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• Public defence: 2019-10-18 09:00 Berzeliussalen, Linköping
Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Dementia diagnostics in primary care: with a focus on cognitive testing2019Doctoral thesis, comprehensive summary (Other academic)

Background

Age is the greatest risk factor for developing dementia and the total number of people aged 60 years and above is expected to more than double globally from 2013 to 2050 (1). Primary health care (PHC) is important for basic diagnostic evaluations. Objective test measurements have been shown to be more reliable than a patient's subjective memory complaints in dementia assessments (2). However, several studies indicate the low use of objective cognitive screening tools in dementia diagnostics in PHC (3). Some general practitioners (GPs) do not perceive today’s cognitive instruments as helpful in the diagnostic process and administration problems have been reported in PHC (4, 5).

The overall aim of this thesis was to investigate the accuracy of several cognitive tests used in dementia assessments in PHC, especially among older patients: A Quick Test of Cognitive Speed (AQT), Cognistat and Cognitive Assessment Battery (CAB). The normative values of the Mini Mental Status Examination (MMSE) in the oldest old was also studied.

Methods

The studies included in this thesis are from two different study populations.

• Studies I, II and IV. Patients with and without cognitive symptoms were recruited from four primary health care centres in Sweden between 2007 and 2009.
• Study III. The Elderly in Linköping Screening Assessment (ELSA 85) cohort-population examined people born in 1922 in the municipality of Linköping, Sweden.

Results

Study I. Results showed that AQT is a usable test for dementia diagnosis in PHC. Sensitivity for AQT is superior to the Clock Drawing Test (CDT), equivalent to MMSE and the combination MMSE and CDT. The AUC for AQT was 0.773, valued good enough.

Study II. Overall, the results for Cognistat in this study are superior to MMSE and CDT, also in combination. Cognistat is promising for improved dementia diagnosis in PHC with a quick and easily administered multi-domain test for dementia assessments.

Study III. This study presents valuable information about normative MMSE data for the oldest patients. Results, suggest using the 25th percentile in MMSE of 25 to 26 points, and indicate that MMSE 26 is as a reasonable cut-off for cognitive decline and further medical evaluation in older persons aged from 85 to 93 years.

Study IV. In summary, the additive value of the CAB test in dementia investigations in PHC is not obvious. In addition to questionable accuracy, the test is quite time consuming and normative values are scarce. By introducing the numerical sum (CABsum) the accuracy was increased.

Conclusion

In conclusion, objective cognitive tests are an important part of dementia diagnosis in PHC and there is a need for improved instruments and norm-values. From our results, several cognitive quick tests are usable in PHC - MMSE, AQT and Cognistat - but they have some disadvantages. MMSE 26 is a reasonable cut-off for cognitive decline in the oldest patients 85 to 93 years from a well-educated population with quite good socioeconomic. There is a great interest in finding short and better multi-domain instruments but the additive value of CAB in dementia investigations in PHC is questionable.

1. A Quick Test of Cognitive Speed (AQT): Usefulness in dementia evaluations in primary care
Open this publication in new window or tab >>A Quick Test of Cognitive Speed (AQT): Usefulness in dementia evaluations in primary care
2013 (English)In: Scandinavian Journal of Primary Health Care, ISSN 0281-3432, E-ISSN 1502-7724, Vol. 31, no 1, p. 13-19Article in journal (Refereed) Published
##### Abstract [en]

Objective. To validate A Quick Test of Cognitive Speed (AQT) as an instrument in diagnostic dementia evaluations against final clinical diagnosis and compare AQT with the Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT) in primary care. Design. Primary health care cohort survey. Setting. Four primary health care centres and a geriatric memory clinic in Sweden. Patients. 81 patients (age 65 and above) were included: 52 with cognitive symptoms and 29 presumed cognitively healthy. None of the patients had a previous documented dementia diagnosis. All patients performed MMSE, CDT, and AQT at the primary health care clinic and were referred for extensive neuropsychological testing at a memory clinic. AQT was validated against final clinical diagnosis determined by a geriatric specialist and a neuropsychologist. Main outcome measures. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratios, correlation data, and receiver operating characteristic (ROC). Results. For MMSE, sensitivity and specificity was 0.587 and 0.909; CDT 0.261 and 0.879; and AQT 0.783 and 0.667, respectively. For the combination of MMSE and CDT, sensitivity and specificity was 0.696 and 0.788, for MMSE and AQT 0.913 and 0.636. The ROC curve for AQT showed an area under curve (AUC) of 0.773. Conclusion. Our results suggest AQT is a usable test for dementia assessments in primary care. Sensitivity for AQT is superior to CDT, equivalent to MMSE, and comparable to the combination MMSE and CDT. MMSE in combination with AQT improves sensitivity. Because AQT is user-friendly and quickly administered, it could be applicable for primary care settings.

##### Place, publisher, year, edition, pages
Informa Healthcare, 2013
##### Keywords
Alzheimers disease, dementia, general practice, A Quick Test of Cognitive Speed (AQT), Clock Drawing Test (CDT), Mini-Mental Status Examination (MMSE), primary care, Sweden
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-89797 (URN)10.3109/02813432.2012.751699 (DOI)000314653700005 ()
##### Note

Funding Agencies|Swedish Brain Power||ALF Grants||County Council of Ostergotland||

Available from: 2013-03-07 Created: 2013-03-07 Last updated: 2019-09-20
2. Clinical Utility of Cognistat in Multiprofessional Team Evalutations of Patients with Cognitive Impairment in Swedish Primary Care
Open this publication in new window or tab >>Clinical Utility of Cognistat in Multiprofessional Team Evalutations of Patients with Cognitive Impairment in Swedish Primary Care
2014 (English)In: International Journal of Family Medicine, ISSN 2090-2042, E-ISSN 2090-2050, Vol. 2014, p. 649253-Article in journal (Refereed) Published
##### Abstract [en]

Background. Diagnostic evaluations of dementia are often performed in primary health care (PHC). Cognitive evaluation requires validated instruments.

Objective. To investigate the diagnostic accuracy and clinical utility of Cognistat in a primary care population.

Methods. Participants were recruited from 4 PHC centres; 52 had cognitive symptoms and 29 were presumed cognitively healthy. Participants were tested using the Mini-Mental State Examination (MMSE), the Clock Drawing Test (CDT), and Cognistat. Clinical diagnoses, based on independent neuropsychological examination and a medical consensus discussion in secondary care, were used as criteria for diagnostic accuracy analyses.

Results. The sensitivity, specificity, positive predictive value, and negative predictive value were 0.85, 0.79, 0.85, and 0.79, respectively, for Cognistat; 0.59, 0.91, 0.90, and 0.61 for MMSE; 0.26, 0.88, 0.75, and 0.46 for CDT; 0.70, 0.79, 0.82, and 0.65 for MMSE and CDT combined. The area under the receiver operating characteristic curve was 0.82 for Cognistat, 0.75 for MMSE, 0.57 for CDT, and 0.74 for MMSE and CDT combined.

Conclusions. The diagnostic accuracy and clinical utility of Cognistat was better than the other tests alone or combined. Cognistat is well adapted for cognitive evaluations in PHC and can help the general practitioner to decide which patients should be referred to secondary care.

##### Place, publisher, year, edition, pages
Hindawi Publishing Corporation, 2014
##### National Category
Clinical Medicine
##### Identifiers
urn:nbn:se:liu:diva-107048 (URN)10.1155/2014/649253 (DOI)
Available from: 2014-06-04 Created: 2014-06-04 Last updated: 2019-09-20Bibliographically approved
3. Age-Normative MMSE Data for Older Persons Aged 85 to 93 in a Longitudinal Swedish Cohort
Open this publication in new window or tab >>Age-Normative MMSE Data for Older Persons Aged 85 to 93 in a Longitudinal Swedish Cohort
2019 (English)In: Journal of The American Geriatrics Society, ISSN 0002-8614, E-ISSN 1532-5415, Vol. 67, no 3, p. 534-538Article in journal (Refereed) Published
##### Abstract [en]

BACKGROUND/OBJECTIVES: Normative Mini-mental state examination (MMSE) reference values in elderly are scarce. Therefore, the aim is to present normative MMSE values for 85-93 year olds.

DESIGN: A longitudinal age cohort study.

SETTING: A population study of the residents in the municipality of Linköping, Sweden.

PARTICIPANTS: Residents (n = 650) born in 1922 during the course of 2007. In total, 374 individuals participated and were tested with MMSE at age 85, 280 of these were willing and able to also participate at age 86, 107 at age 90 and 51 at age 93.

MEASUREMENTS: MMSE, from 0-30, with lower scores denoting more impaired cognition.

RESULTS: Median MMSE values for the total population over the ages 85, 86, 90 and 93 years was 28 for all ages investigated. The 25th percentile values were 26, 26, 26 and 27, respectively. For a "brain healthy" sub-group median values were 28, 29, 28, and 28. The 25th percentile values were 27, 28, 26 and 27, respectively. Comparisons for age-effects showed no differences when all individuals for each age group were compared. When only the individuals reaching 93 years of age (n = 50) were analyzed, there was a significant lowering of MMSE in that age group.

CONCLUSION: The literature is variable and in clinical practice a low (24) MMSE cut off is often used for possible cognitive impairment in old age. The present data indicate that MMSE 26 is a reasonable cut off for possible cognitive decline in older persons up to the age of 93. J Am Geriatr Soc 67:534-538, 2019.

##### Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2019
##### Keywords
aged 80 and over, dementia test, mental status
Geriatrics
##### Identifiers
urn:nbn:se:liu:diva-160367 (URN)10.1111/jgs.15694 (DOI)000461567700019 ()30536796 (PubMedID)2-s2.0-85058337422 (Scopus ID)
Available from: 2019-09-20 Created: 2019-09-20 Last updated: 2019-09-30Bibliographically approved
4. Accuracy of the Cognitive Assessment Battery in a Primary Care Population
Open this publication in new window or tab >>Accuracy of the Cognitive Assessment Battery in a Primary Care Population
2019 (English)In: Dementia and geriatric cognitive disorders extra, E-ISSN 1664-5464, Vol. 9, no 2, p. 294-301Article in journal (Refereed) Published
##### Abstract [en]

Background: There are several cognitive assessment tools used in primary care, e.g., the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment. The Cognitive Assessment Battery (CAB) was introduced as a sensitive tool to detect cognitive decline in primary care. However, primary care validation is lacking. Therefore, we investigated the accuracy of the CAB in a primary care population.

Objective: To investigate the accuracy of the CAB in a primary care population.

Methods: Data from 46 individuals with cognitive impairment and 33 individuals who visited the primary care with somatic noncognitive symptoms were analyzed. They were investigated with the MMSE, the CAB, and a battery of neuropsychological tests; they also underwent consultation with a geriatric specialist. The accuracy of the CAB was assessed using c-statistics and the area under the receiver operating characteristic curve (AUC) was used to quantify the binary outcomes (“no cognitive impairment” or “cognitive impairment”).

Results: The “cognitive impairment” group was significantly different from the unimpaired group for all the subtests of the CAB. When accuracy was based on binary significant reduction or not in one or several domains of the CAB, the AUC varied between 0.685 and 0.772. However, when a summation or logistic regression of several subcategories was performed, using the numerical values for each subcategory, the AUC was >0.9. For comparison, the AUC for the MMSE was 0.849.

Conclusions: The accuracy of the CAB in a primary care population is poor to good when using binary cutoffs. Accuracy can be improved to high when using a summation or logistic regression of the numerical data of the subcategories. Considering CAB time, lack of adequate age norms, and a good accuracy for the MMSE, implementation of the CAB in primary care is not recommended at present based on the results of this study.

##### Place, publisher, year, edition, pages
S. Karger, 2019
##### Keywords
Primary care cognitive tests, Cognitive Assessment Battery, Cognitive assessment tools
##### National Category
Neurology Geriatrics
##### Identifiers
urn:nbn:se:liu:diva-160370 (URN)10.1159/000501365 (DOI)2-s2.0-85071030454 (Scopus ID)
Available from: 2019-09-20 Created: 2019-09-20 Last updated: 2019-09-30Bibliographically approved
• Public defence: 2019-10-18 13:00 Berzeliussalen, Linköping
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
Biomarkers and Disease Activity in Multiple Sclerosis: A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis2019Doctoral thesis, comprehensive summary (Other academic)

This thesis focuses on disease activity in clinically isolated syndrome (CIS) and newly diagnosed relapsing remitting multiple sclerosis (RRMS). The papers are based on data from 41 patients in a prospective longitudinal cohort study. All patients were untreated at baseline. Age- and sex-matched healthy controls (n=22) for blood and cerebrospinal fluid (CSF) samples were recruited from blood donors.

Paper I evaluated the prognostic value of baseline levels of CXCL1, CXCL8, CXCL10, CXCL13, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9) and osteopontin in CSF in relation to disease activity during the first two years of follow-up. Disease activity was defined as clinical relapses, new T2 lesions in brain magnetic resonance imaging (MRI) and/or sustained Expanded Disability Status Scale (EDSS) progression. Absence of these three signs of disease activity was called no evidence of disease activity (NEDA-3). Logistic regression analysis showed that NFL in CSF was the best predictive marker of disease activity and correctly classified 93% of the patients with evidence of disease activity during two years of follow-up and 67% of those without.

Paper II presented four year follow-up data from the cohort and also included brain volume data as well as serum levels of NFL. The correlation between NFL in CSF and serum was fairly strong (r=0.74, p<0.001). NFL in CSF was associated with new T2 lesions as well as with brain volume loss, whereas CHI3L1 in CSF was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22 and MMP-9 in CSF were mainly associated with new T2 lesions. Taken together, paper I and II confirm and extend the knowledge of NFL as a useful biomarker in CIS and RRMS and suggests that NFL, rather than total brain volume loss, could be included in an expanded NEDA concept and used in clinical monitoring of disease activity/treatment effect. Although serum levels of NFL were correlated with the corresponding CSF levels, CSF-NFL showed a stronger association to subsequent disease activity (NEDA-3).

Paper III addressed the patients´ self-reported Modified Fatigue Impact Scale (MFIS) scores in relation to other cohort study data. MFIS scores correlated with other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36) scores (Spearman´s rho 0.45-0.78, all p≤0.01)) but not with EDSS ratings, number of T2 lesions, total brain volume or NFL levels, indicating that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters.

Paper IV focused on the complement factors C1q, C3, C3a and sC5b-9 in CSF and plasma. CSFC1q was significantly higher in patients than in controls at baseline. The subgroup of patients with ongoing relapse at baseline also had higher levels of CSF-C3a than controls. Baseline levels of CSF-C1q and CSF-C3a correlated significantly with several pro-inflammatory chemokines as well as with MMP-9, CHI3L1 and NFL in CSF. Baseline CSF-C3a also correlated significantly with the number of T2 lesions and Gadolinium enhancing lesions in brain MRI at baseline, as well as with the number of new T2 lesions during follow-up. This study indicates that the complement system is involved already at early stages of MS. It also suggests that especially CSF-C1q and CSF-C3a levels are associated with other neuroinflammatory and neurodegenerative markers and that CSF-C3a levels may carry some prognostic information.

1. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis
Open this publication in new window or tab >>Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis
2017 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 24, no 5, p. 703-712Article in journal (Refereed) Published
##### Abstract [en]

Background and purpose: Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS. Methods: Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study. Results: In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results. Conclusions: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.

WILEY, 2017
##### Keywords
biomarker; clinically isolated syndrome; disease activity; multiple sclerosis; neurofilament light chain
Neurology
##### Identifiers
urn:nbn:se:liu:diva-137379 (URN)10.1111/ene.13274 (DOI)000399704400010 ()28261960 (PubMedID)
##### Note

Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Linkoping University, Sweden; University Hospital Linkoping, Sweden; Novartis; Torsten Soderberg foundation; Royal Academy of Sciences, Sweden

Available from: 2017-05-18 Created: 2017-05-18 Last updated: 2019-10-07
2. Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis
Open this publication in new window or tab >>Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis
2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 209Article in journal (Refereed) Published
##### Abstract [en]

Background: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. Methods: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI (R)) were recorded during 4 years of follow-up. Results: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p amp;lt; 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. Conclusions: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.

