{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/397965"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/397965","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Cardiovascular, autonomic and neuropathic physiology and their involvement in the extra-articular manifestations of hypermobility disorders","abstract":"Joint hypermobility has been recognised since the fourth century BC (1, 2), however, despite this there remains limited knowledge surrounding hypermobile Ehlers-Danlos Syndrome (hEDS (2017) (3), EDS Hypermobility Type (Villefranche 1998) (4), EDS III (Berlin 1988) (5)) and the less severe Hypermobility Spectrum Disorders (HSD (2017) (6), benign joint hypermobility syndrome (BJHS/JHS) (7)). In addition, although extra-articular manifestations associated with these syndromes including, but not limited to, postural orthostatic tachycardia syndrome (POTS) (8, 9), chronic pain (8) and local anaesthetic inefficacy (8, 10, 11) are recognised as being highly burdensome (3, 6, 9) research regarding their causes is scarce, limiting our understanding of their association with hypermobility and the development of evidence-based care. Therefore, this thesis focuses on potential pathophysiology relating hypermobility with the extra-articular manifestations and how this differs from the ‘normal’ physiology of healthy individuals. The initial chapters address the utility of a commercially available device (SphygmoCor, AtCor Medical) for the assessment of heart rate variability (HRV) as an indirect measure of autonomic nervous system (ANS) activity, followed by an examination of the effect of age and sex on HRV, recorded using this device in a large population of healthy volunteers, with the aim of developing a substantial normative HRV dataset in healthy individuals across a wide age-span. These results showed that older age was associated with lower HRV, attenuated parasympathetic activity and increased sympathetic activity. Furthermore, sex-specific differences were clearer in the young (≤40 years), likely due to confounding factors in the older age groups such as the menopause, with results suggestive of sympathetic dominance in young males compared to predominantly parasympathetic autonomic control in young females. In addition, this chapter contributes towards our understanding of age and sex related differences in HRV and its involvement in the genesis of young-onset hypertension which may be related to decreased parasympathetic nervous system activity. Chapters in the second half of this thesis focus on hypermobile patients with hEDS (or similar diagnoses) and the potential physiological mechanisms underlying the aforementioned extra-articular manifestations, research which is essential to improve the diagnosis and treatment of this patient population. Firstly, autonomic and cardiovascular function were explored in hypermobile patients with and without POTS alongside healthy control subjects to better understand physiological differences which may contribute towards the development of POTS in the hypermobile patient population. The HRV results suggest that hypermobile patients may have abnormal autonomic function regardless of whether they have a diagnosis of POTS since the hypermobile patient groups had HRV measurements indicative of lower parasympathetic and higher sympathetic activity than what is ‘normal’ according to healthy individuals. In addition, the cardiovascular results suggest that hypermobile patients with POTS are in a relatively vasoconstricted state, in light of their increased peripheral vascular resistance (PVR) when compared to healthy individuals, and that the hallmark orthostatic tachycardia of POTS is likely driven by low stroke volume (SV) in this patient population. Lastly, as the cardiovascular profile of hypermobile patients without POTS was not dissimilar to that of healthy individuals, it may be inferred that although POTS is a common comorbidity of hEDS it is unlikely that the cardiovascular physiology of hypermobile patients predisposes them to developing POTS. Hypermobile patients also underwent skin biopsies at the distal leg for the measurement of intraepidermal nerve fibre density (IENFd) in light of emerging evidence for reduced values in hEDS and HSD (or previous nomenclature) as well as possible associations with comorbidities such as small fibre neuropathy (SFN) (12-15) and POTS (16-20). However, results of this thesis show that reduced IENFd, according to published normative reference values (21), was present in only four of the ten hypermobile patients studied. Furthermore, although it was thought that reduced IENFd may play a role in the relationship between hypermobility and the extra-articular manifestations, this study