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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 c

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/treatm

Olfactory loss is a common non-motor symptom of Parkinson’s disease (PD), often preceding the cardinal motor symptoms of the disease. The aim of this thesis was to: (a) evaluate whether olfactory examination can increase diagnostic accuracy, and (b) study the structural and functional neural basis of olfactory dysfunction in PD with different applications of Magnetic Resonance Imaging (MRI). Paper I was a comparison of the diagnostic accuracy between a simple smell identification test and DaTSCAN Single Photon Emission Computerized Tomography (SPECT), a nuclear medicine tomographic imaging technique that is commonly used in patients with suspected parkinsonism. The results indicate that smell test is inferior to DaTSCAN SPECT, but the combination of these two methods can lead to improved diagnostic accuracy. Paper II showed that diffusion MRI could detect discrete microstructural changes in the white matter of brain areas that participate in higher order olfactory neurotransmission, whereas MRI with Magnetization Transfer contrast could not. Paper III was a methodological study on how two different acquisition parameters can affect the activation pattern of olfactory brain areas, as observed with functional MRI (fMRI). The results indicate that brief olfactory stimulation and fast sampling rate should be preferred on olfactory fMRI studies. Paper IV used olfactory fMRI and resting-state fMRI in order to elucidate potentially altered activation patterns and functional connectivity within olfactory brain areas, between PD patients and healthy controls. Olfactory fMRI showed that olfactory impairment in PD is associated with significantly lower recruitment of the olfactory network. Resting-state fMRI did not detect any significant changes in the functional connectivity within the olfactory network of PD patients. In conclusion, the included studies provide evidence of: (a) disease-related structural and functional changes in olfactory brain areas, and (b) beneficial ad

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) comprise microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Two serotypes are recognized: myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA. Renal involvement is a common and severe manifestation associated with increased mortality. The incidence varies geographically, but studies are difficult to compare due to heterogeneous methodology and inclusion criteria. AAV is commonly found in the elderly, but there are little data on outcome and optimal treatment in the highest age groups. This thesis focuses on the epidemiology of AAV: incidence, geographical distribution, and outcome. In Paper I annual incidence rates and outcome were compared between nephritis in AAV and nephritis in systemic lupus erythematosus (SLE) in two geographically defined populations in Sweden. Even though SLE is twice as common as AAV, ANCA-associated nephritis outnumbered lupus nephritis by three to one, and was significantly more severe in terms of mortality and development of end stage renal disease. In Paper II associations between ANCA serotype and geographical and demographic factors were investigated in a large multi-centre study of 1408 patients with renal biopsy-proven AAV. PR3-ANCA was associated with male gender, younger age and higher glomerular filtration rate. PR3-ANCA was also associated with higher latitude and lower ultraviolet radiation levels, but analyses of subgroups suggested that genetic rather than environmental explanations might be more important for this geographical gradient. In Paper III a consecutive cohort of 151 elderly patients with MPA and GPA was studied with a focus on treatment, mortality and renal survival. Patients who had received immunosuppressive treatment with cyclophosphamide or rituximab had better survival rates compared to less intensively treated or untreated patients. Severely impaired r

This thesis project focuses on measurements of dermal microcirculation during vascular provocations with polarised light spectroscopy. This is done with a non-invasive method commercially available as Tissue viability imaging (TiVi) which measures concentration and oxygenation of red blood cells in the papillary dermis. Three studies were done with human subjects and one with an animal model, to validate and compare the TiVi technique with laser Doppler flowmetry, which is an established method of measuring dermal microcirculation. The TiVi consists of a digital camera with polarisation filters in front of the flash and lens, with software for analysis of the picture. When taking a picture with the TiVi, the polarised light that is reflected on the skin surface is absorbed by the second filter over the lens (which is perpendicular to the first filter) but a portion of light penetrates the surface of the skin and is scattered when it is reflected on tissue components. This makes the light depolarised, passes the second filter, and produces a picture for analysis. The red blood cell (RBC) has a distinct absorption pattern that differs between red and green colour compared to melanin and other components of tissue. This difference is used by the software that calculates differences in each picture element and produces a measure of output which is proportional to the concentration of red blood cells. The oxygenation of RBC can also be calculated, as there is a difference in absorption depending on oxygen state. The first paper takes up possible sources of error such as ambient light, and the angle and distance of the camera. The main experiment was to investigate how the local heating reaction is detected with TiVi compared to LDF. In the second paper arterial and venous stasis are examined in healthy subjects with TiVi. The Third paper is an animal study where skin flaps were raised on pigs, and the vascular pedicle is isolated to enable control of inflow and outflow o

Background: Postpartum infections are a major cause of maternal mortality and morbidity worldwide. Breast infection, endometritis, urinary tract infection and wound infections are the most common postpartum infections and together they affect almost 20% of women after childbirth. Some risk factors for postpartum infections, for example cesarean section, have been relatively well studied, but other presumable risk factors are yet to be confirmed. The proportion of pregnant women who are overweight or obese is increasing in most parts of the world. Increased maternal body mass index (BMI) is associated with maternal and infant morbidity. The association between overweight / obesity and postpartum infections is incompletely understood. Vitamin D deficiency has in epidemiological studies been shown to increase the risk of various infections. Furthermore, vitamin D is an important factor in the human immune system. Concomitantly, vitamin D supplementation seems protective against some types of infections. Whether vitamin D deficiency is a risk factor for postpartum infections has not been studied. Material and Methods: In a population-based observational study using questionnaires, the prevalences of postpartum wound infections, endometritis, urinary tract infections and mastitis in the southeast region of Sweden were estimated (Paper I). All women giving birth in the region during one year (n=11 124) were asked to participate. Papers II and III were cohort studies based on all deliveries in Sweden during eight years (2005-2012). Data sources were the Swedish Medical Birth Register, the Swedish National Patient Register and the Swedish Prescribed Drugs Register. In paper II all term deliveries were included (n=795 072). Risk factors for postpartum wound infections, endometritis and urinary tract infection were evaluated. Paper III included all deliveries (n=841 780) and examined the impact of BMI on the risk of postpartum wound infections, endometritis and breast abscess