BMC, 2018
##### Keywords
Multiple sclerosis; Clinically isolated syndrome; Disease activity; Neurofilament light chain; CHI3L1; CXCL10; Brain volume
Neurology
##### Identifiers
urn:nbn:se:liu:diva-150263 (URN)10.1186/s12974-018-1249-7 (DOI)000439133500001 ()30021640 (PubMedID)
##### Note

Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Linkoping University; University Hospital of Linkoping, Sweden; Novartis; Torsten Soderberg Foundation; Royal Academy of Sciences, Sweden

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2019-10-07
• Public defence: 2019-10-25 10:00 Planck, Linköping
Immigrant entrepreneurs in a changing institutional context: a mixed embeddedness approach2019Doctoral thesis, comprehensive summary (Other academic)

Immigrant entrepreneurs are known to be heterogeneous in terms of available resources and entrepreneurial outcomes. However, this heterogeneity, as well as immigrant entrepreneurs’ embeddedness in social networks and the institutional context of high-income welfare states such as Sweden, remains understudied. Sweden represents an interesting case as a popular immigration destination which liberalized its migration policy for entrepreneurs and changed other regulations, encouraging immigrant entrepreneurship after 2008.

Theoretically, the dissertation contributes to the mixed embeddedness approach to immigrant entrepreneurship by considering three stages of the entrepreneurial process – entry, performance, and potential exit – in a changing institutional environment.

Methodologically, the dissertation operationalizes the mixed embeddedness approach by studying these three stages – entry (propensity to start a business), performance (entrepreneurial incomes), and potential exit (duration in business) – among different categories of immigrants. Explanatory factors are drawn from three levels of analysis: institutional change (macro), social, ethnic and family networks (meso), and the individual’s human capital (micro). A range of statistical tools is used for empirical analyses: Difference-in-difference methods in combination with Coarsened Exact Matching and Oaxaca-Blinder decomposition are used to investigate the influence of institutional change on entrepreneurial entry and performance. Survival models based on Cox regression are applied to investigate the influence of social and family ties on the likelihood of entrepreneurial exit. A combination of clustering and association analysis allows heterogeneity to be approached via the categorization of immigrant entrepreneurs.

Empirically, based on rich data from Swedish registers, the dissertation reveals that the propensity to start businesses in expanding ICT industries among labour immigrants was increased, and performance in terms of income among new immigrant entrepreneurs was improved after institutional change, compared to earlier. It also stresses that family networks mitigate a lack of other resources for refugee entrepreneurs, allowing them to stay in business longer. Two main categories of new immigrant entrepreneurs were distinguished in the overall heterogeneous population.

The dissertation consists of four papers and an introductory chapter.

1. Entrepreneurial response to changing opportunity structures: Self-selection and incomes among new immigrant entrepreneurs in Sweden
Open this publication in new window or tab >>Entrepreneurial response to changing opportunity structures: Self-selection and incomes among new immigrant entrepreneurs in Sweden
2019 (English)In: International Journal of Entrepreneurial Behaviour & Research, ISSN 1355-2554, E-ISSN 1758-6534, Vol. 25, no 5, p. 859-879Article in journal (Refereed) Published
##### Abstract [en]

Purpose

The purpose of this paper is to analyse how the introduction of a liberalised regime for labour immigration in Sweden affected the self-selection of new immigrant entrepreneurs and to what extent the changes in entrepreneurial income among new immigrants was due to self-selection or to a changing business environment.

Design/methodology/approach

Based on rich microdata from Swedish administrative registers, this paper investigates how incomes changed during the years before and after the migration policy reform. By decomposing the income differential of new immigrant entrepreneurs arriving before and after the reform, this study estimates the contribution of a changed composition of migrants to the changing entrepreneurial income.

Findings

Entrepreneurial income among self-employed new immigrants improved after the reform, narrowing the immigrant–native income gap, while among employees, the income gap remained during the whole period of the study. Out of the total 10.9 per cent increase in log income, the authors find that 2.7 per cent was due to selectivity, i.e., changing characteristics of new immigrant entrepreneurs. The remaining 8.2 per cent was due to increased returns to characteristics, i.e., the characteristics of new immigrant entrepreneurs were better rewarded in the markets in the latter period. Hence, increases in entrepreneurial income among new immigrants were due both to self-selection and changes in the business environment.

Practical implications

The authors find that the migration policy reform had the effect of attracting successful immigrant entrepreneurs. Hence, the findings have implications for migration policy as well as for growth and employment policy.

Originality/value

This paper reveals a positive trend regarding income from the entrepreneurship of new immigrants after the liberalisation of labour immigration policy in Sweden. Theoretically and methodologically, the authors combine self-selection theory and the mixed-embeddedness perspective in a novel way, using rich data and a quantitative approach.

##### Place, publisher, year, edition, pages
Emerald Group Publishing Limited, 2019
##### Keywords
Entrepreneurship, Migration, Entrepreneurial income, Self-selection
##### Identifiers
urn:nbn:se:liu:diva-153309 (URN)10.1108/IJEBR-02-2018-0090 (DOI)000479278800006 ()2-s2.0-85058087573 (Scopus ID)
##### Note

Funding agencies: Marianne and Marcus Wallenberg Foundation; Handelsbanken Research Foundations

Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2019-09-25Bibliographically approved
• Public defence: 2019-10-25 10:15 ACAS, A-huset, Linköping
Linköping University, Department of Management and Engineering, Energy Systems. Linköping University, Faculty of Science & Engineering.
Energy renovation of multi-family buildings in Sweden: An evaluation of life cycle costs, indoor environment and primary energy use, and a comparison with constructing a new building2019Doctoral thesis, comprehensive summary (Other academic)

Residential buildings account for 27% of the final energy use in the European Union. In cold climates, space heating represents the largest proportion of the energy demand in residential buildings. By implementing energy efficiency measures (EEMs) in existing buildings, energy use can be significantly reduced. The Energy Performance of Buildings Directive states that renovations of buildings offer an opportunity to improve energy efficiency. Renovations that include measures implemented with the specific purpose of reducing energy use are referred to as energy renovations. In addition to improving energy efficiency, an energy renovation can also improve the indoor environment. Sweden, like many other European countries, faces the challenge of renovating an ageing building stock with poor energy performance. Improving energy efficiency and performing energy renovations in a cost-effective manner is central, and optimization approaches are often used to identify suitable EEMs and energy renovation approaches. New buildings usually feature better energy performance compared to older buildings, and one approach for reducing energy use in the building sector could be to demolish old buildings with poor thermal performance and build new buildings with better thermal performance.

The aim of this thesis is to evaluate energy renovations of multi-family buildings with regard to space heating demand, life cycle costs, indoor environment and primary energy use. The choice between energy renovation of a multi-family building and the demolition and construction of a new one is also investigated with regard to life cycle costs (LCCs). A Swedish multi-family building in which energy renovation has been carried out is used as a case study. The building was originally constructed in 1961 and has a lightweight concrete construction. The renovation included improving the thermal performance of the building envelope and replacing the exhaust air ventilation system with a mechanical supply and exhaust air ventilation system with heat recovery.

The methods used in the studies include dynamic whole building energy simulation, life cycle cost analysis and optimizations, and a questionnaire on indoor environment perception. Extensive field measurements have been performed in the building prior to and after renovation to provide input data and to validate numerical predictions. In addition to the studied building, the analysis of the choice between energy renovation and the demolition and construction of a new building includes three other building construction types, representing common Swedish building types from the 1940s, 1950s and 1970s.

The analysis shows that the energy renovation led to a 44% reduction in space heating demand and an improved indoor environment. The indoor temperature was higher after the renovation and the perception of the indoor temperature, air quality and noise in the building improved. The EEMs implemented as part of the energy renovation have a slightly higher LCC than the optimal combinations of EEMs identified in the LCC optimization. It is not cost-optimal to implement any EEMs in the building if the lowest possible LCC is the objective function. Attic insulation has a low cost of implementation but has limited potential in the studied building with its relatively good thermal properties. Insulation of the façade is an expensive measure, but has a great potential to reduce heat demand because of the large façade area. Façade insulation is thus required to achieve significant energy savings. Heat recovery in the ventilation system is cost-effective with an energy saving target above 40% in the studied building. The primary energy factors in the Swedish Building Code favor ground source heat pumps as a heat supply system in the studied building.

The LCC of renovation is lower compared to demolishing and constructing a new building. A large proportion of the LCC of demolition and new construction relates to the demolition of the existing building. In a building with a high internal volume to floor area ratio, it is not always possible to renovate to the same energy performance level as when constructing a new building. A more ambitious renovation approach is also needed compared to a building with a smaller volume to floor area ratio.

1. Energy Performance of a Renovated Multi-Family Building in Sweden
Open this publication in new window or tab >>Energy Performance of a Renovated Multi-Family Building in Sweden
2017 (English)In: Mediterranean Green Buildings & Renewable Energy / [ed] Sayigh, Ali, Springer International Publishing , 2017, p. 531-539Conference paper, Published paper (Refereed)
##### Abstract [en]

Increased attention is being directed towards reducing energy use in buildings, and implementing energy-saving measures when renovating buildings has become of central importance. The aim of this chapter is to study the effects on heat demand of a deep renovation of a Swedish post-war, multi-family building. The studied building was renovated in 2014, and the renovation measures included thermal improvement of the climate envelope and installation of a mechanical supply and exhaust air ventilation system with heat recovery. The effect on heat demand is studied through a whole-building energy simulation, using IDA Indoor Climate and Energy. The IDA model is empirically validated with regard to its ability to predict indoor temperature and energy use. The results indicate a technical potential for a 50.3 % reduction of heat demand from implemented renovation measures, but measured data indicate that actual energy use is around 15 % higher than the technical potential. The reasons for this gap could be overestimated heat recovery efficiency or airing.

##### Place, publisher, year, edition, pages
Springer International Publishing, 2017
##### National Category
Building Technologies Energy Systems
##### Identifiers
urn:nbn:se:liu:diva-160813 (URN)10.1007/978-3-319-30746-6_39 (DOI)9783319307459 (ISBN)9783319307466 (ISBN)
##### Conference
Springer Cham
Available from: 2019-10-09 Created: 2019-10-09 Last updated: 2019-10-09
2. Measured and predicted energy use and indoor climate before and after a major renovation of an apartment building in Sweden
Open this publication in new window or tab >>Measured and predicted energy use and indoor climate before and after a major renovation of an apartment building in Sweden
2017 (English)In: Energy and Buildings, ISSN 0378-7788, E-ISSN 1872-6178, Vol. 146, p. 98-110Article in journal (Refereed) Published
##### Abstract [en]

This article presents a case study of a renovated Swedish apartment building with a common design built in 1961. The aim is to present numerical predictions, validation and evaluation of energy use and indoor climate for the building before and after renovation. Comprehensive field measurements were carried out before and after the renovation to be used as input data in the building energy simulation tool IDA ICE and for validation of model results. Indoor temperature is predicted with maximum standard deviation of 0.4 degrees C during winter. Annual heat demand is in good agreement with measurements. The building had an annual climate normalized district heat demand of 99.0 MWh before renovation and 55.4 MWh after, resulting in a 44% reduction. A slight under-prediction of the saving potential is noted, since the indoor air temperature has increased after the renovation. The results also show that assumptions of user behavior have significant impact on the energy-saving potential, and that choice of renovation measures, such as level of insulation, and efficiency of the ventilation heat recovery system need careful consideration. Choice of system boundaries also has a major effect on climate and resource impact from selected renovation measures. (C) 2017 Elsevier B.V. All rights reserved.

##### Place, publisher, year, edition, pages
ELSEVIER SCIENCE SA, 2017
##### Keywords
Renovation; Multi-family buildings; Building energy simulation; Field measurements; Validation; Energy use; CO2 emissions; Primary energy
##### National Category
Building Technologies
##### Identifiers
urn:nbn:se:liu:diva-138876 (URN)10.1016/j.enbuild.2017.04.042 (DOI)000403122200010 ()
##### Note

Funding Agencies|Swedish Research Council Formas

Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2019-09-18
3. Energy Use and Perceived Indoor Environment in a Swedish Multifamily Building before and after Major Renovation
Open this publication in new window or tab >>Energy Use and Perceived Indoor Environment in a Swedish Multifamily Building before and after Major Renovation
2018 (English)In: Sustainability, ISSN 2071-1050, E-ISSN 2071-1050, Vol. 10, no 3, article id 766Article in journal (Refereed) Published
##### Abstract [en]

Improved energy efficiency in the building sector is a central goal in the European Union and renovation of buildings can significantly improve both energy efficiency and indoor environment. This paper studies the perception of indoor environment, modelled indoor climate and heat demand in a building before and after major renovation. The building was constructed in 1961 and renovated in 2014. Insulation of the facade and attic and new windows reduced average U-value from 0.54 to 0.29 W/m(2).K. A supply and exhaust ventilation system with heat recovery replaced the old exhaust ventilation. Heat demand was reduced by 44% and maximum supplied heating power was reduced by 38.5%. An on-site questionnaire indicates that perceived thermal comfort improved after the renovation, and the predicted percentage dissatisfied is reduced from 23% to 14% during the heating season. Overall experience with indoor environment is improved. A sensitivity analysis indicates that there is a compromise between thermal comfort and energy use in relation to window solar heat gain, internal heat generation and indoor temperature set point. Higher heat gains, although reducing energy use, can cause problems with high indoor temperatures, and higher indoor temperature might increase thermal comfort during heating season but significantly increases energy use.

MDPI, 2018
##### Keywords
renovation; indoor environment; thermal comfort; building energy simulation; energy use; multifamily buildings
##### National Category
Building Technologies
##### Identifiers
urn:nbn:se:liu:diva-147818 (URN)10.3390/su10030766 (DOI)000428567100193 ()
##### Note

Funding Agencies|Swedish Research Council Formas

Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2019-09-18
4. Energy Renovation versus Demolition and Construction of a New BuildingA Comparative Analysis of a Swedish Multi-Family Building
Open this publication in new window or tab >>Energy Renovation versus Demolition and Construction of a New BuildingA Comparative Analysis of a Swedish Multi-Family Building
2019 (English)In: Energies, ISSN 1996-1073, E-ISSN 1996-1073, Vol. 12, no 11, article id 2218Article in journal (Refereed) Published
##### Abstract [en]

This study addresses the life cycle costs (LCC) of energy renovation, and the demolition and construction of a new building. A comparison is made between LCC optimal energy renovations of four different building types with thermal performance, representing Swedish constructions from the 1940s, 1950s, 1960s, and 1970s, as well as the demolition of the building and construction of a new building that complies with the Swedish building code. A Swedish multi-family building from the 1960s is used as a reference building. LCC optimal energy renovations are identified with energy saving targets ranging between 10% and 70%, in addition to the lowest possible life cycle cost. The analyses show that an ambitious energy renovation is not cost-optimal in any of the studied buildings, if achieving the lowest LCC is the objective function. The cost of the demolition and construction of a new building is higher compared to energy renovation to the same energy performance. The higher rent in new buildings does not compensate for the higher cost of new construction. A more ambitious renovation is required in buildings that have a shape factor with a high internal volume to heated floor area ratio.

MDPI, 2019
##### Keywords
renovation; energy renovation; demolition; new construction; energy use; energy performance; life cycle cost; optimization; OPERA-MILP; multi-family buildings
##### National Category
Building Technologies
##### Identifiers
urn:nbn:se:liu:diva-158988 (URN)10.3390/en12112218 (DOI)000472635900185 ()
##### Note

Funding Agencies|Swedish Research Council Formas

Available from: 2019-07-19 Created: 2019-07-19 Last updated: 2019-10-02
• Public defence: 2019-10-25 13:00 Berzeliussalen, Linköping
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
Non-Alcoholic Fatty Liver Disease: Aspects on Diagnosis and Long-term Prognosis2019Doctoral thesis, comprehensive summary (Other academic)

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting approximately 25% of the global population and is commonly recognized as the hepatic manifestation of the metabolic syndrome. The histological spectrum of NAFLD ranges from isolated steatosis to non-alcoholic steatohepatitis (NASH), with risk of developing fibrosis and subsequent cirrhosis and hepatocellular carcinoma. The gold standard for diagnosing NAFLD is liver biopsy. However, because of its invasive nature, several non-invasive methods have been developed and validated in evaluating fat and fibrosis in patients with NAFLD.

