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• 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: 2019-11-08 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
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.