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Wallden, M., Dahlberg, G., Månflod, J., Knez, R., Winkvist, M., Zetterström, A., . . . Nyberg, F. (2024). Evaluation of 6 years of eHealth data in the alcohol use disorder field indicates improved efficacy of care. FRONTIERS IN DIGITAL HEALTH, 5, Article ID 1282022.
Open this publication in new window or tab >>Evaluation of 6 years of eHealth data in the alcohol use disorder field indicates improved efficacy of care
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2024 (English)In: FRONTIERS IN DIGITAL HEALTH, ISSN 2673-253X, Vol. 5, article id 1282022Article in journal (Refereed) Published
Abstract [en]

Background: Predictive eHealth tools will change the field of medicine, however long-term data is scarce. Here, we report findings on data collected over 6 years with an AI-based eHealth system for supporting the treatment of alcohol use disorder.

Methods: Since the deployment of Previct Alcohol, structured data has been archived in a data warehouse, currently comprising 505,641 patient days. The frequencies of relapse and caregiver-patient messaging over time was studied. The effects of both introducing an AI-driven relapse prediction tool and the COVID-19 pandemic were analyzed.

Results: The relapse frequency per patient day among Previct Alcohol users was 0.28 in 2016, 0.22 in 2020 and 0.25 in 2022 with no drastic change during COVID-19. When a relapse was predicted, the actual occurrence of relapse in the days immediately after was found to be above average. Additionally, there was a noticeable increase in caregiver interactions following these predictions. When caregivers were not informed of these predictions, the risk of relapse was found to be higher compared to when the prediction tool was actively being used. The prediction tool decreased the relapse risk by 9% for relapses that were of short duration and by 18% for relapses that lasted more than 3 days.

Conclusions: The eHealth system Previct Alcohol allows for high resolution measurements, enabling precise identifications of relapse patterns and follow up on individual and population-based alcohol use disorder treatment. eHealth relapse prediction aids the caregiver to act timely, which reduces, delays, and shortens relapses.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2024
Keywords
addiction, eHealth, prediction, relapse, alcohol
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-521807 (URN)10.3389/fdgth.2023.1282022 (DOI)001144319500001 ()38250054 (PubMedID)
Available from: 2024-01-29 Created: 2024-01-29 Last updated: 2024-01-29Bibliographically approved
Karlsson, B., Nyberg, F., Svärdsudd, K., Burell, G., Björkegren, K. & Kristiansson, P. (2023). Neuropeptide Y and measures of stress in a longitudinal study of women with the fibromyalgia syndrome. Scandinavian Journal of Pain, 23(1), 59-65
Open this publication in new window or tab >>Neuropeptide Y and measures of stress in a longitudinal study of women with the fibromyalgia syndrome
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2023 (English)In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 23, no 1, p. 59-65Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Neuropeptide Y is associated with stress in animal and human laboratory studies. However, data from clinical studies are scarce and no clinical longitudinal studies have been published. The aim of this clinical study was to assess the possible association between changes in the levels of pain, depression, and stress measures, on the one hand, and plasma neuropeptide Y levels, on the other.

METHODS: Forty-four women with the fibromyalgia syndrome were exposed to a Cognitive Behavioral Therapy intervention. Levels of the plasma neuropeptide Y as well as pain, depression, and stress measures were obtained at the start and at the end of the intervention, and after a further six month follow-up. Based on these data, a before-and-after analysis was performed.

RESULTS: Almost all measures of pain, depression, and stress improved during the study; specifically, variables measuring life control (coping), depression, and stress-related time urgency improved significantly. Moreover, during the same time period, the mean plasma neuropeptide Y level was reduced from 93.2 ± 38.8 fmol/mL before the Cognitive Behavioral Therapy to 75.6 ± 42.9 fmol/mL (p<0.001) at the end of the study.

CONCLUSIONS: After exposure to a Cognitive Behavioral Therapy intervention, levels of most of the pain, depression, and stress measures improved, half of them significantly, as did the levels of neuropeptide Y. This circumstance indicates a possible functional relationship between pain-depression-stress and neuropeptide Y.