Liver fat content can be assessed using various methods. The conventional histopathological method consists of a visual semiquantitative approach in which the pathologist uses a four-point scale: grade 0 corresponds to fat deposition in <5% of hepatocytes and grade 1−3 (which is needed for the diagnosis of NAFLD) corresponds to ≥5%. An alternate approach is to quantitatively assess steatosis using stereological point counting (SPC) – which rely on liver biopsy. However, in vivo proton magnetic resonance spectroscopy (1H-MRS) is a reliable noninvasive method that can be used to quantitatively assess total hepatic lipid content, or proton density fat fraction (PDFF).

In Paper I we compared the conventional semiquantitative histological method (grade 0-3) with SPC and 1H-MRS. We found a strong positive correlation between 1H-MRS and SPC, whereas the correlations between 1H-MRS or SPC and histopathological grading were substantially weaker. Using the widely used cut-off value of PDFF ≥5%, all participants were found to have steatosis (specificity 100%, sensitivity 53%). Reducing the cut-off value to 3% maintained 100% specificity while increasing sensitivity to 79%.

In Paper IV we evaluated quantitative steatosis, by SPC, in 106 biopsy-proven NAFLD patients during a 20-year follow-up. SPC was independently associated with an increased risk of all-cause mortality and development of T2DM. Moreover, in the 59 patients with sequential biopsies (approximately 10 years apart), a reduction of quantitative hepatic steatosis decreased the all-time risk of developing T2DM.

NASH is commonly seen as a histological feature portending a worse prognosis in NAFLD. Interestingly, no dual biopsy study has ever shown that NASH predicts fibrosis progression. Yet, NASH is seen as a surrogate marker in pharmaceutical trials – were resolution in NASH is equivalent to future resolution of fibrosis.

In Paper II we conducted a long-term follow-up study (20 years) in a large cohort of biopsy-proven NAFLD patients (n=646), in a collaboration with Karolinska Institute. We could not ascertain that NASH had any effect on all-cause, or disease-specific mortality. However, higher stages of fibrosis predicted all-cause and disease specific mortality. In Paper III, we present 129 biopsy-proven NAFLD patients, in which we had prospective, longitudinal data. They were included between 1988 and 1993. All patients alive, were re-invited 2003-2005 and 2013-2015. Dual biopsies were present in 68 patients, and three consecutive biopsies were available in 33 patients. Results showed that NAFLD is a highly heterogeneous disease, with 9.3% developing end-stage liver disease and 16% progressing to advanced stages of fibrosis without any clinically significant baseline data predicting disease progression. In summary, when using 1H-MRS as a diagnostic method for NAFLD, the diagnostic cut-off should be reduced from 5% to 3%. Furthermore, quantitative amount of hepatic steatosis could be used to stratify patients with NAFLD related to future risk of developing T2DM. Moreover, we have shown that NASH does not predict future all-cause or disease-specific mortality nor end-stage liver disease, therefore a different surrogate marker should be used in clinical trials when assessing NAFLD improvement, so to not imbue false reliance in new therapies. Lastly, we have shown that NAFLD has a more dismal prognosis than previously reported, and that it is unexpectedly difficult to predict fibrosis progression in individual NAFLD patients, emphasizing the need for robust non-invasive biomarkers suitable to monitor large number of patients.

1. Using a 3% Proton Density Fat Fraction as a Cut-off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results from Histopathology Analysis
Open this publication in new window or tab >>Using a 3% Proton Density Fat Fraction as a Cut-off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results from Histopathology Analysis
2017 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, no 1, p. 53-+Article in journal (Refereed) Published
##### Abstract [en]

It is possible to estimate hepatic triglyceride content by calculating the proton density fat fraction (PDFF), using proton magnetic resonance spectroscopy (less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS), instead of collecting and analyzing liver biopsies to detect steatosis. However, the current PDFF cut-off value (5%) used to define steatosis by magnetic resonance was derived from studies that did not use histopathology as the reference standard. We performed a prospective study to determine the accuracy of less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF in measurement of steatosis using histopathology analysis as the standard. We collected clinical, serologic, less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF, and liver biopsy data from 94 adult patients with increased levels of liver enzymes (6 months or more) referred to the Department of Gastroenterology and Hepatology at Linköping University Hospital in Sweden from 2007 through 2014. Steatosis was graded using the conventional histopathology method and fat content was quantified in biopsy samples using stereological point counts (SPCs). We correlated less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF findings with SPCs (r = 0.92; P less than.001). less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF results correlated with histopathology results (ρ = 0.87; P less than.001), and SPCs correlated with histopathology results (ρ = 0.88; P less than.001). All 25 subjects with PDFF values of 5.0% or more had steatosis based on histopathology findings (100% specificity for PDFF). However, of 69 subjects with PDFF values below 5.0% (negative result), 22 were determined to have steatosis based on histopathology findings (53% sensitivity for PDFF). Reducing the PDFF cut-off value to 3.0% identified patients with steatosis with 100% specificity and 79% sensitivity; a PDFF cut-off value of 2.0% identified patients with steatosis with 94% specificity and 87% sensitivity. These findings might be used to improve non-invasive detection of steatosis.

##### Place, publisher, year, edition, pages
Elsevier, 2017
##### National Category
Gastroenterology and Hepatology
##### Identifiers
urn:nbn:se:liu:diva-136544 (URN)10.1053/j.gastro.2017.03.005 (DOI)000403918300022 ()
##### Note

Funding agencies: Swedish Research Council/Medicine and Health [VR/M 2007-2884, VR/M 2012-3199]; Swedish Research Council/Natural and Engineering Sciences [VR/NT 2014-6157]; Swedish Innovation Agency VINNOVA [2013-01314]; Region Ostergotland (ALF)

Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2019-09-25Bibliographically approved
2. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD
Open this publication in new window or tab >>Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD
2017 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 67, no 6, p. 1265-1273Article in journal (Refereed) Published
##### Abstract [en]

Background amp; Aims: Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. Methods: We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. Results: During a follow-up of mean 20 years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p amp;lt; 0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test amp;gt; 0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10th percentile of time to development of severe liver disease was 22-26 years in F0-1, 9.3 years in F2, 2.3 years in F3, and 0.9 years to liver decompensation in F4. Conclusions: In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

##### Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
##### Keywords
Steatosis; Cirrhosis; Epidemiology
##### National Category
Gastroenterology and Hepatology
##### Identifiers
urn:nbn:se:liu:diva-143355 (URN)10.1016/j.jhep.2017.07.027 (DOI)000415325900019 ()
##### Note

Funding Agencies|Swedish Royal Academy of Sciences; Bengt Ihre scholarship; Swedish Gastroenterology Fund

Available from: 2017-12-05 Created: 2017-12-05 Last updated: 2019-09-25
3. Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies.
Open this publication in new window or tab >>Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies.
2018 (English)In: Hepatology communications, ISSN 2471-254X, Vol. 2, no 2, p. 199-210Article in journal (Refereed) Published
##### Abstract [en]

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high-quality follow-up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow-up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow-up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end-stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty-six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy-proven fibrosis stage F3-F4 and 2 patients with end-stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end-stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end-stage liver disease. (Hepatology Communications 2018;2:199-210).

##### Place, publisher, year, edition, pages
John Wiley & Sons, 2018
##### National Category
Gastroenterology and Hepatology
##### Identifiers
urn:nbn:se:liu:diva-146233 (URN)10.1002/hep4.1134 (DOI)29404527 (PubMedID)
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2019-09-25
• Public defence: 2019-10-25 13:00 Planck, Linköping
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
Monitoring of product variants in biopharmaceutical downstream processing: Mechanistic and data-driven modeling approaches2019Doctoral thesis, comprehensive summary (Other academic)

During the manufacturing of biopharmaceuticals, a multistep purification strategy is employed to remove process-related impurities and product variants, to achieve high product quality, assuring patients’ safety. To guarantee that biopharmaceuticals are safe and to accomplish quality, strict policies were established by regulatory agencies as well as guiding principles, such as Quality by Design and process analytical technology. To make the manufacturing process economical, relatively high product yield and productivity are also desirable.

The removal of product variants often poses a challenge in downstream processing due to their structural similarity to the product resulting in similar behavior. One way of overcoming this issue is to employ additional monitoring tools capable to distinguish between the product and product variants.

This thesis demonstrates the development of novel monitoring tools, based on existing monitoring and modeling approaches, to facilitate downstream processing.

Existing techniques are evaluated and critically compared toward meeting the requirements on monitoring quality attributes in downstream processing.

A mechanistic model-based monitoring tool was established for a reversed phase chromatography polishing step of insulin to predict the elution profile of insulin and two insulin variants. By relying on model-based monitoring a significant increase in product yield was achieved.

Further, multi-wavelength fluorescence spectroscopy coupled with the multi-way algorithm parallel factor analysis was utilized to monitor product variants of biopharmaceuticals in downstream processing. This monitoring tool capitalizes on a shift in fluorescence emission between the product and its variant. Developed for monitoring aggregates during antibody purification, the transferability of the approach to other relevant biopharmaceuticals, such as factor VIII and erythropoietin, has been confirmed.

The monitoring tools developed in this thesis, extend existing monitoring tools for downstream processing of biopharmaceuticals. When implementing these monitoring tools into the different phases of biopharmaceuticals’ lifespan, their potential could range from optimizing downstream processes during purification strategy development to supporting manufacturing by facilitating process decisions.

1. On-line monitoring of downstream bioprocesses
Open this publication in new window or tab >>On-line monitoring of downstream bioprocesses
2016 (English)In: CURRENT OPINION IN CHEMICAL ENGINEERING, ISSN 2211-3398, Vol. 14, p. 112-120Article in journal (Refereed) Published
##### Abstract [en]

Downstream bioprocessing can benefit significantly from using on-line monitoring methods for surveillance, control and optimisation. Timely information on critical operational and product quality parameters provided by on-line monitoring may contribute to high product quality, more efficient process operation and better production economy. Here, recent advances in analytical techniques and tools are critically reviewed and assessed based on their capability to meet typical needs and requirements in the biotechnology industry. Soft sensors, which merge the signals generated from on-line monitoring devices into mathematical models, are highlighted for accessing critical information in downstream processing.

##### Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2016
##### National Category
Chemical Process Engineering
##### Identifiers
urn:nbn:se:liu:diva-133391 (URN)10.1016/j.coche.2016.09.007 (DOI)000388517100016 ()
##### Note

Funding Agencies|EU-Horizon 2020 Marie Curie ITN project BIORAPID [643056]; Linkoping University

Available from: 2016-12-27 Created: 2016-12-22 Last updated: 2019-09-25
2. Model-based monitoring of industrial reversed phase chromatography to predict insulin variants
Open this publication in new window or tab >>Model-based monitoring of industrial reversed phase chromatography to predict insulin variants
2019 (English)In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 35, no 4, article id UNSP e2813Article in journal (Refereed) Published
##### Abstract [en]

Downstream processing in the manufacturing biopharmaceutical industry is a multistep process separating the desired product from process- and product-related impurities. However, removing product-related impurities, such as product variants, without compromising the product yield or prolonging the process time due to extensive quality control analytics, remains a major challenge. Here, we show how mechanistic model-based monitoring, based on analytical quality control data, can predict product variants by modeling their chromatographic separation during product polishing with reversed phase chromatography. The system was described by a kinetic dispersive model with a modified Langmuir isotherm. Solely quality control analytical data on product and product variant concentrations were used to calibrate the model. This model-based monitoring approach was developed for an insulin purification process. Industrial materials were used in the separation of insulin and two insulin variants, one eluting at the product peak front and one eluting at the product peak tail. The model, fitted to analytical data, used one component to simulate each protein, or two components when a peak displayed a shoulder. This monitoring approach allowed the prediction of the elution patterns of insulin and both insulin variants. The results indicate the potential of using model-based monitoring in downstream polishing at industrial scale to take pooling decisions.

WILEY, 2019
##### Keywords
biopharmaceuticals; HPLC; mechanistic modeling; pooling decision; preparative chromatography
##### National Category
Bioprocess Technology
##### Identifiers
urn:nbn:se:liu:diva-160061 (URN)10.1002/btpr.2813 (DOI)000481421900007 ()30938075 (PubMedID)
##### Note

Funding Agencies|Horizon 2020 Framework Program [643056]; European Unions Horizon 2020 [643056]

Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-09-25
Linköping University, Department of Mathematics, Computational Mathematics. Linköping University, Faculty of Science & Engineering.
Eigenvalue analysis and convergence acceleration techniques for summation-by-parts approximations2019Doctoral thesis, comprehensive summary (Other academic)

Many physical phenomena can be described mathematically by means of partial differential equations. These mathematical formulations are said to be well-posed if a unique solution, bounded by the given data, exists. The boundedness of the solution can be established through the so-called energy-method, which leads to an estimate of the solution by means of integration-by-parts. Numerical approximations mimicking integration-by-parts discretely are said to fulfill the Summation-By-Parts (SBP) property. These formulations naturally yield bounded approximate solutions if the boundary conditions are weakly imposed through Simultaneous-Approximation-Terms (SAT). Discrete problems with bounded solutions are said to be energy-stable.

Energy-stable and high-order accurate SBP-SAT discretizations for well-posed linear problems were first introduced for centered finite-difference methods. These mathematical formulations, based on boundary conforming grids, allow for an exact mimicking of integration-by-parts. However, other discretizations techniques that do not include one or both boundary nodes, such as pseudo-spectral collocation methods, only fulfill a generalized SBP (GSBP) property but still lead to energy-stable solutions.

This thesis consists of two main topics. The first part, which is mostly devoted to theoretical investigations, treats discretizations based on SBP and GSBP operators. A numerical approximation of a conservation law is said to be conservative if the approximate solution mimics the physical conservation property. It is shown that conservative and energy-stable spatial discretizations of variable coefficient problems require an exact numerical mimicking of integration-by-parts. We also discuss the invertibility of the algebraic problems arising from (G)SBP-SAT discretizations in time of energy-stable spatial approximations. We prove that pseudo-spectral collocation methods for the time derivative lead to invertible fully-discrete problems. The same result is proved for second-, fourth- and sixth-order accurate finite-difference based time integration methods.

Once the invertibility of (G)SBP-SAT discrete formulations is established, we are interested in efficient algorithms for the unique solution of such problems. To this end, the second part of the thesis has a stronger experimental flavour and deals with convergence acceleration techniques for SBP-SAT approximations. First, we consider a modified Dual Time-Stepping (DTS) technique which makes use of two derivatives in pseudo-time. The new DTS formulation, compared to the classical one, accelerates the convergence to steady-state and reduces the stiffness of the problem. Next, we investigate multi-grid methods. For parabolic problems, highly oscillating error modes are optimally damped by iterative methods, while smooth residuals are transferred to coarser grids. In this case, we show that the Galerkin condition in combination with the SBP-preserving interpolation operators leads to fast convergence. For hyperbolic problems, low frequency error modes are rapidly expelled by grid coarsening, since coarser grids have milder stability restrictions on time steps. For such problems, Total Variation Dimishing Multi-Grid (TVD-MG) allows for faster wave propagation of first order upwind discretizations. In this thesis, we extend low order TVD-MG schemes to high-order SBP-SAT upwind discretizations.