demonstrates that this is not the case for all patients. Indeed, reduced IENFd was only found in half (n=3/6) of the hypermobile patients with POTS, and there was no notable pattern regarding IENFd and self-reported pain since all hypermobile patients (n=10) reported musculoskeletal pain in addition to nine also reporting chronic widespread pain. In addition, only three hypermobile patients who reported a history of local anaesthetic issues in addition to being unable to identify which leg had received local anaesthetic (EMLA) rather than placebo during the “pin-prick” test were found to have reduced IENFd. Therefore, although larger sample sizes are necessary to form a definitive conclusion, it is likely that reduced IENFd is not a universal characteristic of hEDS and its extra-articular manifestations. Finally, results suggest that hypermobile patients may have normal small-fibre function and abnormal large-fibre function, however it was not possible to confidently determine the causal mechanism of hEDS-related pain. Furthermore, conflicting results, namely those regarding small nerve fibre function assessed using thermal threshold testing as well as differences in pain responses to “pin-prick” stimuli highlight the need for further research. Nevertheless, a notable finding of this chapter was that although local anaesthetic (EMLA cream) was more effective in healthy volunteers compared to hypermobile patients, no patient demonstrated a total failure in response to local anaesthetic contrary to common anecdotal reports. In summary, this thesis broadly explores the potential physiological mechanisms related to POTS, chronic pain and local anaesthetic inefficacy within the hypermobile patient population with the work conducted during this PhD contributing to the currently scarce knowledge surrounding this topic. Furthermore, despite being disrupted by the COVID-19 pandemic, this work provides important foundations on which larger future studies can build upon in an aim to identify targets against which effective mechanism-specific therapies can be developed in addition to evidence-based management strategies.","abstract_html":"Joint hypermobility has been recognised since the fourth century BC (1, 2), however, despite this there remains limited knowledge surrounding hypermobile Ehlers-Danlos Syndrome (hEDS (2017) (3), EDS Hypermobility Type (Villefranche 1998) (4), EDS III (Berlin 1988) (5)) and the less severe Hypermobility Spectrum Disorders (HSD (2017) (6), benign joint hypermobility syndrome (BJHS/JHS) (7)). In addition, although extra-articular manifestations associated with these syndromes including, but not limited to, postural orthostatic tachycardia syndrome (POTS) (8, 9), chronic pain (8) and local anaesthetic inefficacy (8, 10, 11) are recognised as being highly burdensome (3, 6, 9) research regarding their causes is scarce, limiting our understanding of their association with hypermobility and the development of evidence-based care. Therefore, this thesis focuses on potential pathophysiology relating hypermobility with the extra-articular manifestations and how this differs from the ‘normal’ physiology of healthy individuals. The initial chapters address the utility of a commercially available device (SphygmoCor, AtCor Medical) for the assessment of heart rate variability (HRV) as an indirect measure of autonomic nervous system (ANS) activity, followed by an examination of the effect of age and sex on HRV, recorded using this device in a large population of healthy volunteers, with the aim of developing a substantial normative HRV dataset in healthy individuals across a wide age-span. These results showed that older age was associated with lower HRV, attenuated parasympathetic activity and increased sympathetic activity. Furthermore, sex-specific differences were clearer in the young (≤40 years), likely due to confounding factors in the older age groups such as the menopause, with results suggestive of sympathetic dominance in young males compared to predominantly parasympathetic autonomic control in young females. In addition, this chapter contributes towards our understanding of age and sex related differences in HRV and its involvement in the genesis of young-onset hypertension which may be related to decreased parasympathetic nervous system activity. Chapters in the second half of this thesis focus on hypermobile patients with hEDS (or similar diagnoses) and the potential physiological mechanisms underlying the aforementioned extra-articular manifestations, research which is essential to improve the diagnosis and treatment of this patient population. Firstly, autonomic and cardiovascular function were explored in hypermobile patients with and without POTS alongside healthy