Place, publisher, year, edition, pages
Walter de Gruyter, 2023
Keywords
depression, fibromyalgia, pain, plasma neuropeptide Y, stress, women
National Category
Applied Psychology General Practice
Identifiers
urn:nbn:se:uu:diva-494265 (URN)10.1515/sjpain-2022-0016 (DOI)000814052400001 ()35728621 (PubMedID)
Funder
Swedish Research Council, 9459Stiftelsen Söderström - Königska sjukhemmet, 2003-139Swedish Rheumatism Association, 51/04Uppsala University, UVF 2003/39Swedish Social Insurance Agency, 9459
Available from: 2023-01-16 Created: 2023-01-16 Last updated: 2024-01-11Bibliographically approved
Zetterström, A., Dahlberg, G., Lundqvist, S., Hämäläinen, M. D., Winkvist, M., Nyberg, F. & Andersson, K. (2022). Processing incomplete questionnaire data into continuous digital biomarkers for addiction monitoring. PLOS ONE, 17(7), Article ID e0271465.
Open this publication in new window or tab >>Processing incomplete questionnaire data into continuous digital biomarkers for addiction monitoring
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2022 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 7, article id e0271465Article in journal (Refereed) Published
Abstract [en]

Purpose: eHealth systems allow efficient daily smartphone-based collection of self-reported data on mood, wellbeing, routines, and motivation; however, missing data is frequent. Within addictive disorders, missing data may reflect lack of motivation to stay sober. We hypothesize that qualitative questionnaire data contains valuable information, which after proper handling of missing data becomes more useful for practitioners.

Methods: Anonymized data from daily questionnaires containing 11 questions was collected with an eHealth system for 751 patients with alcohol use disorder (AUD). Two digital continuous biomarkers were composed from 9 wellbeing questions (WeBe-i) and from two questions representing motivation/self-confidence to remain sober (MotSC-i). To investigate possible loss of information in the process of composing the digital biomarkers, performance of neural networks to predict exacerbation events (relapse) in alcohol use disorder was compared.

Results: Long short-term memory (LSTM) neural networks predicted a coming exacerbation event 1-3 days (AUC 0.68-0.70) and 5-7 days (AUC 0.65-0.68) in advance on unseen patients. The predictive capability of digital biomarkers and raw questionnaire data was equal, indicating no loss of information. The transformation into digital biomarkers enable a continuous graphical display of each patient's clinical course and a combined interpretation of qualitative and quantitative aspects of recovery on a time scale.

Conclusion: By transforming questionnaire data with large proportion of missing data into continuous digital biomarkers, the information captured by questionnaires can be more easily used in clinical practice. Information, assessed by the capability to predict exacerbation events of AUD, is preserved when processing raw questionnaire data into digital biomarkers.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2022
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-501092 (URN)10.1371/journal.pone.0271465 (DOI)000965303000084 ()35834544 (PubMedID)
Available from: 2023-05-05 Created: 2023-05-05 Last updated: 2023-05-05Bibliographically approved
Zelleroth, S., Nylander, E., Örtenblad, A., Stam, F., Nyberg, F., Grönbladh, A. & Hallberg, M. (2021). Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures. Journal of Steroid Biochemistry and Molecular Biology, 210, Article ID 105863.
Open this publication in new window or tab >>Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures
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2021 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 210, article id 105863Article in journal (Refereed) Published
Abstract [en]

The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.

Keywords
Anabolic androgenic steroids, Neurite outgrowth, Neurotoxicity, Primary cortical cell culture, Rat
National Category
Basic Medicine Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-439046 (URN)10.1016/j.jsbmb.2021.105863 (DOI)000652020500001 ()33677017 (PubMedID)
Funder
Kjell and Marta Beijer FoundationThe Swedish Brain FoundationSwedish Research Council, 9459
Available from: 2021-03-29 Created: 2021-03-29 Last updated: 2022-08-03Bibliographically approved
Nyman, J., Guo, N., Sandström, A., Hallberg, M., Nyberg, F. & Yu, L. (2021). The amino-terminal heptapeptide of the algesic substance P provides analgesic effect in relieving chronic neuropathic pain. European Journal of Pharmacology, 892, Article ID 173820.
Open this publication in new window or tab >>The amino-terminal heptapeptide of the algesic substance P provides analgesic effect in relieving chronic neuropathic pain
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2021 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 892, article id 173820Article in journal (Refereed) Published
Abstract [en]