1. On conservation and stability properties for summation-by-parts schemes
Open this publication in new window or tab >>On conservation and stability properties for summation-by-parts schemes
2017 (English)In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 344, p. 14p. 451-464Article in journal (Refereed) Published
##### Abstract [en]

We discuss conservative and stable numerical approximations in summation-by-parts form for linear hyperbolic problems with variable coefficients. An extended setting, where the boundary or interface may or may not be included in the grid, is considered. We prove that conservative and stable formulations for variable coefficient problems require a boundary and interface conforming grid and exact numerical mimicking of integration-by-parts. Finally, we comment on how the conclusions from the linear analysis carry over to the nonlinear setting.

p. 14
##### Keywords
Hyperbolic problems Summation-by-parts Boundary conditions Interface conditions Stability Conservation
##### National Category
Computational Mathematics
##### Identifiers
urn:nbn:se:liu:diva-137544 (URN)10.1016/j.jcp.2017.05.002 (DOI)000402481300023 ()
##### Note

Funding agencies: VINNOVA [2013-01209]

Available from: 2017-05-21 Created: 2017-05-21 Last updated: 2019-09-03
2. On pseudo-spectral time discretizations in summation-by-parts form
Open this publication in new window or tab >>On pseudo-spectral time discretizations in summation-by-parts form
2018 (English)In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 360, p. 192-201Article in journal (Refereed) Published
##### Abstract [en]

Fully-implicit discrete formulations in summation-by-parts form for initial-boundary value problems must be invertible in order to provide well functioning procedures. We prove that, under mild assumptions, pseudo-spectral collocation methods for the time derivative lead to invertible discrete systems when energy-stable spatial discretizations are used.

##### Place, publisher, year, edition, pages
Springer Publishing Company, 2018
##### Keywords
Time integration; Initial boundary value problem; Summation-by-parts operators; Pseudo-spectral methods; Eigenvalue problem
Mathematics
##### Identifiers
urn:nbn:se:liu:diva-145083 (URN)10.1016/j.jcp.2018.01.043 (DOI)000428966300011 ()2-s2.0-85041575964 (Scopus ID)
Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2019-09-03Bibliographically approved
3. Eigenvalue analysis for summation-by-parts finite difference time discretizations
Open this publication in new window or tab >>Eigenvalue analysis for summation-by-parts finite difference time discretizations
##### Abstract [en]

Diagonal norm finite-difference based time integration methods in summation-by-parts form are investigated. The second, fourth and sixth order accurate discretizations are proven to have eigenvalues with strictly positive real parts. This leads to provably invertible fully-discrete approximations of initial boundary value problems.

Our findings also allow us to conclude that the second, fourth and sixth order time discretizations are stiffly accurate, strongly S-stable and dissipatively stable Runge-Kutta methods. The procedure outlined in this article can be extended to even higher order summation-by-parts approximations with repeating stencil.

##### Series
LiTH-MAT-R, ISSN 0348-2960 ; 2019:9
##### Keywords
Time integration, Initial value problem, Summation-by-parts operators, Finite difference methods, Eigenvalue problem
Mathematics
##### Identifiers
urn:nbn:se:liu:diva-160009 (URN)LiTH-MAT-R-2019/09-SE (ISRN)
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-09-03Bibliographically approved
4. Dual Time-Stepping Using Second Derivatives
Open this publication in new window or tab >>Dual Time-Stepping Using Second Derivatives
2019 (English)In: Journal of Scientific Computing, ISSN 0885-7474, E-ISSN 1573-7691Article in journal (Refereed) Epub ahead of print
##### Abstract [en]

We present a modified formulation of the dual time-stepping technique which makes use of two derivatives in pseudo-time. This new technique retains and improves the convergence properties to the stationary solution. When compared with the conventional dual time-stepping, the method with two derivatives reduces the stiffness of the problem and requires fewer iterations for full convergence to steady-state. In the current formulation, these positive effects require that an approximation of the square root of the spatial operator is available and inexpensive.

##### Place, publisher, year, edition, pages
Springer, 2019
Mathematics
##### Identifiers
urn:nbn:se:liu:diva-160245 (URN)10.1007/s10915-019-01047-5 (DOI)
Available from: 2019-09-13 Created: 2019-09-13 Last updated: 2019-09-13
5. A new multigrid formulation for high order finite difference methods on summation-by-parts form
Open this publication in new window or tab >>A new multigrid formulation for high order finite difference methods on summation-by-parts form
2018 (English)In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 359, p. 216-238Article in journal (Refereed) Published
##### Abstract [en]

Multigrid schemes for high order finite difference methods on summation-by-parts form are studied by comparing the effect of different interpolation operators. By using the standard linear prolongation and restriction operators, the Galerkin condition leads to inaccurate coarse grid discretizations. In this paper, an alternative class of interpolation operators that bypass this issue and preserve the summation-by-parts property on each grid level is considered. Clear improvements of the convergence rate for relevant model problems are achieved.

##### Keywords
High order finite difference methodsSummation-by-partsMultigridRestriction and prolongation operatorsConvergence acceleration
Mathematics
##### Identifiers
urn:nbn:se:liu:diva-145086 (URN)10.1016/j.jcp.2018.01.011 (DOI)000427396200011 ()
##### Note

Funding agencies:  VINNOVA, the Swedish Governmental Agency for Innovation Systems [2013-01209]

Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2019-09-03
6. Multigrid schemes for high order discretizations of hyperbolic problems
Open this publication in new window or tab >>Multigrid schemes for high order discretizations of hyperbolic problems
2019 (English)In: 2019 AIAA Aerospace Sciences Meeting, AIAA Scitech Forum, American Institute of Aeronautics and Astronautics, 2019, p. 1-25, article id AIAA 2019-0103Conference paper, Published paper (Refereed)
##### Abstract [en]

Total variation diminishing multigrid methods have been developed for first order accurate discretizations of hyperbolic conservation laws. This technique is based on a so-called upwind biased residual interpolation and allows for algorithms devoid of spurious numerical oscillations in the transient phase. In this paper, we justify the introduction of such prolongation and restriction operators by rewriting the algorithm in a matrix-vector notation. This perspective sheds new light on multigrid procedures for hyperbolic problems and provides a direct extension for high order accurate difference approximations. The new multigrid procedure is presented, advantages and disadvantages are discussed and numerical experiments are performed.

##### Place, publisher, year, edition, pages
American Institute of Aeronautics and Astronautics, 2019
Mathematics
##### Identifiers
urn:nbn:se:liu:diva-154393 (URN)10.2514/6.2019-0103 (DOI)978-1-62410-578-4 (ISBN)
##### Conference
2019 AIAA Aerospace Sciences Meeting, AIAA Scitech Forum, San Diego, California, 7-11 January 2019
Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-09-03
• Public defence: 2019-10-31 14:00 Mott, Linköping
Linköping University, Department of Physics, Chemistry and Biology, Nanostructured Materials. Linköping University, Faculty of Science & Engineering. Department of Material Science, Saarland University, Saarbrücken, Germany.
Eutectic Modification of Al-Si casting alloys2019Doctoral thesis, comprehensive summary (Other academic)

Aluminum alloys with silicon as the major alloying element are the most widely used aluminum casting alloys. The eutectic phase in these alloys is formed by hard and brittle silicon plates in an aluminum matrix. Such silicon plates can act as crack propagation paths deteriorating the toughness of the material. To enhance ductility, silicon can be modified to a coral-like microstructure by addition of a modifying agent. Amongst the elements proposed as modifiers, only strontium, sodium and europium induce a plate-tocoral transition, while others such as ytterbium, only refine the silicon plates. The exact mechanism for the remarkable plate-to-coral change, and the reason why certain elements only refine the structure, is still not completely understood.

In this investigation, atom probe tomography and transmission electron microscopy were used to analyze and compare the crystal structure and the distribution of solute atoms in silicon at the atomic level. An unmodified alloy and alloys modified by strontium, sodium, europium and ytterbium were studied. Elements inducing silicon plate-to-coral transition were found to contain nanometer sized clusters at the defects in silicon with stoichiometries corresponding to compounds formed at the ternary eutectic reaction of each system. In contrast, the addition of ytterbium, that only refines the silicon plates, is unable to form clusters in silicon. We propose that the formation of ternary compound clusters AlSiNa, Al2Si2Sr and Al2Si2Eu at the silicon / liquid interface during solidification restrict silicon growth. The formation of clusters on silicon facets create growth steps and increase growth direction diversity. The incorporation of clusters in silicon explains the high density of crystallographic defects and the structural modification from plates to corals.

The parallel lattice plane-normals 011Si // 0001Al2Si2Eu, 011Si // 6$\tiny\overline{7}$10Al2Si2Eu and 111Si // 6$\tiny\overline{7}$10Al2Si2Eu were found between Al2Si2Eu and silicon, and absent between Al2Si2Yb and silicon. We propose a favorable heterogeneous formation of Al2Si2Eu on silicon. The misfit between 011Si and 0002Al2Si2X interplanar spacings shows a consistent trend with the potency of modification for several elements such as strontium, sodium, europium, calcium, barium, ytterbium and yttrium.

1. Comparison of segregations formed in unmodified and Sr-modified Al-Si alloys studied by atom probe tomography and transmission electron microscopy
Open this publication in new window or tab >>Comparison of segregations formed in unmodified and Sr-modified Al-Si alloys studied by atom probe tomography and transmission electron microscopy
2014 (English)In: Journal of Alloys and Compounds, ISSN 0925-8388, E-ISSN 1873-4669, Vol. 611, p. 410-421Article in journal (Refereed) Published
##### Abstract [en]

The mechanical properties of Al-7 wt.% Si can be enhanced by structural modifications of its eutectic phase. Addition of low concentrations of certain elements, in this case 150 wt-ppm Sr, is enough to cause a transition from a coarse plate-like Si structure to a finer coralline one. To fully understand the operating mechanism of this modification, the composition of the eutectic Si phase in unmodified and Sr-modified alloys was analysed and compared by atom probe tomography and (scanning) transmission electron microscopy. The unmodified alloy showed nanometre sized Al-segregations decorating defects, while the Sr-modified sample presented three types of Al-Sr segregations: (1) rod-like segregations that promote smoothening of the Al-Si boundaries in the eutectic phase, (2) particle-like segregations comparable to the ones seen in the unmodified alloy, and (3) planar segregations favouring the formation of twin boundaries. Al and Sr solubilities in Si after solidification were determined to be 430 +/- 160 at-ppm and 40 +/- 10 at-ppm, respectively. Sr predominantly segregates to the Si phase confirming its importance in the modification of the eutectic growth.

##### Place, publisher, year, edition, pages
Elsevier, 2014
##### Keywords
Aluminium-silicon alloys; Strontium modification; Atom probe tomography; Transmission electron microscopy; Microstructure
##### National Category
Physical Sciences
##### Identifiers
urn:nbn:se:liu:diva-109356 (URN)10.1016/j.jallcom.2014.05.121 (DOI)000338932400064 ()
Available from: 2014-08-15 Created: 2014-08-15 Last updated: 2019-09-13Bibliographically approved
2. Cluster formation at the Si/liquid interface in Sr and Na modified Al-Si alloys
Open this publication in new window or tab >>Cluster formation at the Si/liquid interface in Sr and Na modified Al-Si alloys
2016 (English)In: Scripta Materialia, ISSN 1359-6462, E-ISSN 1872-8456, Vol. 117, p. 16-19Article in journal (Refereed) Published
##### Abstract [en]

Atom probe tomography was used to compare Na and Sr modified Al-Si hypoeutectic alloys. Both Na and Sr promote the formation of nanometre-sized clusters in the Si eutectic phase. Compositional analyses of the clusters show an Al:Sr ratio of 2.92 +/- 0.46 and an Al:Na ratio of 1.07 +/- 0.23. It is proposed that SrAl2Si2 and NaAlSi clusters are formed at the Si/liquid interface and take part in the modification process by altering the eutectic Si growth.

##### Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2016
##### Keywords
Eutectic solidification; Atom probe tomography; Aluminium alloys; Eutectic modification; Transmission electron microscopy
##### National Category
Physical Sciences
##### Identifiers
urn:nbn:se:liu:diva-127548 (URN)10.1016/j.scriptamat.2016.02.018 (DOI)000373547500004 ()
##### Note

Funding Agencies|German Federal Ministry of Economics and Technology [AiF 17204 N]; European Regional Development Fund (AME-Lab) [C/4-EFRE-13/2009/Br]; German Research Foundation (DFG); Federal State Government of Saarland [INST 256/298-1 FUGG]; Erasmus Mundus Doctoral Programme DocMASE of the European Commission [FPA 2011-0020]; VINNOVA Strategic Faculty Grant VINNMER Marie Curie Chair [2011-03464]; Major International (Regional) Joint Research Project from China [51420105005]

Available from: 2016-05-04 Created: 2016-05-03 Last updated: 2019-09-13
3. Eutectic modification by ternary compound cluster formation in Al-Si alloys
Open this publication in new window or tab >>Eutectic modification by ternary compound cluster formation in Al-Si alloys
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5506Article in journal (Refereed) Published
##### Abstract [en]

Al-alloys with Si as the main alloying element constitute the vast majority of Al castings used commercially today. The eutectic Si microstructure in these alloys can be modified from plate-like to coral-like by the addition of a small amount of a third element to improve ductility and toughness. In this investigation the effects of Eu and Yb are studied and their influence on the microstructure is compared to further understand this modification. The two elements impact the alloy differently, where Eu modifies Si into a coral-like structure while Yb does not. Atom probe tomography shows that Eu is present within the Si phase in the form of ternary compound Al2Si2Eu clusters, while Yb is absent in the Si phase. This indicates that the presence of ternary compound clusters within Si is a necessary condition for the formation of a coral-like structure. A crystallographic orientation relationship between Si and the Al2Si2Eu phase was found, where the following plane normals are parallel: 011(Si) //0001(Al2Si2Eu), 111(Si)//6 (7) over bar 10(Al2Si2Eu) and 011(Si)//6 (7) over bar 10(Al2Si2Eu). No crystallographic relationship was found between Si and Al2Si2Yb. The heterogeneous formation of coherent Al2Si2Eu clusters inside the Si-phase is suggested to trigger the modification of the microstructure.

##### Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
##### National Category
Metallurgy and Metallic Materials
##### Identifiers
urn:nbn:se:liu:diva-156563 (URN)10.1038/s41598-019-41919-2 (DOI)000462990000048 ()30940873 (PubMedID)
##### Note

Funding Agencies|European Regional Development Fund (ERDF); DFG; Federal State Government of Saarland [INST 256/298-1 FUGG]; Erasmus Mundus Programme of the European Commission within the Doctoral Programme DocMASE; Major International (Regional) Joint Research Project from China [51420105005]; Overseas, Hong Kong, Macao Scholars Cooperative Research Fund from China [51728101]

Available from: 2019-05-15 Created: 2019-05-15 Last updated: 2019-09-13
4. Nucleation and Growth of Eutectic Si in Al-Si Alloys with Na Addition
Open this publication in new window or tab >>Nucleation and Growth of Eutectic Si in Al-Si Alloys with Na Addition
2015 (English)In: Metallurgical and Materials Transactions. A, ISSN 1073-5623, E-ISSN 1543-1940, Vol. 46, no 3, p. 1300-1311Article in journal (Refereed) Published
##### Abstract [en]

Al-5 wt pct Si-based alloys with Na additions (19 and 160 ppm) have been produced by controlled sand casting and melt spinning. Entrained droplet technique and differential scanning calorimetry were employed to investigate the nucleation behavior of eutectic Si. High-resolution transmission electron microscopy and atom probe tomography were used to investigate the distribution of Na atoms within eutectic Si and at the interfaces between eutectic Si and eutectic Al. It was found that (i) only 19 ppm Na addition results into a high undercooling (49 K (49 °C)) of the entrained eutectic droplet. However, further increasing Na addition up to 160 ppm exerts no positive effect on the nucleation of eutectic Si, instead a decreased undercooling (29 K (29 °C)) was observed. (ii) Na addition suppresses the growth of eutectic Si due to the Na segregation at the interface between eutectic Si and eutectic Al, and (iii) Na addition promotes significant multiple Si twins, which can be attributed to the proposed adsorption of Na atoms at the intersection of Si twins and along the 〈112〉Si growth direction of Si. The present investigation demonstrates, for the first time, a direct observation on the distribution of Na atoms within eutectic Si and thereby provides strong experimental supports to the well-accepted impurity-induced twinning growth mechanism and poisoning of the twin plane re-entrant edge growth mechanism.