control subjects to better understand physiological differences which may contribute towards the development of POTS in the hypermobile patient population. The HRV results suggest that hypermobile patients may have abnormal autonomic function regardless of whether they have a diagnosis of POTS since the hypermobile patient groups had HRV measurements indicative of lower parasympathetic and higher sympathetic activity than what is ‘normal’ according to healthy individuals. In addition, the cardiovascular results suggest that hypermobile patients with POTS are in a relatively vasoconstricted state, in light of their increased peripheral vascular resistance (PVR) when compared to healthy individuals, and that the hallmark orthostatic tachycardia of POTS is likely driven by low stroke volume (SV) in this patient population. Lastly, as the cardiovascular profile of hypermobile patients without POTS was not dissimilar to that of healthy individuals, it may be inferred that although POTS is a common comorbidity of hEDS it is unlikely that the cardiovascular physiology of hypermobile patients predisposes them to developing POTS. Hypermobile patients also underwent skin biopsies at the distal leg for the measurement of intraepidermal nerve fibre density (IENFd) in light of emerging evidence for reduced values in hEDS and HSD (or previous nomenclature) as well as possible associations with comorbidities such as small fibre neuropathy (SFN) (12-15) and POTS (16-20). However, results of this thesis show that reduced IENFd, according to published normative reference values (21), was present in only four of the ten hypermobile patients studied. Furthermore, although it was thought that reduced IENFd may play a role in the relationship between hypermobility and the extra-articular manifestations, this study demonstrates that this is not the case for all patients. Indeed, reduced IENFd was only found in half (n=3/6) of the hypermobile patients with POTS, and there was no notable pattern regarding IENFd and self-reported pain since all hypermobile patients (n=10) reported musculoskeletal pain in addition to nine also reporting chronic widespread pain. In addition, only three hypermobile patients who reported a history of local anaesthetic issues in addition to being unable to identify which leg had received local anaesthetic (EMLA) rather than placebo during the “pin-prick” test were found to have reduced IENFd. Therefore, although larger sample sizes are necessary to form a definitive conclusion, it is likely that reduced IENFd is not a universal characteristic of hEDS and its extra-articular manifestations. Finally, results suggest that hypermobile patients may have normal small-fibre function and abnormal large-fibre function, however it was not possible to confidently determine the causal mechanism of hEDS-related pain. Furthermore, conflicting results, namely those regarding small nerve fibre function assessed using thermal threshold testing as well as differences in pain responses to “pin-prick” stimuli highlight the need for further research. Nevertheless, a notable finding of this chapter was that although local anaesthetic (EMLA cream) was more effective in healthy volunteers compared to hypermobile patients, no patient demonstrated a total failure in response to local anaesthetic contrary to common anecdotal reports. In summary, this thesis broadly explores the potential physiological mechanisms related to POTS, chronic pain and local anaesthetic inefficacy within the hypermobile patient population with the work conducted during this PhD contributing to the currently scarce knowledge surrounding this topic. Furthermore, despite being disrupted by the COVID-19 pandemic, this work provides important foundations on which larger future studies can build upon in an aim to identify targets against which effective mechanism-specific therapies can be developed in addition to evidence-based management strategies.","abstract_has_math":false,"creators":["Evans, Sarah"],"institution":"University of Cambridge","degree_name":null,"degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["McEniery, Carmel"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-06-17","date_published":"2025-06-17","updated_at":"2026-07-22T22:23:59Z","subjects":["cardiovascular","autonomic nervous system","neuropathic","hypermobility","hypermobile Ehlers-Danlos Syndrome","Heart Rate Variability","postural orthostatic tachycardia syndrome","Intraepidermal Nerve Fibre Density","local