Of painful conditions, somatic pain of acute nociceptive origin can be effectively managed clinically, while neuropathic pain of chronic neuropathy origin is difficult to control. For molecules involved in pain sensation, substance P (SP) is algesic, exacerbating painful sensation, while its amino-terminal fragment, heptapeptide SP(1-7), confers biological activities different from its full-length parent neuropeptide precursor. We previously demonstrated SP(1-7) interaction with pain processing to alleviate chronic pain. Here we evaluated SP(1-7) and its C-terminal amidated analogue SP(1-7) amide, together with SP and opioid agonist DAMGO. We tested mouse behaviors of both acute somatic pain in tail-flick latency assay, and neuropathic pain in sciatic nerve injury model of chronic constriction injury (CCI). DAMGO produced dose-dependent analgesia for somatic pain as expected, so did both SP(1-7) and its analogue SP(1-7) amide, while SP yielded the opposite effect of algesia, in a phenomenon we termed `contrintus', meaning 'opposite from within' to denote that two peptides of the same origin (SP and its metabolic fragment SP(1-7)) produced opposite effects. In CCI model, DAMGO showed a general reduction in allodynia sensitivity for both nerve-injured and normal paws, without selective effect for neuropathic pain, consistent with clinical observation that opioids are less effective for chronic neuropathic pain. On the other hand, both SP(1-7) and SP(1-7) amide displayed dose-dependent anti-allodynia effect that is selective for neuropathic pain. These findings suggest that SP(1-7) and its analogue may be useful for developing pharmaceuticals to treat neuropathic pain.

Place, publisher, year, edition, pages
ElsevierELSEVIER, 2021
Keywords
Substance P (SP), Amino-terminal fragment, SP(1-7), Neuropathic pain, Analgesia, ICR CD-1 mice, CCI-model
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-434721 (URN)10.1016/j.ejphar.2020.173820 (DOI)000606799900032 ()33345847 (PubMedID)
Funder
Swedish Research Council, 9459Kjell and Marta Beijer FoundationThe Swedish Brain Foundation
Available from: 2021-02-19 Created: 2021-02-19 Last updated: 2024-01-15Bibliographically approved
Zetterström, A., Hämäläinen, M. D., Winkvist, M., Söderquist, M., Öhagen, P., Andersson, K. & Nyberg, F. (2021). The Clinical Course of Alcohol Use Disorder Depicted by Digital Biomarkers. Frontiers in Digital Health, 3, Article ID 732049.
Open this publication in new window or tab >>The Clinical Course of Alcohol Use Disorder Depicted by Digital Biomarkers
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2021 (English)In: Frontiers in Digital Health, ISSN 2673-253X, Vol. 3, article id 732049Article in journal (Refereed) Published
Abstract [en]

Aims: This study introduces new digital biomarkers to be used as precise, objective tools to measure and describe the clinical course of patients with alcohol use disorder (AUD).

Methods: An algorithm is outlined for the calculation of a new digital biomarker, the recovery and exacerbation index (REI), which describes the current trend in a patient's clinical course of AUD. A threshold applied to the REI identifies the starting point and the length of an exacerbation event (EE). The disease patterns and periodicity are described by the number, length, and distance between EEs. The algorithms were tested on data from patients from previous clinical trials (n = 51) and clinical practice (n = 1,717).

Results: Our study indicates that the digital biomarker-based description of the clinical course of AUD might be superior to the traditional self-reported relapse/remission concept and conventional biomarkers due to higher data quality (alcohol measured) and time resolution. We found that EEs and the REI introduce distinct tools to identify qualitative and quantitative differences in drinking patterns (drinks per drinking day, phosphatidyl ethanol levels, weekday and holiday patterns) and effect of treatment time.