##### National Category
Condensed Matter Physics
##### Identifiers
urn:nbn:se:liu:diva-160234 (URN)10.1007/s11661-014-2702-6 (DOI)
Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2019-09-13
5. Phase Selective Sample Preparation of Al-Si alloys for Atom Probe Tomography
Open this publication in new window or tab >>Phase Selective Sample Preparation of Al-Si alloys for Atom Probe Tomography
2019 (English)In: Praktische metallographie, ISSN 0032-678X, E-ISSN 2195-8599, Vol. 56, no 2, p. 76-90Article in journal (Refereed) Published
##### Abstract [en]

We present how the conventional focused ion beam (FIB) lift-out method can be modified to obtain phase selective specimens for atom probe tomography (APT). The modified method combines selective deep etching with site-specific lift-out using a micromanipulator in a FIB/SEM workstation. This method is used for phase-selective sample preparation in alloys with complex microstructures such as the coral- and plate-like silicon structures in the eutectic phase of Al-Si castings. The method proves to be both, practical and robust, with a high success rate of high-quality phase-specific APT specimens.

##### Place, publisher, year, edition, pages
CARL HANSER VERLAG, 2019
##### National Category
Analytical Chemistry
##### Identifiers
urn:nbn:se:liu:diva-154847 (URN)10.3139/147.110557 (DOI)000458507500002 ()
##### Note

Funding Agencies|EU; DFG; Federal State Government of Saarland [INST 256/298-1 FUGG]; Erasmus Mundus Programme of the European Commission within the Doctoral Programme DocMASE

Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-09-13
• Public defence: 2019-11-07 09:00 Berzelius, Linköping
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Investigation of the intercellular transmission of α-synuclein, amyloid-β and TDP-432019Doctoral thesis, comprehensive summary (Other academic)

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are disorders characterized by the progressive deposition of proteinaceous inclusions throughout the brain in a predictable manner. Each disease is described by the involvement of different misfolded and aggregated proteins (AD, amyloid-β and tau; PD, α-synuclein; ALS and FTLD, TDP-43) that spread between anatomically connected brain regions, causing cell death in previously healthy regions. Disease progresses as these aggregated proteins spread throughout the brain in a prion-like fashion. Oligomeric forms of these proteins (aggregates comprising of ≈3-30 individual proteins) are thought to be the most relevant to disease, as they are capable of prion-like propagation and can cause cellular toxicity. The work in this thesis aims to elucidate the mechanisms by which different neurodegenerative disease related proteins (amyloid-β, α-synuclein and TDP-43) are taken up and transferred between cells, and the effects exerted by these proteins on downstream cells.

Paper I examined the uptake and cell to cell transmission of oligomeric α-synuclein (α-syn). Using a 3D co-culture model, we determined that α-syn (monomeric, oligomeric and fibrillar assemblies) were readily taken up and transferred between neuron-like cells, and that this transfer was mediated by an endosomal/lysosomal mechanism. It was also determined that larger α-syn assemblies (oligomers and fibrils) were found in donor and acceptor cells more frequently than monomeric α-syn, which we speculate is a due to the larger aggregates’ resistance to cellular proteases.

In Paper II, we identified a novel mechanism for the uptake of oligomeric proteins, in the discovery that the gap junction channel protein connexin 32 mediates the uptake of α-syn oligomers in a preferential manner. Gap junction proteins act as a means of communication between adjacent cells, forming a transmembrane pore to facilitate the passage of small molecules. Here, we determined that connexin 32 drives the preferential uptake of oligomeric α-syn relative to monomeric and fibrillar α-syn. This system was not exclusive to α-syn however, as the preferential uptake of oligomeric amyloid-β (Aβ) was also observed. In addition to the uptake of oligomers, we observed that increased α-syn expression elicited the increased expression of connexin 32, in a positive feedback mechanism. When connexin 32 was inhibited pharmacologically or knocked out using CRISPR/Cas9, the preferential uptake of oligomers was abolished. These phenomena were also observed in oligodendrocytes (the accumulation of oligomeric α-syn in oligodendrocytes is a hallmark of Multiple Systems Atrophy), three different mouse models of α-syn overexpression, as well as in post-mortem human tissues.

Paper III undertook the investigation of cell to cell transfer of TDP-43. Although it was recently confirmed that TDP-43 propagates throughout the brain in a prion-like fashion, it remains unclear how post-translational modifications of TDP-43 affect its propensity to be transferred between cells. This leaves a gap in the understanding of how TDP-43 proteinopathies progress, as post-translationally modified TDP-43 is understood to be critical to pathogenesis. To study this, we generated several TDP-43 cell lines, expressing full-length TDP-43 or C-/N-terminally truncated fragments, known contributors to TDP-43 proteinopathies. Using the 3D co-culture model, we determined that preservation of the N-terminus of TDP-43 enhanced its ability to transmit between cells, whereas an intact the C-terminus reduced transfer. Additionally, since we have previously shown that both oligomeric Aβ and α-syn are incorporated into extracellular vesicles (EVs) such as exosomes, and that these EVs can sufficiently mediate the transfer of protein oligomers to downstream cells, we investigated whether this was also true for TDP-43. We demonstrated that full-length TDP-43 and TDP-43 fragments could be found within EVs generated by these cells, but that these EVs were unable to propagate the protein to downstream cells. Instead, the transmission of TDP-43 occurs in a manner dependent upon physical proximity between cells, possibly across the synaptic cleft itself.

Next, we studied the acute effects exerted by oligomeric Aβ upon healthy neurons in order to understand the earliest effects of oligomeric Aβ challenge. In Paper IV, we used iPSC-derived neurons generated from human donors expressing different amyloid-β precursor protein (APP) genes, one harbouring the familial AD-causing V717I London mutation, the other expressing WT APP. After differentiating these cells into functional neurons in vitro, the neurons were challenged with acute exposure to exogenous oligomeric Aβ and analyzed by LC-MS/MS to observe the early effects. By analyzing the proteome and phosphoproteome of these cells, we identified many proteins and phosphoproteins that were up- or down-regulated in response to oligomeric Aβ at this early timepoint. Among these changes, oligomeric Aβ caused the downregulation of TDP-43, heterogeneous nuclear ribonucleoproteins, and coatomer complex I proteins. Conversely, increases were observed in 20S proteasome subunits and vesicle associated proteins VAMP1/2. We also observed the differential phosphorylation of tau at serine 208, indicating that phosphorylation at this residue might be an important early event in tauopathy.

Altogether, the work described in this thesis has provided new understanding as to how different neurodegenerative disease related proteins are taken up and transferred between cells. In doing so, we have identified some of the mechanisms by which this spreading occurs, and that the changes elicited by these toxic oligomeric proteins are rapid and widespread. By learning about these processes, we have identified novel targets that could be used in the development of disease modifying therapeutics.

1. Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes
Open this publication in new window or tab >>Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes
2016 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 11, no 12, article id e0168700Article in journal (Refereed) Published
##### Abstract [en]

Parkinsons disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

##### Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
##### National Category
Neurosciences
##### Identifiers
urn:nbn:se:liu:diva-134306 (URN)10.1371/journal.pone.0168700 (DOI)000391222000063 ()28030591 (PubMedID)
##### Note

Funding Agencies|Swedish Research Council [MH: 523-2013-2735]; Swedish Brain Power Program; Research Foundation of the Swedish Parkinsons Disease Association; Ostergotland Research Foundation for Parkinsons Disease; Parkinson Research Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Gustav V and Queen Victorias Foundation; Swedish Dementia Foundation; Linkoping University Neurobiology Centre; County Council of Ostergotland; Marianne and Marcus Wallenberg Foundation

Available from: 2017-02-06 Created: 2017-02-03 Last updated: 2019-10-14
2. Binding of -synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
Open this publication in new window or tab >>Binding of -synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
2019 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 23-47Article in journal (Refereed) Published
##### Abstract [en]

The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinsons disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.

##### Place, publisher, year, edition, pages
SPRINGER, 2019
##### Keywords
Parkinsons disease (PD); Multiple system atrophy (MSA); Alzheimers disease (AD); Cell-to-cell transfer; Prion-like transfer; Gap junction proteins; Cx32; GJB1; alpha-Synuclein (-syn)
##### National Category
Neurosciences
##### Identifiers
urn:nbn:se:liu:diva-158850 (URN)10.1007/s00401-019-02007-x (DOI)000471708700002 ()30976973 (PubMedID)
##### Note

Funding Agencies|Swedish Research Council [523-2013-2735]; Deutsche Forschungsgemeinschaft (DFG) [GRK2162]

Available from: 2019-07-16 Created: 2019-07-16 Last updated: 2019-10-14
• Public defence: 2019-11-07 10:15 Nobel BL32, Linköping
Linköping University, Department of Mathematics, Mathematics and Applied Mathematics. Linköping University, Faculty of Science & Engineering.
Dynamics of Coinfection: Complexity and Implications2019Doctoral thesis, comprehensive summary (Other academic)

Living beings are always on risk from multiple infectious agents in individual or in groups. Though multiple pathogens' interactions have widely been studied in epidemiology. Despite being well known, the co-existence of these pathogens and their coinfection remained a mystery to be uncovered. Coinfection is one of the important and interesting phenomenon in multiple interactions when two infectious agents coexist at a time in a host. The aim of this thesis is to understand the complete dynamics of coinfection and the role of different factors affecting these interactions.

Mathematical modelling is one of the tools to study the coinfection dynamics. Each model has its own limitations and choice of the model depends on the questions to be addressed. There is always a crosstalk between the choice of model and limitation of their solvability. The complexity of the problem defines the restriction in analytical possibilities.

In this thesis we formulate and analyse the mathematical models of coinfection with different level of complexities. Since viral infections are a major class of infectious diseases, in the first three papers we formulated a susceptible, infected, recovered (SIR) model for coinfection of the two viral strains in a single host population introducing carrying capacity as limited growth factor in susceptible class. In the first study, we made some assumptions for the transmission of coinfection in the model. In the following papers, the analysis is expanded by relaxing these assumptions which has generated the complexity in dynamics. We showed that the dynamics of stable equilibrium points depends on the fundamental parameters including carrying capacity K. A parameter dependent transition dynamics exists starting from disease free state to a level where coinfection can persists only with susceptible class. A disease-free equilibrium point is stable only when K is small. With increase in carrying capacity to a level where only single infection can invade and persists. Further increase in carrying capacity becomes large enough for the existence and persistence of coinfection due to the high density of susceptible class. In paper I, we proved the existence of a globally stable equilibrium point for any set of parameter values, revealing persistence of disease in a population. This shows a close relationship between the intensity of infection and carrying capacity as a crucial parameter of the population. So there is always a positive correlation between risk of infection and carrying capacity which leads to destabilization of the population.

In paper IV, we formulated mathematical models using different assumptions and multiple level of complexities to capture the effect of additional phenomena such as partial cross immunity, density dependence in each class and a role of recovered population in the dynamics. We found the basic reproduction number for each model which is the threshold that describes the invasion of disease in population. The basic reproduction number in each model shows that the persistence of disease or strains depends on the carrying capacity K. In the first model of this paper, we have also shown the local stability analysis of the boundary equilibrium points and showed that the recovered population is not uniformly bounded with respect to K.

Paper V uses simulations to analyse the dynamics and specifically studies how temporal variation in the carrying capacity of the population affects its dynamics. The degree of autocorrelation in variability of carrying capacity influences whether the different classes exhibit temporal variation or not. The fact that the different classes respond differently to the variation depends in itself on whether their equilibrium densities show a dependence on the carrying capacity or not. An important result is that at high autocorrelation, the healthy part of the population is not affected by the external variation and at the same time the infected part of the population exhibits high variation. A transition to lower autocorrelation, more randomness, means that the healthy population varies over time and the size of the infected population decreases in variation.

1. Dynamical behaviour of SIR model with coinfection: The case of finite carrying capacity
Open this publication in new window or tab >>Dynamical behaviour of SIR model with coinfection: The case of finite carrying capacity
2019 (English)In: Mathematical methods in the applied sciences, ISSN 0170-4214, E-ISSN 1099-1476, Vol. 42, p. 1-22Article in journal (Refereed) Published
##### Abstract [en]

Multiple viruses are widely studied because of their negative effect on the health of host as well as on whole population. The dynamics of coinfection are important in this case. We formulated an susceptible infected recovered (SIR) model that describes the coinfection of the two viral strains in a single host population with an addition of limited growth of susceptible in terms of carrying capacity. The model describes five classes of a population: susceptible, infected by first virus, infected by second virus, infected by both viruses, and completely immune class. We proved that for any set of parameter values, there exists a globally stable equilibrium point. This guarantees that the disease always persists in the population with a deeper connection between the intensity of infection and carrying capacity of population. Increase in resources in terms of carrying capacity promotes the risk of infection, which may lead to destabilization of the population.

##### Place, publisher, year, edition, pages
John Wiley & Sons, 2019
##### Keywords
carrying capacity, coinfection, global stability, linear complementarity problem, SIR model
##### National Category
Mathematical Analysis
##### Identifiers
urn:nbn:se:liu:diva-160293 (URN)10.1002/mma.5671 (DOI)2-s2.0-85066086382 (Scopus ID)
Available from: 2019-09-17 Created: 2019-09-17 Last updated: 2019-10-16Bibliographically approved
2. Mathematical analysis of complex SIR model with coinfection and density dependence
Open this publication in new window or tab >>Mathematical analysis of complex SIR model with coinfection and density dependence
2019 (English)In: Computational and Mathematical Methods, ISSN 2577-7408, Vol. 1, no 4Article in journal (Refereed) Published
##### Abstract [en]

An SIR model with the coinfection of the two infectious agents in a single host population is considered. The model includes the environmental carry capacity in each class of population. A special case of this model is analyzed, and several threshold conditions are obtained, which describes the establishment of diseases in the population. We prove that, for small carrying capacity K, there exists a globally stable disease-free equilibrium point. Furthermore, we establish the continuity of the transition dynamics of the stable equilibrium point, that is, we prove that, (1) for small values of K, there exists a unique globally stable equilibrium point, and (b) it moves continuously as K is growing (while its face type may change). This indicates that the carrying capacity is the crucial parameter and an increase in resources in terms of carrying capacity promotes the risk of infection.

##### Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2019
##### Keywords
carrying capacity, coinfection, global stability, SIR model
##### National Category
Mathematics Immunology
##### Identifiers
urn:nbn:se:liu:diva-160284 (URN)10.1002/cmm4.1042 (DOI)
##### Conference
2019/09/17
Available from: 2019-09-17 Created: 2019-09-17 Last updated: 2019-10-16Bibliographically approved
• Public defence: 2019-11-07 13:00 Berzelius salen, Linköping
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Visual grading evaluation of reconstruction methods and dose optimisation in abdominal Computed Tomography2019Doctoral thesis, comprehensive summary (Other academic)

Since its introduction in the 1970’s CT has emerged as a modality of choice because of its high sensitivity in producing accurate diagnostic images. A third of all Computed Tomography (CT) examinations are abdominal CTs which deliver one of the highest doses among common examinations. An increase in the number of CT examinations has raised concerns about the negative effects of ionising radiation as the dose is cumulative over the life span of the individual. Image quality in CT is closely related to the radiation dose, so that a certain dose with an associated small, but not negligible, risk is a prerequisite for high image quality. Typically, dose reduction in CT results in higher noise and a decrease in low contrast resolution which can be detrimental to the image quality produced. New technology presents a wide range of dose reduction strategies, the latest being iterative reconstruction (IR).The aim of this thesis was to evaluate two different classes of iterative reconstruction algorithms: statistical (SAFIRE) and model-based (ADMIRE) as well as to explore the diagnostic value of a low-dose abdominal CT for optimisation purposes.