anaesthetic"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/7061a1d8-9614-4a9e-bdce-49f6a4430eb6/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.126933","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["McEniery, Carmel"]},{"key":"dc:creator","label":"Author","values":["Evans, Sarah"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-06-17"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/397965"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["cardiovascular","autonomic nervous system","neuropathic","hypermobility","hypermobile Ehlers-Danlos Syndrome","Heart Rate Variability","postural orthostatic tachycardia syndrome","Intraepidermal Nerve Fibre Density","local anaesthetic"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/7061a1d8-9614-4a9e-bdce-49f6a4430eb6/download","http://purl.org/NET/rdflicense/allrightsreserved"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.126933"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/d8275a0d-c5ed-44b6-bab7-294839ae6c81/download","https://www.repository.cam.ac.uk/bitstreams/c5fe6222-1247-4ec0-8008-156680b03155/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Joint hypermobility has been recognised since the fourth century BC (1, 2), however, despite this there remains limited knowledge surrounding hypermobile Ehlers-Danlos Syndrome (hEDS (2017) (3), EDS Hypermobility Type (Villefranche 1998) (4), EDS III (Berlin 1988) (5)) and the less severe Hypermobility Spectrum Disorders (HSD (2017) (6), benign joint hypermobility syndrome (BJHS/JHS) (7)). In addition, although extra-articular manifestations associated with these syndromes including, but not limited to, postural orthostatic tachycardia syndrome (POTS) (8, 9), chronic pain (8) and local anaesthetic inefficacy (8, 10, 11) are recognised as being highly burdensome (3, 6, 9) research regarding their causes is scarce, limiting our understanding of their association with hypermobility and the development of evidence-based care. Therefore, this thesis focuses on potential pathophysiology relating hypermobility with the extra-articular manifestations and how this differs from the ‘normal’ physiology of healthy individuals. The initial chapters address the utility of a commercially available device (SphygmoCor, AtCor Medical) for the assessment of heart rate variability (HRV) as an indirect measure of autonomic nervous system (ANS) activity, followed by an examination of the effect of age and sex on HRV, recorded using this device in a large population of healthy volunteers, with the aim of developing a substantial normative HRV dataset in healthy individuals across a wide age-span. These results showed that older age was associated with lower HRV, attenuated parasympathetic activity and increased sympathetic activity. Furthermore, sex-specific differences were clearer in the young (≤40 years), likely due to confounding factors in the older age groups such as the menopause, with results suggestive of sympathetic dominance in young males compared to predominantly parasympathetic autonomic control in young females. In addition, this chapter contributes towards our understanding of age and sex related differences in HRV and its involvement in the genesis of young-onset hypertension which may be related to decreased parasympathetic nervous system activity. Chapters in the second half of this thesis focus on hypermobile patients with hEDS (or similar diagnoses) and the potential physiological mechanisms underlying the aforementioned extra-articular manifestations, research which is essential to improve the diagnosis and treatment of this patient population. Firstly, autonomic and cardiovascular function were explored in hypermobile patients with and without POTS alongside healthy control subjects to better understand physiological differences which may contribute towards the development of POTS in the hypermobile patient population. The HRV results suggest that hypermobile patients may have abnormal autonomic function regardless of whether they have a diagnosis of POTS since the hypermobile patient groups had HRV measurements indicative of lower parasympathetic and higher sympathetic activity than what is ‘normal’ according to healthy individuals. In addition, the cardiovascular results suggest that hypermobile patients with POTS are in a relatively vasoconstricted state, in light of their increased peripheral vascular resistance (PVR) when compared to healthy individuals, and that the hallmark orthostatic tachycardia of POTS is likely driven by low stroke volume (SV) in this patient population. Lastly, as the cardiovascular profile of hypermobile patients without POTS was not dissimilar to that of healthy individuals, it may be inferred that although POTS is a common comorbidity of hEDS it is unlikely that the cardiovascular physiology of hypermobile patients predisposes them to developing POTS. Hypermobile patients also underwent skin biopsies at the distal leg for the measurement of intraepidermal