Conclusions: This study indicates that the disease state-level, trend and periodicity-can be mathematically described and visualized with digital biomarkers, thereby improving knowledge about the clinical course of AUD and enabling clinical decision-making and adaptive care. The algorithms provide a basis for machine-learning-driven research that might also be applied for other disorders where daily data are available from digital health systems.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
digital biomarker, recovery and exacerbation index, addiction monitoring index, maximum time between tests, identification of a relapse
National Category
Public Health, Global Health, Social Medicine and Epidemiology Substance Abuse
Identifiers
urn:nbn:se:uu:diva-510959 (URN)10.3389/fdgth.2021.732049 (DOI)001033291000001 ()34950928 (PubMedID)
Funder
Vinnova, 2014-03659
Available from: 2023-09-07 Created: 2023-09-07 Last updated: 2023-09-07Bibliographically approved
Nylander, E., Zelleroth, S., Nyberg, F., Gröndbladh, A. & Hallberg, M. (2021). The effects of morphine, methadone, and fentanyl on mitochondria: A live cell imaging study. Brain Research Bulletin, 171, 126-134
Open this publication in new window or tab >>The effects of morphine, methadone, and fentanyl on mitochondria: A live cell imaging study
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2021 (English)In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 171, p. 126-134Article in journal (Refereed) Published
Abstract [en]

The important role of mitochondria in maintaining normal brain cell function has been demonstrated in several neurodegenerative diseases where mitochondrial dysfunction is a prominent feature. Accumulating evidence indicates that opioids may induce neuronal cell death and inhibit neurogenesis, two factors that are dependent on normal mitochondrial function. The aim of the present study was to examine the effects of morphine, methadone, and fentanyl on mitochondrial morphology. Cells from the neuroblastoma/glioma hybrid cell-line NG108-15 were seeded on 96-well cell culture plates and treated with MitoTracker™ for 30 min prior to opioid treatment. Morphine, methadone, and fentanyl were added at various concentrations and images of mitochondria were acquired every 30 min for four hours using a high-content imaging device. The morphological parameters total mitochondrial area, mitochondrial network, number of mitochondrial objects, and the mean area of mitochondrial objects were analyzed using automated image analysis. Methadone and fentanyl, but not morphine, decreased the mitochondrial network, the number of mitochondrial objects, and increased the mean area of mitochondrial objects. Both methadone and fentanyl altered mitochondrial morphology with no effects seen from morphine treatment. These data suggest that methadone and fentanyl disrupt mitochondrial morphology, which may contribute to neuronal cell death.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Cell culture, Fentanyl, Live cell imaging, Methadone, Mitochondria, Morphine, Morphology, NG108-15, Opioids, Time-lapse
National Category
Cell and Molecular Biology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-393936 (URN)10.1016/j.brainresbull.2021.03.009 (DOI)000642263400003 ()33741459 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain FoundationKjell and Marta Beijer Foundation
Note

Title in dissertation list of papers: The effects of morphine, methadone, and fentanyl on mitochondrial morphology: a live cell imaging study

Available from: 2019-09-30 Created: 2019-09-30 Last updated: 2024-01-15Bibliographically approved
Hamalainen, M. D., Zetterström, A., Winkvist, M., Soderquist, M., Öhagen, P., Andersson, K. & Nyberg, F. (2020). Breathalyser-Based eHealth Data Suggest That Self-Reporting of Abstinence Is a Poor Outcome Measure for Alcohol Use Disorder Clinical Trials. Alcohol and Alcoholism, 55(3), 237-245
Open this publication in new window or tab >>Breathalyser-Based eHealth Data Suggest That Self-Reporting of Abstinence Is a Poor Outcome Measure for Alcohol Use Disorder Clinical Trials
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2020 (English)In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 55, no 3, p. 237-245Article, review/survey (Refereed) Published
Abstract [en]

Aims: To evaluate the efficacy and monitoring capabilities of a breathalyser-based eHealth system for patients with alcohol use disorder (AUD) and to investigate the quality and validity of timeline follow-back (TLFB) as outcome measure in clinical trials and treatment.

Methods: Patients (n = 115) were recruited to clinical trials from a 12-step aftercare programme (12S-ABS) and from hospital care with abstinence (HC-ABS) or controlled drinking (HC-CDR) as goal and randomly divided into an eHealth and a control group. The effect of the eHealth system was analysed with TLFB-derived primary outcomes-change in number of abstinent days (AbsDay) and heavy drinking days (HDDs) compared to baseline-and phosphatidyl ethanol (PEth) measurements. Validity and quality of TLFB were evaluated by comparison with breath alcohol content (BrAC) and eHealth digital biomarkers (DBs): Addiction Monitoring Index (AMI) and Maximum Time Between Tests (MTBT). TLFB reports were compared to eHealth data regarding reported abstinence.