This thesis included a total of 140 human subjects in four image quality evaluation studies, three of which were prospective studies (Papers I, II and IV) and one retrospective study (Paper III). Visual grading experiments to determine the potential dose reductions, were performed with pairwise comparison of image quality in the same patient at different tube loads (dose) and reconstructed with Filtered back projection (FBP) and SAFIRE strength 1 in a low-dose abdominal CT (Paper I) and FBP and ADMIRE strengths 3 and 5 in a standard dose abdominal CT (Paper II). Paper IV evaluated the impact of slice thicknesses in CT images reconstructed with ADMIRE strengths 3 and 5 when comparing multiplanar reconstruction (MPR) formatted images in a standard dose abdominal CT. Paper III, on the other hand, was an absolute assessment of image quality and pathology between the three phases of a CT Urography (CTU) protocol to explore the diagnostic value of low-dose abdominal CT. The anonymised images were displayed in random order and image quality was assessed by a group of radiologists using image quality criteria from the “European guidelines of quality criteria for CT”. The responses from the reviewer assessment were analysed statistically with ordinal logistic regression i.e. Visual Grading Regression (VGR).

Results in Paper I show that a small dose reduction (5-9 %) was possible using SAFIRE strength 1and indicated the need for further research to evaluate the dose reduction potential of higher strengths of the algorithm. In Paper II a 30% dose reduction was possible without change in ADMIRE algorithm strength as no improvement in image quality was observed between tube loads 98- and 140 mAs. When comparing tube loads 42 and 98 mAs, further dose reduction was possible with ADMIRE strength 3 (22-47%). However, for images reconstructed with ADMIRE strength 5, a dose reduction of 34-74% was possible for some, but not all image criteria. Image quality in low-contrast objects such as the liver parenchyma, was affected and a decline in diagnostic confidence was observed. Paper IV showed potential dose reductions are possible with increasing slice thickness from 1 mm to 2 mm (24-35%) and 1 mm to 3mm (25-41%). ADMIRE strength 3 continued to provide diagnostically acceptable images with possible dose reductions for all image criteria assessed. Despite objective evaluations showing a decrease in noise and an increase in contrast to noise ratio, ADMIRE strength 5 had diverse effects on the five image criteria, depending on slice thickness and further dose reductions were limited to certain image criteria. The findings do not support a general recommendation to replace ADMIRE3 with ADMIRE5 in clinical abdominal CT protocols.

Paper III studied another aspect of optimisation and results show that visualisation of renal anatomy was as expected in favour of the post-contrast phases when compared to the native phase. Assessment of pathology showed no significant differences between the three phases. Significantly higher diagnostic certainty for renal anatomy was observed for the post-contrast phases when compared to the native phase. Significantly high certainty scores were also seen for the nephrographic phase for incidental findings. The conclusion is that a low-dose series seems to be sufficient as a first-line modality in certain patient groups.

This thesis clinically evaluated the effect of IR in abdominal CT imaging and estimated potential dose reductions. The important conclusion from papers I, II and IV is that IR improves image quality in abdominal CT allowing for some dose reductions. However, the clinical utility of the highest strength of the algorithm is limited to certain criteria. The results can be used to optimise the clinical abdominal CT protocol. The conclusion from paper III may increase clinical awareness of the value of the low-dose abdominal protocol when choosing an imaging method for certain patient groups who are more sensitive to radiation.

1. Patient dose and image quality in low-dose abdominal CT: a comparison between iterative reconstruction and filtered back projection
Open this publication in new window or tab >>Patient dose and image quality in low-dose abdominal CT: a comparison between iterative reconstruction and filtered back projection
2013 (English)In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 54, no 5, p. 540-548Article in journal (Refereed) Published
##### Abstract [en]

Background In computed tomography (CT), there is increasing concern for potential CT radiation hazards. Several raw-data-based iterative reconstruction techniques attempt to facilitate low-dose imaging without compromising image quality, which raises the question whether these techniques may allow further dose reduction.

Purpose To compare image quality of iterative reconstruction and filtered back projection in low-dose abdominal CT and study the potential for further dose reduction.

Material and Methods Forty-five patients underwent CT of the abdomen twice: with standard low-dose technique and with 30% reduced dose, using both iterative reconstruction and filtered back projection. Four radiologists made pair-wise image quality assessment using five visual criteria. Visual grading regression (VGR) and weighted kappa (κ w) were used to analyze the data.

Results There were significant effects of log(mAs) (P <0.001) and reconstruction algorithm (P <0.01) on all image quality criteria with an estimated potential dose reduction of 5–9%. Inter-observer agreement ranged from 70% to 91% and κ w from −0.01 to 0.57.

Conclusion An iterative reconstruction algorithm improved image quality in abdominal CT, but the estimated dose reduction was rather small. The full potential of the algorithm remains unclear.

##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-90019 (URN)10.1177/0284185113476019 (DOI)000322323400014 ()23474768 (PubMedID)
Available from: 2013-03-15 Created: 2013-03-15 Last updated: 2019-10-15Bibliographically approved
2. Assessment of image quality in abdominal CT: potential dose reduction with model-based iterative reconstruction
Open this publication in new window or tab >>Assessment of image quality in abdominal CT: potential dose reduction with model-based iterative reconstruction
2018 (English)In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084Article in journal (Refereed) Published
##### Abstract [en]

Purpose To estimate potential dose reduction in abdominal CT by visually comparing images reconstructed with filtered back projection (FBP) and strengths of 3 and 5 of a specific MBIR.

Material and methods A dual-source scanner was used to obtain three data sets each for 50 recruited patients with 30, 70 and 100% tube loads (mean CTDIvol 1.9, 3.4 and 6.2 mGy). Six image criteria were assessed independently by five radiologists. Potential dose reduction was estimated with Visual Grading Regression (VGR).

Results Comparing 30 and 70% tube load, improved image quality was observed as a significant strong effect of log tube load and reconstruction method with potential dose reduction relative to FBP of 22–47% for MBIR strength 3 (p < 0.001). For MBIR strength 5 no dose reduction was possible for image criteria 1 (liver parenchyma), but dose reduction between 34 and 74% was achieved for other criteria. Interobserver reliability showed agreement of 71–76% (κw 0.201–0.286) and intra-observer reliability of 82–96% (κw 0.525–0.783).

Conclusion MBIR showed improved image quality compared to FBP with positive correlation between MBIR strength and increasing potential dose reduction for all but one image criterion.

##### Place, publisher, year, edition, pages
Heidelberg: Springer, 2018
##### Keywords
Dose Computed tomography Iterative reconstruction Abdomen FBP
##### National Category
Radiology, Nuclear Medicine and Medical Imaging
##### Identifiers
urn:nbn:se:liu:diva-145274 (URN)10.1007/s00330-017-5113-4 (DOI)000431653200023 ()29368163 (PubMedID)2-s2.0-85040915759 (Scopus ID)
##### Note

Funding agencies: ALF-grant from Region Ostergotland; LFoU-grant from Region Ostergotland; Medical Faculty at Linkoping University

Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2019-10-15Bibliographically approved
3. Image quality and pathology assessment in CT Urography: when is the low-dose series sufficient?
Open this publication in new window or tab >>Image quality and pathology assessment in CT Urography: when is the low-dose series sufficient?
2019 (English)In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 19, no 1, article id 64Article in journal (Refereed) Published
##### Abstract [en]

Background

Our aim was to compare CT images from native, nephrographic and excretory phases using image quality criteria as well as the detection of positive pathological findings in CT Urography, to explore if the radiation burden to the younger group of patients or patients with negative outcomes can be reduced.

Methods

This is a retrospective study of 40 patients who underwent a CT Urography examination on a 192-slice dual source scanner. Image quality was assessed for four specific renal image criteria from the European guidelines, together with pathological assessment in three categories: renal, other abdominal, and incidental findings without clinical significance. Each phase was assessed individually by three radiologists with varying experience using a graded scale. Certainty scores were derived based on the graded assessments. Statistical analysis was performed using visual grading regression (VGR). The limit for significance was set at p = 0.05.

Results

For visual reproduction of the renal parenchyma and renal arteries, the image quality was judged better for the nephrogram phase (p < 0.001), whereas renal pelvis/calyces and proximal ureters were better reproduced in the excretory phase compared to the native phase (p < 0.001). Similarly, significantly higher certainty scores were obtained in the nephrogram phase for renal parenchyma and renal arteries, but in the excretory phase for renal pelvis/calyxes and proximal ureters. Assessment of pathology in the three categories showed no statistically significant differences between the three phases. Certainty scores for assessment of pathology, however, showed a significantly higher certainty for renal pathology when comparing the native phase to nephrogram and excretory phase and a significantly higher score for nephrographic phase but only for incidental findings.

Conclusion

Visualisation of renal anatomy was as expected with each post-contrast phase showing favourable scores compared to the native phase. No statistically significant differences in the assessment of pathology were found between the three phases. The low-dose CT (LDCT) seems to be sufficient in differentiating between normal and pathological examinations. To reduce the radiation burden in certain patient groups, the LDCT could be considered a suitable alternative as a first line imaging method. However, radiologists should be aware of its limitations.

##### Place, publisher, year, edition, pages
BioMed Central, 2019
##### Keywords
Computed tomography; Urography; Low-dose; Optimization; Image quality; Dose
##### National Category
Radiology, Nuclear Medicine and Medical Imaging
##### Identifiers
urn:nbn:se:liu:diva-160048 (URN)10.1186/s12880-019-0363-z (DOI)000480486200001 ()31399078 (PubMedID)2-s2.0-85070460822 (Scopus ID)
##### Note

Funding Agencies|ALF-and LFoU-grants from Region Ostergotland; Medical Faculty at Linkoping University

Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-10-15Bibliographically approved
• Public defence: 2019-11-08 13:00 Berzeliussalen, Linköping
Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences.
Injury Prevention in Youth Football Players: Training Effects and Programme Implementation2019Doctoral thesis, comprehensive summary (Other academic)

Background With 17–35% of all 14-year-olds in Sweden being active in football, injuries do occur, most frequently during match play. Based on knowledge of injury mechanisms and risk factors, different injury prevention exercise programmes (IPEPs) have been developed. In this thesis, the Swedish IPEP Knee Control was used as a model for injury preventive training.

Aim The overall aim of this thesis was to improve our understanding of the effects of the Knee Control injury prevention exercise programme on sports performance and jump-landing technique, as well as exploring programme implementation and coach experiences of using the programme in youth football.

Methods Studies I and IV were cluster-randomised trials focusing on the performance effects of Knee Control. Study I included four teams with 41 female youth football players (mean age 14). The intervention group used Knee Control twice weekly for 11 weeks, whereas the control group teams did their usual training. Knee Control includes six different exercises at four levels of difficulty and with partner exercises and is meant to be used during warm-up at every training session. Performance was tested using a battery of balance, agility, jump and sprint tests at baseline and follow-up at an indoor venue. Study IV had a similar set-up but included two different interventions: Knee Control and a new, further-developed version of the programme, Knee Control+, which were studied during an eight-week intervention involving eight youth football teams, four male, four female (mean age 14), with 77 players. Similar, but not identical, performance tests were used in Study IV, along with drop vertical jumps and tuck jump assessment to assess jump-landing technique.

Studies II and III focused on the implementation context. Study II was questionnaire based, using the RE-AIM framework covering the reach, effectiveness, adoption, implementation and maintenance of Knee Control. Coaches for female youth teams (n=352), one representative of the national football association and representatives of eight district football associations responded to web-based questionnaires. Data collection was performed two years after the nation-wide implementation of Knee Control started. Study III was a qualitative study that followed up on the results of Study II. Interviews were conducted with 20 coaches for female football teams and analysed using qualitative content analysis. The interviews focused on factors that affected the adoption and use of Knee Control. All 20 coaches had experience of Knee Control.

Results Limited positive effects were seen on jump-landing technique in girls, with the total tuck jump assessment score improving, as well as two separate criteria, the number of jumps accomplished during the 10-second test and additionally an increased knee-flexion angle upon landing from a drop vertical jump. No improvements on the performance tests were found in either Study I or Study IV. Both studies, however, suffered from low player compliance with the IPEPs and as a result low training dosage. No major differences in results were seen between Knee Control and Knee Control+ in Study IV.

Study II showed that 91% of the responding coaches were familiar with Knee Control, they perceived the programme to be effective, 74% had started to use it, and it was fairly well maintained over time. However, only one third of the coaches used the programme every week and few used the whole programme. There were no formal policies for programme implementation and use in the district football associations and clubs. Study III showed that the coach was vital for programme use but needed social support, buy-in from players, resources and a feasible programme to facilitate programme adoption and use. When facing challenges with Knee Control implementation and use, the coaches did their best to work around these obstacles; for example, by modifying the programme content or dosage.

Conclusions In conclusion, limited positive effects on jump-landing technique were seen in girls, potentially affecting risk factors for injury positively. No clinically meaningful effects from Knee Control or Knee Control+ were seen on performance tests as measured in the studies in either boys or girls. This may be related to the low training dosage. The high programme reach, perceived effectiveness, adoption and fairly high maintenance of Knee Control were positive. The modifications of programme content and/or dosage were concerning but will hopefully decrease with a more user-friendly programme.

1. No effect on performance tests from a neuromuscular warm-up programme in youth female football: a randomised controlled trial
Open this publication in new window or tab >>No effect on performance tests from a neuromuscular warm-up programme in youth female football: a randomised controlled trial
2012 (English)In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 20, no 10, p. 2116-2123Article in journal (Refereed) Published
##### Abstract [en]

The objective of the present randomised controlled trial was to study the effect of a neuromuscular warm-up programme on performance tests in youth female football. less thanbrgreater than less thanbrgreater thanFour youth female football teams with players aged 12-16 years were randomised into an intervention group and control group. The intervention was a 15-min neuromuscular warm-up programme carried out twice a week during the 11-week study period. Baseline and follow-up measurements of performance were made indoors and included the star excursion balance test, a countermovement jump test, a triple-hop for distance test, a modified Illinois agility test, and 10- and 20-m sprint tests. less thanbrgreater than less thanbrgreater thanFifty-two players (intervention 28; control 24) took part in baseline measurements, and after dropout, 41 players (intervention 23; control 18) were included for analysis. Minor positive changes were seen in the control group compared to the intervention group for a sub-score of the star excursion balance test (P andlt; 0.05) and in the modified Illinois agility test (P andlt; 0.05). No improvement was seen in the intervention group from baseline to follow-up. less thanbrgreater than less thanbrgreater thanThe study showed that a neuromuscular warm-up programme carried out during 11 weeks did not improve performance in youth female football. This could indicate that the programme does not contain sufficient stimulus to improve performance. A low player attendance at training sessions, and low specificity between exercises in the warm-up programme and the evaluated performance tests may also contribute to the lack of effect. less thanbrgreater than less thanbrgreater thanI.

##### Place, publisher, year, edition, pages
Springer Verlag (Germany), 2012
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-84893 (URN)10.1007/s00167-011-1846-9 (DOI)000308968500033 ()
##### Note

Funding Agencies|Swedish Football Association||Swedish National Centre for Research in Sports||

Available from: 2012-10-26 Created: 2012-10-26 Last updated: 2019-10-08
2. Implementation of a neuromuscular training programme in female adolescent football: 3-year follow-up study after a randomised controlled trial
Open this publication in new window or tab >>Implementation of a neuromuscular training programme in female adolescent football: 3-year follow-up study after a randomised controlled trial
2014 (English)In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 19, p. 1425-1430Article in journal (Refereed) Published
##### Abstract [en]

BACKGROUND: Neuromuscular training (NMT) has been shown to reduce anterior cruciate ligament injury rates in highly structured clinical trials. However, there is a paucity of studies that evaluate implementation of NMT programmes in sports.

AIM: To evaluate the implementation of an NMT programme in female adolescent football 3 years after a randomised controlled trial (RCT).

METHODS: Cross-sectional follow-up after an RCT using the Reach, Effectiveness, Adoption, Implementation, and Maintenance Sports Setting Matrix (RE-AIM SSM) framework. Questionnaires were sent to the Swedish Football Association (FA), to eight district FAs and coaches (n=303) that participated in the RCT in 2009, and coaches who did not participate in the RCT but were coaching female adolescent football teams during the 2012 season (n=496).