nerve fibre density (IENFd) in light of emerging evidence for reduced values in hEDS and HSD (or previous nomenclature) as well as possible associations with comorbidities such as small fibre neuropathy (SFN) (12-15) and POTS (16-20). However, results of this thesis show that reduced IENFd, according to published normative reference values (21), was present in only four of the ten hypermobile patients studied. Furthermore, although it was thought that reduced IENFd may play a role in the relationship between hypermobility and the extra-articular manifestations, this study demonstrates that this is not the case for all patients. Indeed, reduced IENFd was only found in half (n=3/6) of the hypermobile patients with POTS, and there was no notable pattern regarding IENFd and self-reported pain since all hypermobile patients (n=10) reported musculoskeletal pain in addition to nine also reporting chronic widespread pain. In addition, only three hypermobile patients who reported a history of local anaesthetic issues in addition to being unable to identify which leg had received local anaesthetic (EMLA) rather than placebo during the “pin-prick” test were found to have reduced IENFd. Therefore, although larger sample sizes are necessary to form a definitive conclusion, it is likely that reduced IENFd is not a universal characteristic of hEDS and its extra-articular manifestations. Finally, results suggest that hypermobile patients may have normal small-fibre function and abnormal large-fibre function, however it was not possible to confidently determine the causal mechanism of hEDS-related pain. Furthermore, conflicting results, namely those regarding small nerve fibre function assessed using thermal threshold testing as well as differences in pain responses to “pin-prick” stimuli highlight the need for further research. Nevertheless, a notable finding of this chapter was that although local anaesthetic (EMLA cream) was more effective in healthy volunteers compared to hypermobile patients, no patient demonstrated a total failure in response to local anaesthetic contrary to common anecdotal reports. In summary, this thesis broadly explores the potential physiological mechanisms related to POTS, chronic pain and local anaesthetic inefficacy within the hypermobile patient population with the work conducted during this PhD contributing to the currently scarce knowledge surrounding this topic. Furthermore, despite being disrupted by the COVID-19 pandemic, this work provides important foundations on which larger future studies can build upon in an aim to identify targets against which effective mechanism-specific therapies can be developed in addition to evidence-based management strategies."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["c77dc1d4ced6a86d069e9c8ff3fcd8d5","267f969a30f80fbf6b00145f18670220","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["Cardiovascular, autonomic and neuropathic physiology and their involvement in the extra-articular manifestations of hypermobility disorders"]}]}],"canonical_facts":{"dc:contributor.advisor":["McEniery, Carmel"],"dc:creator":["Evans, Sarah"],"dc:date.issued":["2025-06-17"],"dc:description.abstract":["Joint hypermobility has been recognised since the fourth century BC (1, 2), however, despite this there remains limited knowledge surrounding hypermobile Ehlers-Danlos Syndrome (hEDS (2017) (3), EDS Hypermobility Type (Villefranche 1998) (4), EDS III (Berlin 1988) (5)) and the less severe Hypermobility Spectrum Disorders (HSD (2017) (6), benign joint hypermobility syndrome (BJHS/JHS) (7)). In addition, although extra-articular manifestations associated with these syndromes including, but not limited to, postural orthostatic tachycardia syndrome (POTS) (8, 9), chronic pain (8) and local anaesthetic inefficacy (8, 10, 11) are recognised as being highly burdensome (3, 6, 9) research regarding their causes is scarce, limiting our understanding of their association with hypermobility and the development of evidence-based care. Therefore, this thesis focuses on potential pathophysiology relating hypermobility with the extra-articular manifestations and how this differs from the ‘normal’ physiology of healthy individuals. The initial chapters address the utility of a commercially available device (SphygmoCor, AtCor Medical) for the assessment of heart rate variability (HRV) as an indirect measure of autonomic nervous system (ANS) activity, followed by an examination of the effect of age and sex on HRV, recorded using this device in a large population of healthy volunteers, with the aim of developing a substantial normative HRV dataset in healthy individuals across a wide age-span. These results showed that older age was associated with lower