Results: The primary outcome (TLFB) showed no significant difference between eHealth and control groups, but PEth did show a significant difference especially at months 2 and 3. Self-reported daily abstinence suffered from severe quality issues: of the 28-day TLFB reports showing full abstinence eHealth data falsified 34% (BrAC measurements), 39% (MTBT), 54% (AMI) and 68% (BrAC/MTBT/AMI). 12S-ABS and HC-ABS patients showed severe under-reporting.

Conclusions: No effect of the eHealth system was measured with TLFB, but a small positive effect was measured with PEth. The eHealth system revealed severe quality problems with TLFB, especially regarding abstinence-should measurement-based eHealth data replace TLFB as outcome measure for AUD?

National Category
Substance Abuse
Identifiers
urn:nbn:se:uu:diva-414257 (URN)10.1093/alcalc/agaa004 (DOI)000535877600001 ()32118260 (PubMedID)
Funder
Vinnova, 2014-03659
Available from: 2020-06-24 Created: 2020-06-24 Last updated: 2020-06-24Bibliographically approved
Nyberg, F. & Hallberg, M. (2020). Growing knowledge: How growth hormone improves learning. Acta Physiologica, 229(2), Article ID e13474.
Open this publication in new window or tab >>Growing knowledge: How growth hormone improves learning
2020 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 229, no 2, article id e13474Article in journal, Editorial material (Other academic) Published
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-414502 (URN)10.1111/apha.13474 (DOI)000537791100011 ()32271983 (PubMedID)
Available from: 2020-06-26 Created: 2020-06-26 Last updated: 2020-06-26Bibliographically approved
Nylander, E., Zelleroth, S., Stam, F., Nyberg, F., Grönbladh, A. & Hallberg, M. (2020). Growth hormone increases dendritic spine density in primary hippocampal cell cultures. Growth Hormone & IGF Research, 50, 42-47
Open this publication in new window or tab >>Growth hormone increases dendritic spine density in primary hippocampal cell cultures
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2020 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 50, p. 42-47Article in journal (Refereed) Published
Abstract [en]

Objective: Growth hormone (GH) is widely known for its peripheral effects during growth and development. However, numerous reports also suggest that GH exert pro-cognitive, restorative, and protective properties in the brain. In in vitro studies, the detection of dendritic spines, small protrusions extending from axons, can act as a marker for cognition-related function as spine formation is considered to be associated with learning and memory. Here we show that an acute 24-hour treatment of GH can increase dendritic spine density in primary hippocampal cell cultures.

Design: Primary hippocampal cells were harvested from embryonic Wistar rats and cultured for 14 days. Cells were treated with supra-physiological doses of GH (10-1000 nM) and subjected to a high-throughput screening protocol. Images were acquired and analyzed using automated image analysis and the number of spines, spines per neurite length, neurite length, and mean area of spines, was reported.

Results: GH treatment increased dendritic spine density using the highest dose while the general health of the cells was unaffected.

Conclusion: The results from the present study further confirms a potential role of GH in the treatment of cognitive dysfunction.

Keywords
growth hormone, dendritic spines, spine formation, cognition, memory, high-throughput screening, hippocampus, cell culture, in vitro
National Category
Cell and Molecular Biology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-393938 (URN)10.1016/j.ghir.2019.12.003 (DOI)000518868300006 ()31862540 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council, 9459
Available from: 2019-09-30 Created: 2019-09-30 Last updated: 2020-04-05Bibliographically approved
Projects
Peptidergic mechanisms involved in the development of drug dependence and of significance for therapeutical strategies [2008-03151_VR]; Uppsala UniversityPeptidergic mechanism in drug addiction and the development of rational strategies for the treatment of drug addicts and repairements of drug-induced brain damages [2011-04579_VR]; Uppsala UniversityNetwork: Uppsala University forum for research on addiction to medical products and illegal drugs - Doping and pathological gambling [2012-02033_Forte]; Uppsala UniversityCentral mechanisms in drug addiction and development of rational strategies for treatment and restoration of drug-induced brain damages [2014-03489_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7142-3479

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