RESULTS: Response rates were 100% among the FAs, 57% among trial coaches and 36% among currently active coaches. The reach of the intervention was high, 99% of trial coaches (control group) and 91% of current coaches were familiar with the programme. The adoption rate was 74% among current coaches, but programme modifications were common among coaches. No district FA had formal policies regarding implementation, and 87% of current coaches reported no club routines for programme use. Maintenance was fairly high; 82% of trial coaches from the intervention group and 68% from the control group still used the programme.

CONCLUSIONS: Reach and adoption of the programme was high among coaches. However, this study identified low programme fidelity and lack of formal policies for its implementation and use in clubs and district FAs.

##### Place, publisher, year, edition, pages
B M J Group, 2014
##### Keywords
ACL; Adolescents; Implementation; Injury Prevention; Soccer
##### National Category
Clinical Medicine
##### Identifiers
urn:nbn:se:liu:diva-110380 (URN)10.1136/bjsports-2013-093298 (DOI)000341947200008 ()24850618 (PubMedID)
Available from: 2014-09-09 Created: 2014-09-09 Last updated: 2019-10-08
3. Adoption and use of an injury prevention exercise program in female football: A qualitative study among coaches
Open this publication in new window or tab >>Adoption and use of an injury prevention exercise program in female football: A qualitative study among coaches
2018 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 28, no 3, p. 1295-1303Article in journal (Refereed) Published
##### Abstract [en]

This study focuses on an injury prevention exercise program (IPEP), Knee Control, which has been shown to reduce the incidence of acute knee injury in female adolescent football players. The aim was to explore the factors influencing coaches adoption and use of Knee Control within female football in Sweden. This was a qualitative study involving interviews with 20 strategically selected coaches for female football teams, predominantly adolescent teams. The semi-structured interview guide was influenced by the Health Belief Model, and an ecological perspective was adopted during the interviews. Interviews were analyzed with qualitative content analysis. The results illustrate the different influences that interact on adoption and use of Knee Control by coaches. The coaches described themselves as crucial for Knee Control adoption and use, but external facilitators and barriers such as resources for training, social support from other coaches, clubs and football associations and player buy-in were also described as important. Knee Control characteristics, such as how well the program fit the team, also influenced use of Knee Control. Many coaches modified the program to improve player buy-in and Knee Control fit. Such modifications may risk compromising the preventive effect but may increase feasibility, that is the ease of using Knee Control, and thereby long-term use. These findings may guide the design and delivery of future IPEPs, and improve use of Knee Control, for example, by expanding the program to fit different target groups and supporting coaches and players in the use of Knee Control.

##### Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
##### Keywords
dissemination; implementation; neuromuscular training; team sports; youth
##### National Category
Sport and Fitness Sciences
##### Identifiers
urn:nbn:se:liu:diva-147150 (URN)10.1111/sms.13012 (DOI)000426529300058 ()29130536 (PubMedID)
##### Note

Funding Agencies|Swedish Research Council for Sport Science; Region Ostergotland

Available from: 2018-04-20 Created: 2018-04-20 Last updated: 2019-10-08
4. Limited positive effects on jump-landing technique in girls but not in boys after 8 weeks of injury prevention exercise training in youth football
Open this publication in new window or tab >>Limited positive effects on jump-landing technique in girls but not in boys after 8 weeks of injury prevention exercise training in youth football
2019 (English)In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347Article in journal (Refereed) Epub ahead of print
##### Abstract [en]

PURPOSE: To evaluate changes in jump-landing technique in football-playing boys and girls after 8 weeks of injury prevention training.

METHODS: Four boys' and four girls' teams (mean age 14.1 ± 0.8 years) were instructed to use either the original Knee Control injury prevention exercise programme (IPEP) or a further developed IPEP, Knee Control + , at every training session for 8 weeks. Baseline and follow-up testing of jump-landing technique included drop vertical jumps (DVJ), assessed subjectively and with two-dimensional movement analysis, and tuck jump assessment (TJA).

RESULTS: Only minor differences in intervention effects were seen between the two IPEPs, and results are therefore presented for both intervention groups combined. At baseline 30% of the boys showed good knee control during the DVJ, normalised knee separation distances of 77-96% (versus hip) and a median of 3 flaws during the TJA. Among girls, 22% showed good knee control, normalised knee separation distances of 67-86% and a median of 4 flaws during the TJA. At follow-up, boys and girls performed significantly more jumps during TJA. No changes in jump-landing technique were seen in boys, whereas girls improved their knee flexion angle at initial contact in the DVJ (mean change + 4.7°, p < 0.001, 95% CI 2.36-6.99, d = 0.7) and their TJA total score (- 1 point, p = 0.045, r = - 0.4).

CONCLUSION: The study showed small positive effects on jump-landing technique in girls, but not in boys, after 8 weeks of injury prevention training.

LEVEL OF EVIDENCE: Level II.

TRIAL REGISTRATION: Clinical Trials gov identifier: NCT03251404.

##### Keywords
Effect mechanisms, Movement quality, Neuromuscular training
##### National Category
Sport and Fitness Sciences
##### Identifiers
urn:nbn:se:liu:diva-160777 (URN)10.1007/s00167-019-05721-x (DOI)31541293 (PubMedID)
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2019-10-08
• Public defence: 2019-11-21 13:00 Berzeliussalen, Linköping
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
The Propagation of Neurodegenerative Diseases by Inflammation and Exosomes2019Doctoral thesis, comprehensive summary (Other academic)

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases with rates increasing along with the ageing global population. Despite best efforts, we still do not understand the etiopathogenesis of these diseases and there are no effective disease-modifying treatments. Cognitive deficiencies or motor complications that emerge during AD and PD are thought to be the result of the accumulation of misfolded, aggregate-prone proteins, such as amyloid-β (Aβ) and tau or α-synuclein (α-syn), respectively. Growing evidence suggests that prefibrillar oligomers of Aβ and α-syn (oAβ and oα-syn) are key contributors to the progression of these diseases. The progressive accumulation of these proteins leads to a gradual spread of pathology throughout interconnected brain regions, but the mechanisms by which this spreading occurs are still largely unknown.

Neuroinflammation has been recognised as an important contributor to neurodegenerative disease. It is hypothesised that a pro-inflammatory environment initiated by the innate immune system, either through activation from Aβ itself or indirectly through neuronal injury signals in AD. These phenomena are thought to either cause or accelerate AD, such that an anti-inflammatory approach may be neuroprotective. In paper I, we investigated whether different inflammatory environments affected the transfer of oAβ between neuron-like cells, in addition to investigating inter- and intracellular protein changes. This study demonstrated that an anti-inflammatory environment reduces the transfer of oAβ between cells. We also provide evidence that these cells begin to take on the “phenotype” of the inflammatory milieu, while also demonstrating that the expression profile of endosomal/lysosomal and protein trafficking proteins is altered during these conditions.

Small extracellular vesicles called exosomes, which are key players in cell to cell communication, have been proposed to play an influential role in spreading neurodegenerative proteins between cells. Exosomes are small membranous vesicles that are formed by the inward budding of multivesicular bodies (MVBs). These MVBs can then merge with the plasma membrane to be released into the extracellular environment as vesicles, which serve as vehicles for transferring proteins, lipids, and mRNAs between cells.

The ESCRT-dependent pathway is the most understood mechanism underlying exosome biogenesis. However, exosomes can also be formed through ESCRT-independent pathways, including through the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2), which produces ceramide. Paper II investigated whether exosomes formed through an ESCRT-independent pathway plays a significant role in the transfer of oα-syn between neuron-like cells. As oxidative stress is a common feature in PD brains, which in turn dysregulates nSMase2 activity, we also tested our model under hypoxic conditions. Inhibition of nSMase2 significantly reduced the transfer of oα-syn between cells but also resulted in decreased α-syn aggregation. Hypoxia did not influence oα-syn transfer, however, it significantly dysregulated the sphingolipid composition, which may be important for α-syn binding to exosomes and exosome communication.

During AD and PD, there is a noted reduction in the effectiveness of autophagy, a process critical to cellular proteostasis. Recent studies have uncovered shared regulatory mechanisms of exosome biogenesis and autophagy, suggesting that they are closely linked. Previous findings have shown that inhibition of autophagy in AD mice mediates Aβ trafficking through altering the secretion of Aβ in MVBs. To further study this effect, we investigated the interplay between autophagy and exosome secretion using ATG7 knock-out x APPNL-F knock-in AD mice in paper III. These autophagy-deficient AD mice had a reduced extracellular Aβ plaque load, but increased intracellular Aβ, which was found to be assembled into higher-ordered assemblies. While exosomal secretion was dysregulated in these mice, the amount of Aβ packaged into the exosomes was unchanged.

Lastly, one of the biggest challenges in developing effective treatments for AD is the lack of early diagnosis of living patients. As the connection between exosomes and the spread of neurodegenerative proteins is still relatively new, there remains a diagnostic potential to be explored with exosomes. Paper IV aimed to develop a new diagnostic assay to detect oAβ in exosomes isolated from human cerebrospinal fluid. Although exosomal oAβ was readily detected in some of these samples, the assay’s sensitivity requires additional optimisation before it can be further validated for the clinic.

In summary, the studies presented in this thesis have furthered our understanding of how inflammation, autophagy, and exosomes contribute to the intercellular transmission of AD and PD associated proteins. We have shown that an anti-inflammatory approach may slow down the progression of AD through reducing the transfer of oAβ between cells. We also provide novel findings relating to the biogenesis of exosomes, which in turn affected the ability of exosomes to transmit neurodegenerative proteins between cells, and their association with autophagic processes. Finally, we have investigated the feasibility of exosomes as an early AD diagnostic marker. This work has helped to elucidate some of the mechanisms underlying the progression of neurodegenerative diseases, which may be useful targets for the investigation of new therapeutic avenues.

1. Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells
Open this publication in new window or tab >>Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells
2017 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 60, p. 173-182Article in journal (Refereed) Published
##### Abstract [en]

Neuroinflammation plays an influential role in Alzheimers disease (AD), although the mechanisms underlying this phenomenon remain largely unknown. Microglia are thought to be responsible for the majority of these effects and can be characterized into resting (M0), proinflammatory (M1), or anti-inflammatory (M2) functional phenotypes. We investigated the effects of conditioned macrophage media, as an analogue to microglia, on the transfer of oligomeric amyloid beta (oA beta) between differentiated SH-SY5Y cells. We also investigated how the different inflammatory environments related to intercellular and intracellular changes. We demonstrate that M2 products decrease interneuronal transfer of oA beta, while recombinant interleukin (IL)-4, IL-10, and IL-13 increase transfer. There were no alterations to the mRNA of a number of AD-related genes in response to the combination of oA beta and M0, M1, or M2, but several intracellular proteins, some relating to protein trafficking and the endosomal/lysosomal system, were altered. Stimulating microglia to an M2 phenotype may thus slow down the progression of AD and could be a target for future therapies. (C) 2017 Elsevier Inc. All rights reserved.

##### Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2017
##### Keywords
Anti-inflammatory; Proinflammatory; Amyloid beta oligomers; Cytokine; Cell-to-cell transfer; Alzheimers disease
##### National Category
Neurosciences
##### Identifiers
urn:nbn:se:liu:diva-143067 (URN)10.1016/j.neurobiolaging.2017.08.022 (DOI)000414424800016 ()28969867 (PubMedID)
##### Note

Funding Agencies|Swedish Research Council [523-2013-2735]; Swedish Alzheimer foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Gustav V and Queen Victorias Foundation; Swedish Dementia Foundation; Linkoping University Neurobiology Centre; County Council of Ostergotland

Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2019-10-16
2. Inhibition of nSMase2 Reduces the Transfer of Oligomeric alpha-Synuclein Irrespective of Hypoxia
Open this publication in new window or tab >>Inhibition of nSMase2 Reduces the Transfer of Oligomeric alpha-Synuclein Irrespective of Hypoxia
2019 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 12, article id 200Article in journal (Refereed) Published
##### Abstract [en]

Recently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of alpha-synuclein (alpha-syn). However, the regulation of EV biogenesis and its relation to Parkinsons disease (PD) is only partially understood. The generation of EVs through the ESCRT-independent pathway depends on the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2) to produce ceramide, which causes the membrane of endosomal multivesicular bodies to bud inward. nSMase2 is sensitive to oxidative stress, a common process in PD brains; however, little is known about the role of sphingomyelin metabolism in the pathogenesis of PD. This is the first study to show that inhibiting nSMase2 decreases the transfer of oligomeric aggregates of alpha-syn between neuron-like cells. Furthermore, it reduced the accumulation and aggregation of high-molecular-weight alpha-syn. Hypoxia, as a model of oxidative stress, reduced the levels of nSMase2, but not its enzymatic activity, and significantly altered the lipid composition of cells without affecting EV abundance or the transfer of alpha-syn. These data show that altering sphingolipids can mitigate the spread of alpha-syn, even under hypoxic conditions, potentially suppressing PD progression.

##### Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
##### Keywords
Parkinsons disease; extracellular vesicles; neutral sphingomyelinase 2; alpha-syn; hypoxia; cell-to-cell transmission; sphingomyelin; ceramide
##### National Category
Neurosciences
##### Identifiers
urn:nbn:se:liu:diva-160421 (URN)10.3389/fnmol.2019.00200 (DOI)000482932300001 ()
##### Note

Funding Agencies|Swedish Research Council [523-2013-2735]; Swedish Brain Foundation; Research Foundation of the Swedish Parkinsons Disease Association; Ostergotland Research Foundation for Parkinsons Disease; Parkinson Research Foundation; Swedish Alzheimers Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Swedish Dementia Foundation; Linkoping University Neurobiology Center; County Council of Ostergotland

Available from: 2019-09-23 Created: 2019-09-23 Last updated: 2019-10-16
• Public defence: 2019-11-22 09:15 Planck, Physics building, LinköpingLindholm, Caroline
Intermittent fasting in chickens: Physiological mechanisms and welfare implications for broiler breeders2019Doctoral thesis, comprehensive summary (Other academic)

Broiler breeder chickens are the parent stock used to produce broiler chickens raised for human consumption and have long been caught in a welfare dilemma. The immensely successful selection of fast-growing meat-type chickens over the last 80 years has created a remarkably efficient meat-producer and given us access to cheap chicken meat but has also created health problems for the animals. These problems especially affect the breeder generation, which must be raised with strict feed restriction to limit weight gain and thus maintain physical health and normal fertility. At the same time, however, feed restriction causes chronic hunger and feeding frustration with reduced animal welfare as a result. In the EU alone 60 million breeders are affected annually and although the problem is well-known within the industry, there is financial incentive to keep selecting for even higher growth potential in broilers, further increasing the problems for broiler breeders.

Many strategies for reducing the impact of growth restriction on breeder welfare have been suggested and are usually aimed at somehow increasing the amount of feed given at feeding times. This can be done either through adding bulky fibers to the diet or by reducing feeding frequency. In this thesis, focus is on the latter as we explore the effects of intermittent fasting (IF) on the welfare of young broiler breeders as well as wild-type Red Junglefowl. Intermittent fasting, or “skip-a-day” feeding, is supposedly the most common feeding strategy for broiler breeders worldwide but is perceived as welfare-reducing and thus illegal in Sweden and several other European countries. In spite of this, the scientific knowledge of how this type of feeding affects chicken welfare is scarce.

Assessing the overall effect of IF on breeder welfare is complicated by large variations in both physiological and behavioral parameters between feeding and fasting days, but it does appear that chicken welfare is improved at least on the feeding days of IF regimens. It also seems that some of the health benefits reported from mammalian studies of IF may apply to chickens as well, although behavioral indicators still point to welfare issues unless the level of feed restriction can be relaxed. In comparison with daily feed restriction, IF appears to increase the motivation for feed consumption but to reduce the motivation for appetitive behaviors such as foraging, which may explain why birds fed on this type of schedule are often reported as calmer.

