months later in a subset of the MDD group (N=24).

Results: Compared to healthy controls, depressed adolescents showed reduced amygdala-based RSFC with the dorsolateral prefrontal cortex (DLPFC)and the ventromedial prefrontal cortex (VMPFC). Within the depressed group, more positive baseline RSFC between the amygdala and insulae was associated with greater reduction in depression symptoms three months later.

Limitations: Only a subset of depressed participants was assessed at follow-up and treatment type and delivery were not standardized.

Conclusions: Adolescent depression may be characterized by dysfunction of frontolimbic circuits (amygdala-DLPFC, amygdala-VMPFC) underpinning emotional regulation, whereas those circuits (amygdala-insula) subserving affective integration may index changes in depression symptom severity and may therefore potentially serve as a candidate biomarker for treatment response. Furthermore, these results suggest that the biomarkers of MDD presence are distinct from those associated with change in depression symptoms over time.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Adolescent major depression, Resting-state, Amygdala, Dorsolateral prefrontal cortex, Ventromedial prefrontal cortex
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-135776 (URN)10.1016/j.jad.2016.09.026 (DOI)000389088600013 ()27716542 (PubMedID)
Available from: 2017-07-06 Created: 2017-07-06 Last updated: 2018-06-09Bibliographically approved
Ho, T. C., Zhang, S., Sacchet, M. D., Weng, H., Connolly, C. G., Henje Blom, E., . . . Yang, T. T. (2016). Fusiform gyrus dysfunction is associated with perceptual processing efficiency to emotional faces in adolescent depression: a model-based approach. Frontiers in Psychology, 7, Article ID 40.
Open this publication in new window or tab >>Fusiform gyrus dysfunction is associated with perceptual processing efficiency to emotional faces in adolescent depression: a model-based approach
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2016 (English)In: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078, Vol. 7, article id 40Article in journal (Refereed) Published
Abstract [en]

While the extant literature has focused on major depressive disorder (MDD) as being characterized by abnormalities in processing affective stimuli (e.g., facial expressions), little is known regarding which specific aspects of cognition influence the evaluation of affective stimuli, and what are the underlying neural correlates. To investigate these issues, we assessed 26 adolescents diagnosed with MDD and 37 well-matched healthy controls (HCL) who completed an emotion identification task of dynamically morphing faces during functional magnetic resonance imaging (fMRI). We analyzed the behavioral data using a sequential sampling model of response time (RT) commonly used to elucidate aspects of cognition in binary perceptual decision making tasks: the Linear Ballistic Accumulator (LBA) model. Using a hierarchical Bayesian estimation method, we obtained group-level and individual-level estimates of LBA parameters on the facial emotion identification task. While the MDD and HCL groups did not differ in mean RT, accuracy, or group-level estimates of perceptual processing efficiency (i.e., drift rate parameter of the LBA), the MDD group showed significantly reduced responses in left fusiform gyrus compared to the HCL group during the facial emotion identification task. Furthermore, within the MDD group, fMRI signal in the left fusiform gyrus during affective face processing was significantly associated with greater individual-level estimates of perceptual processing efficiency. Our results therefore suggest that affective processing biases in adolescents with MDD are characterized by greater perceptual processing efficiency of affective visual information in sensory brain regions responsible for the early processing of visual information. The theoretical, methodological, and clinical implications of our results are discussed.

Place, publisher, year, edition, pages
Lausanne: Frontiers Media S.A., 2016
Keywords
adolescent, depression, fMRI BOLD, face processing, fusiform gyrus, mood disorders, response time modeling
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-135780 (URN)10.3389/fpsyg.2016.00040 (DOI)000368981200001 ()26869950 (PubMedID)
Available from: 2017-07-06 Created: 2017-07-06 Last updated: 2018-06-09Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-5790-0518

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