HRV, attenuated parasympathetic activity and increased sympathetic activity. Furthermore, sex-specific differences were clearer in the young (≤40 years), likely due to confounding factors in the older age groups such as the menopause, with results suggestive of sympathetic dominance in young males compared to predominantly parasympathetic autonomic control in young females. In addition, this chapter contributes towards our understanding of age and sex related differences in HRV and its involvement in the genesis of young-onset hypertension which may be related to decreased parasympathetic nervous system activity. Chapters in the second half of this thesis focus on hypermobile patients with hEDS (or similar diagnoses) and the potential physiological mechanisms underlying the aforementioned extra-articular manifestations, research which is essential to improve the diagnosis and treatment of this patient population. Firstly, autonomic and cardiovascular function were explored in hypermobile patients with and without POTS alongside healthy control subjects to better understand physiological differences which may contribute towards the development of POTS in the hypermobile patient population. The HRV results suggest that hypermobile patients may have abnormal autonomic function regardless of whether they have a diagnosis of POTS since the hypermobile patient groups had HRV measurements indicative of lower parasympathetic and higher sympathetic activity than what is ‘normal’ according to healthy individuals. In addition, the cardiovascular results suggest that hypermobile patients with POTS are in a relatively vasoconstricted state, in light of their increased peripheral vascular resistance (PVR) when compared to healthy individuals, and that the hallmark orthostatic tachycardia of POTS is likely driven by low stroke volume (SV) in this patient population. Lastly, as the cardiovascular profile of hypermobile patients without POTS was not dissimilar to that of healthy individuals, it may be inferred that although POTS is a common comorbidity of hEDS it is unlikely that the cardiovascular physiology of hypermobile patients predisposes them to developing POTS. Hypermobile patients also underwent skin biopsies at the distal leg for the measurement of intraepidermal nerve fibre density (IENFd) in light of emerging evidence for reduced values in hEDS and HSD (or previous nomenclature) as well as possible associations with comorbidities such as small fibre neuropathy (SFN) (12-15) and POTS (16-20). However, results of this thesis show that reduced IENFd, according to published normative reference values (21), was present in only four of the ten hypermobile patients studied. Furthermore, although it was thought that reduced IENFd may play a role in the relationship between hypermobility and the extra-articular manifestations, this study demonstrates that this is not the case for all patients. Indeed, reduced IENFd was only found in half (n=3/6) of the hypermobile patients with POTS, and there was no notable pattern regarding IENFd and self-reported pain since all hypermobile patients (n=10) reported musculoskeletal pain in addition to nine also reporting chronic widespread pain. In addition, only three hypermobile patients who reported a history of local anaesthetic issues in addition to being unable to identify which leg had received local anaesthetic (EMLA) rather than placebo during the “pin-prick” test were found to have reduced IENFd. Therefore, although larger sample sizes are necessary to form a definitive conclusion, it is likely that reduced IENFd is not a universal characteristic of hEDS and its extra-articular manifestations. Finally, results suggest that hypermobile patients may have normal small-fibre function and abnormal large-fibre function, however it was not possible to confidently determine the causal mechanism of hEDS-related pain. Furthermore, conflicting results, namely those regarding small nerve fibre function assessed using thermal threshold testing as well as differences in pain responses to “pin-prick” stimuli highlight the need for further research. Nevertheless, a notable finding of this chapter was that although local anaesthetic (EMLA cream) was more effective in healthy volunteers compared to hypermobile patients, no patient demonstrated a total failure in response to local anaesthetic contrary to common anecdotal reports. In summary, this thesis broadly explores the potential physiological mechanisms related to POTS, chronic pain and local anaesthetic inefficacy within the hypermobile patient population with the work conducted during this PhD contributing to the currently scarce knowledge surrounding this topic. 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