1. Slow and steady wins the race? No signs of reduced welfare in smallerbroiler breeder hens at four weeks of age
Open this publication in new window or tab >>Slow and steady wins the race? No signs of reduced welfare in smallerbroiler breeder hens at four weeks of age
2015 (English)In: Animal Welfare, ISSN 0962-7286, Vol. 24, no 4, p. 447-454Article in journal (Refereed) Published
##### Abstract [en]

Broiler breeder chickens are commonly reared under strict feed-restriction regimes to reduce obesity-induced health and fertilityproblems during adult life, and are assumed to experience a reduced welfare due to the resulting hunger. In these conditions, feedcompetition could influence the growth rate, so that the individuals falling behind in growth would experience more stress and hunger.We hypothesised that these chickens are poor competitors due to a reactive coping style and experience a further reduced welfaresituation before size-sorting (‘grading’) at four weeks of age. Our results from open field, tonic immobility and home pen activity monitoringshow signs of lower fear and higher home-pen activity levels in smaller hens and do not support the idea of reactive coping.H/L ratios of smaller hens were also found to be lower, indicating less stress in these birds. Dissections of smaller and larger fourweekbreeder hens may offer an explanation in the form of a relatively larger gastrointestinal tract in smaller birds. We argue thatthis is a form of habituation to restricted feeding, offering these birds a physiological stress coping mechanism, and that low earlygrowth rate may not always be a sign of poorer welfare in broiler breeders.

##### Place, publisher, year, edition, pages
Universities Federation for Animal Welfare, 2015
##### Keywords
animal welfare, broiler breeders, chicken, feed restriction, growth, stress
Zoology
##### Identifiers
urn:nbn:se:liu:diva-122024 (URN)10.7120/09627286.24.4.447 (DOI)000363898500009 ()
##### Note

Funding agencies: Swedish research council Formas [2013-293]

Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2019-10-10
2. Growth heterogeneity in broiler breeder pullets is settled before the onset of feed restriction but is not predicted by size at hatch
Open this publication in new window or tab >>Growth heterogeneity in broiler breeder pullets is settled before the onset of feed restriction but is not predicted by size at hatch
2017 (English)In: Journal of Animal Science, ISSN 0021-8812, E-ISSN 1525-3163, Vol. 95, no 1, p. 182-193, article id 2017.95Article in journal (Refereed) Published
##### Abstract [en]

Uniform growth is a desirable trait in  all large-scale animal production systems because it  simplifies animal management and increases profitability.  In parental broiler flocks, so-called broiler  breeders, low growth uniformity is largely attributed  to the feed competition that arises from quantitatively  restricted feeding. As feed restriction is crucial to  maintaining healthy and fertile breeders, several practices  for reducing feed competition and the associated  growth heterogeneity have been suggested and range  from nutrient dilution by increasing fiber content in  feed to intermittent fasting with increased portion size  (“skip a day”), but no practice appears to be entirely  effective. The fact that a large part of the heterogeneity  remains even when feed competition is minimized  suggests that some growth variation is caused by other  factors. We investigated whether this variation arises  during embryonic development (as measured by size at  hatch) or during posthatch development by following  the growth and body composition of birds of varying  hatch sizes. Our results support the posthatch alternative,  with animals that later grow to be small or large  (here defined as >1 SD lighter or heavier than mean  BW of the flock) being significantly different in size as  early as 1 d after gaining access to feed (P < 0.05). We  then investigated 2 possible causes for different postnatal  growth: that high growth performance is linked 1) to  interindividual variations in metabolism (as measured  by cloacal temperature and verified by respirometry)  or 2) to higher levels of social motivation (as measured  in a social reinstatement T-maze), which should reduce  the stress of being reared in large-scale commercial  flocks. Neither of these follow-up hypotheses could  account for the observed heterogeneity in growth. We  suggest that the basis of growth heterogeneity in broiler  breeder pullets may already be determined at the time  of hatch in the form of qualitatively different maternal  investments or immediately thereafter as an indirect  result of differences in incubation conditions, hatching  time, and resulting fasting time. Although this potential  difference in maternal investment is not seen in body  mass, tarsometatarsal length, or full body length of  day-old chicks arriving at the farm, it may influence  the development of differential feed and water intake  during the first day of feeding, which in turn has direct  effects on growth heterogeneity.

##### Place, publisher, year, edition, pages
Champaign, IL, United States: American Society of Animal Science, 2017
##### Keywords
broiler breeders, feed restriction
Ecology
##### Identifiers
urn:nbn:se:liu:diva-133189 (URN)10.2527/jas.2016.0929 (DOI)000397115100019 ()28177396 (PubMedID)
Available from: 2016-12-13 Created: 2016-12-13 Last updated: 2019-10-10Bibliographically approved
3. The physiological and neuroendocrine correlates of hunger in the Red Junglefowl (Gallus gallus)
Open this publication in new window or tab >>The physiological and neuroendocrine correlates of hunger in the Red Junglefowl (Gallus gallus)
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17984Article in journal (Refereed) Published
##### Abstract [en]

The ability to regulate food intake is critical to survival. The hypothalamus is central to this regulation, integrating peripheral signals of energy availability. Although our understanding of hunger in rodents is advanced, an equivalent understanding in birds is lacking. In particular, the relationship between peripheral energy indices and hypothalamic hunger peptides, agouti-related protein (AgRP), proopiomelanocortin (POMC) and neuropeptide Y (NPY) is poorly understood. Here, we compare AgRP, POMC and NPY RNA levels in the hypothalamus of Red Junglefowl chicks raised under ad libitum, chronic restriction and intermittent feeding regimens. Hypothalamic gene expression differed between chronically and intermittently restricted birds, confirming that different restriction regimens elicit different patterns of hunger. By assessing the relationship between hypothalamic gene expression and carcass traits, we show for the first time in birds that AgRP and POMC are responsive to fat-related measures and therefore represent long-term energy status. Chronically restricted birds, having lower indices of fat, show elevated hunger according to AgRP and POMC. NPY was elevated in intermittently fasted birds during fasting, suggesting a role as a short-term index of hunger. The different physiological and neuroendocrine responses to quantitative versus temporal feed restriction provide novel insights into the divergent roles of avian hunger neuropeptides.

##### Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
##### National Category
Other Biological Topics
##### Identifiers
urn:nbn:se:liu:diva-144265 (URN)10.1038/s41598-017-17922-w (DOI)000418562100024 ()29269733 (PubMedID)
##### Note

Funding Agencies|Swedish research council Formas [2013-293]; Swedish Centre of Excellence in Animal Welfare Science; Carl Tryggers Stiftelse for Vetenskaplig Forskning

Available from: 2018-01-12 Created: 2018-01-12 Last updated: 2019-10-10
4. Measuring ketones in the field: rapid and reliable measures of beta-hydroxybutyrate in birds
Open this publication in new window or tab >>Measuring ketones in the field: rapid and reliable measures of beta-hydroxybutyrate in birds
2019 (English)In: Ibis, ISSN 0019-1019, E-ISSN 1474-919X, Vol. 161, no 1, p. 205-210Article in journal (Refereed) Published
##### Abstract [en]

Ketone bodies such as beta-hydroxybutyrate are important indicators of metabolic condition in birds and are linked to a suite of ecologically relevant factors including migratory decision-making, hunger level and ectoparasite load. Portable point-of-care (POC) devices designed to measure ketones in humans offer a cheap and easy solution to field physiologists in comparison with previous laboratory methods; however, their accuracy for use in birds has received scant attention. Here, we assessed the accuracy of a POC ketone meter (FreeStyle Precision Neo, Abbott, IL, USA) using samples from intermittently fed Red Junglefowl Gallus gallus. Although the device overestimated ketone levels in comparison with laboratory-derived values, random error was low and laboratory vs. device values correlated well, indicating that the Precision Neo is of sufficient accuracy for use in the field and is a pragmatic choice for avian physiologists.

WILEY, 2019
##### Keywords
intermittent feeding; ketosis; point-of-care; Red Junglefowl
Ecology
##### Identifiers
urn:nbn:se:liu:diva-153969 (URN)10.1111/ibi.12643 (DOI)000454604400018 ()
##### Note

Funding Agencies|Swedish research council Formas [2013-293]; Swedish Centre of Excellence in Animal Welfare Science; Carl Tryggers Stiftelse for Vetenskaplig Forsknin

Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-10-10
5. The Quest for Welfare-Friendly Feeding of Broiler Breeders: Effects of Daily vs. 5:2 Feed Restriction Schedules
Open this publication in new window or tab >>The Quest for Welfare-Friendly Feeding of Broiler Breeders: Effects of Daily vs. 5:2 Feed Restriction Schedules
2018 (English)In: Poultry Science, ISSN 0032-5791, E-ISSN 1525-3171, Vol. 97, no 2, p. 368-377Article in journal (Refereed) Published
##### Abstract [en]

Restricted feeding of broiler breeders is required for improved long-term health and welfare. Because feeding frustration and hunger are major welfare concerns during rearing, many suggestions have been made to decrease the negative feelings of hunger while maintaining suitable growth rates and reproductive health. Non-daily ("skip-a-day") feeding schedules are commonly used around the world to increase portion sizes at meal times while restricting intake but these practices are prohibited in many countries due to welfare concerns on fasting days. We compared birds raised on a non-daily feeding schedule (2 non-consecutive fasting days per week, 5:2), previously suggested as a welfare-friendlier non-daily alternative, to birds raised on daily feed restriction. We found signs of increased physiological stress levels in 5:2 birds, including elevated heterophil to lymphocyte ratios (1.00 for 5:2 vs. 0.75 for daily fed at 12 weeks of age), increased adiposity (0.21% lean body weight [LBW] for 5:2 vs. 0.13% LBW for daily fed), and reduced muscle growth (pectoral muscle 5.94% LBW for 5: 2 vs. 6.52% LBW for daily fed). At the same time, 5:2 birds showed signs of lower anxiety before feeding times (activity was reduced from 10.30 in daily fed to 4.85) which may be a result of the lower feed competition associated with larger portion sizes. Although we found no difference in latency to first head movement in tonic immobility between the treatments (136.5 s on average for both groups), 5:2 birds generally showed more interest in a novel object in the home pen which indicated increased risk taking and reduced fear while fasting. The 5:2 birds in this study showed no signs of learning the feeding schedule, and this unpredictability may also increase stress. Taken together, the effects of 5:2 vs. daily feed restriction on the welfare of broiler breeder pullets remain inconclusive and differ between feeding and fasting days. In addition to reducing stress by minimizing the number of fasting days, we suggest that a shift to more predictable schedules may help improve the welfare of broiler breeder pullets.

##### Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
##### Keywords
animal welfare; broiler breeders; feed restriction; intermittent fasting; skip-a-day
Zoology
##### Identifiers
urn:nbn:se:liu:diva-145242 (URN)10.3382/ps/pex326 (DOI)000424248600003 ()29182752 (PubMedID)
##### Note

Funding Agencies|Swedish research council Formas [2013-293]; Swedish Centre of Excellence in Animal Welfare Science

Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2019-10-10
Linköping University, Department of Electrical Engineering, Integrated Circuits and Systems. Linköping University, Faculty of Science & Engineering.
Studies on Selected Topics in Radio Frequency Digital-to-Analog Converters2019Doctoral thesis, comprehensive summary (Other academic)

The network latency in fifth generation mobile technology (5G) will be around one millisecond which is much lower than in 4G technology. This significantly faster response time together with higher information capacity and ultra-reliable communication in 5G technology will pave the way for future innovations in a smart and connected society. This new 5G network should be built on a reasonable wireless infrastructure and 5G radio base-stations that can be vastly deployed. That is, while the electrical specification of a radio base-station in 5G should be met in order to have the network functioning, the size, weight and power consumption of the radio system should be optimized to be able to commercially deploy these radios in a huge network.

As the number of antenna elements increases in massive multiple-input multiple-output based radios such as in 5G, designing true multi-band base-station radios, with efficient physical size, power consumption and cost in emerging cellular bands especially in mid-bands (frequencies up to 10~GHz), is becoming a challenge. This demands a hard integration of radio components; particularly the radio's digital application-specific integrated circuits (ASIC) with high-performance energy-efficient multi-band data converters.

In this dissertation radio frequency digital-to-analog converter (RF DAC) and semi-digital finite-impulse response (FIR) filter digital-to-analog converter has been studied. Different techniques are used in these structures to improve the transmitter's overall performance.

In the RF DAC part, a radio frequency digital-to-analog converter solution is presented, which is capable of monolithic integration into today's digital ASIC due to its digital-in-nature architecture, while fulfills the stringent requirements of cellular network radio base station linearity and bandwidth. A voltage-mode conversion method is used as output stage, and configurable mixing logic is employed in the data path to create a higher frequency lobe and utilize the output signal in the first or the second Nyquist zone and hence achieving output frequencies up to the sample rate.

In the semi-digital FIR part, optimization problem formulation for semi-digital FIR digital-to-analog converter is investigated. Magnitude and energy metrics with variable coefficient precision are defined for cascaded digital Sigma-Delta modulators, semi-digital FIR filter, and Sinc roll-off frequency response of the DAC. A set of analog metrics as hardware cost is also defined to be included in semi-digital FIR DAC optimization problem formulation. It is shown that hardware cost of the semi-digital FIR DAC, can be reduced by introducing flexible coefficient precision in filter optimization while the semi-digital FIR DAC is not over-designed either. Different use cases are selected to demonstrate the optimization problem formulations. A combination of magnitude metric, energy metric, coefficient precision and analog metric are used in different use cases of the optimization problem formulation and solved to find out the optimum set of analog FIR taps.

Moreover, a direct digital-to-RF converter (DRFC) is presented in this thesis where a semi-digital FIR topology utilizes voltage-mode RF DAC cells to synthesize spectrally clean signals at RF frequencies. Due to its digital-in-nature design, the DRFC benefits from technology scaling and can be monolithically integrated into advance digital VLSI systems. A fourth-order single-bit quantizer bandpass digital Sigma-Delta modulator is used preceding the DRFC, resulting in a high in-band signal-to-noise ratio (SNR). The out-of-band spectrally-shaped quantization noise is attenuated by an embedded semi-digital FIR filter. The RF output frequencies are synthesized by a configurable voltage-mode RF DAC solution with a high linearity performance.

A compensation technique to cancel the code-dependent supply current variation in voltage-mode RF DAC for radio frequency direct digital frequency synthesizer is also presented in this dissertation and is studied analytically. The voltage-mode RF DAC and the compensation technique are mathematically modeled and system-level simulation is performed to support the analytical discussion.

• Public defence: 2019-12-13 10:15 Planck, E-House, Linköping
Linköping University, Department of Management and Engineering, Solid Mechanics. Linköping University, Faculty of Science & Engineering.
Modelling of Crack Growth in Single-Crystal Nickel-Base Superalloys2019Doctoral thesis, comprehensive summary (Other academic)

This dissertation was produced at the Division of Solid Mechanics at Linköping University and is part of a research project, which comprises modelling, microstructure investigations and material testing of cast nickel-base superalloys. The main objective of this work was to deepen the understanding of the fracture behaviour of single-crystal nickel-base superalloys and to develop a model to predict the fatigue crack growth behaviour. Frequently, crack growth in these materials has been observed to follow one of two distinct cracking modes; Mode I like cracking perpendicular to the loading direction or crystallographic crack growth on the octahedral {111}-planes, where the latter is associated with an increased fatigue crack growth rate. Thus, it is of major importance to account for this behaviour in component life prediction. Consequently, a model for the prediction of the transition of cracking modes and the correct active crystallographic plane, i.e. the crack path, and the crystallographic crack growth rate has been developed. This model is based on the evaluation of appropriate crack driving forces using three-dimensional finite-element simulations. A special focus was given towards the influence of the crystallographic orientation on the fracture behaviour. Further, a model to incorporate residual stresses in the crack growth modelling is presented. All modelling work is calibrated and validated by experiments on different specimen geometries with different crystallographic orientations. This dissertation consists of two parts, where Part I gives an introduction and background to the field of research, while Part II consists of six appended papers.