Fear of childbirth (FOC) is common and affects approximately 5-20 % of all pregnant women. FOC is associated with giving birth by caesarean section on maternal request (CSMR). The rate of caesarean sections (CS) and CSMR has increased during the last decades. To decrease these women’s fear, the rate of CSMR and to promote a more positive birth experience, many treatments for FOC have been evaluated. In Sweden, the treatment is individualized and given by obstetricians, midwives, psychologists or psychotherapists in the specialist care. Women with FOC suffer more often from psychiatric illness and rate their general health as less good, which is important to consider when counselling these women and deciding on mode of delivery. Little is known about the long term obstetric and reproductive outcomes for women with FOC. Therefore, the aim of the studies on which this thesis is based was to compare psychiatric care before and after childbirth in women giving birth by CSMR to women giving birth by other modes of delivery and to follow the subsequent obstetric and reproductive outcomes in women receiving counselling for FOC in their first childbirth. Furthermore, we hypothesized that women with localized provoked vulvodynia (LPV) and/or vaginismus might fear vaginal childbirth and little is known about their reproduction and obstetric outcomes which is why we investigated the parity and obstetric outcomes in women diagnosed with LPV/vaginismus before first childbirth. Based on data linked from several Swedish National registers, the prevalence of psychiatric in- and outpatient care before (paper I) and after first childbirth (paper II) was compared in primiparae giving birth by CSMR to primiparae giving birth by other modes of delivery. The prevalence of psychiatric disorders was found to be significantly higher in women giving birth by CSMR, indicating a severe burden of psychiatric illness in these women. In paper III, also based on data from several Swedish National r

Background: The prevalence of obesity is increasing worldwide. The treatment of morbid obesity is dominated by bariatric surgery, for example Roux-en-Y gastric bypass (RYGB) surgery. If other contraceptive options are available, women with obesity should not be prescribed combined hormonal contraceptives due to the obesity-related increased risk of venous thromboembolism. Women are advised not to become pregnant during the first 12-18 months after RYGB surgery. There is a lack of knowledge of what type of contraceptive methods women with obesity are prescribed and whether they experience more or different side effects compared to normal-weight women. It is not known if the absorption and pharmacokinetic profile of progestins are affected by RYGB. The aim of this thesis was to investigate the pattern of contraceptive use in women with obesity, what type of contraceptive counselling was given to women in relation to RYGB, and whether the pharmacokinetics of two different progestins were affected by RYGB surgery. Material and Methods: Paper I is a retrospective cohort study analysing the patterns of contraceptive prescription, adverse effects, duration of treatment, reasons for discontinuation and bleeding pattern in 371 women with obesity compared with 744 normal-weight women. Medical records were scrutinised from 1 Jan 2010 until 31 Dec 2014. Paper II is based on a questionnaire sent to 987 women who had undergone RYGB during 2010. The questionnaire concerned preoperative and present contraceptive use, contraceptive counselling in relation to surgery and what type of recommendations they had received regarding pregnancy after RYGB. Papers III and IV are experimental studies investigating the pharmacokinetics of desogestrel (etonogestrel) and levonorgestrel in relation to RYGB. Results and conclusions: The most commonly prescribed contraceptive method for women with obesity was the progestin-only pill but many women with obesity were prescribed combined hormonal contr

Blood vessels are more than simple pipes, passively enabling blood to pass through them. Their form and function are dynamic, changing with both aging and disease. This process involves a feedback loop wherein changes to the shape of a blood vessel affect the hemodynamics, causing yet more structural adaptation. This feedback loop is driven in part by the hemodynamic forces generated by the blood flow, and the distribution and strength of these forces appear to play a role in the initiation, progression, severity, and the outcome of vascular diseases. Magnetic Resonance Imaging (MRI) offers a unique platform for investigating both the form and function of the vascular system. The form of the vascular system can be examined using MR-based angiography, to generate detailed geometric analyses, or through quantitative techniques for measuring the composition of the vessel wall and atherosclerotic plaques. To complement these analyses, 4D Flow MRI can be used to quantify the functional aspect of the vascular system, by generating a full time-resolved three-dimensional velocity field that represents the blood flow. This thesis aims to develop and evaluate new methods for assessing vascular disease using novel hemodynamic markers generated from 4D Flow MRI and quantitative MRI data towards the larger goal of a more comprehensive non-invasive examination oriented towards vascular disease. In Paper I, we developed and evaluated techniques to quantify flow stasis in abdominal aortic aneurysms to measure this under-explored aspect of aneurysmal hemodynamics. In Paper II, the distribution and intensity of turbulence in the aorta was quantified in both younger and older men to understand how aging changes this aspect of hemodynamics. A method to quantify the stresses generated by turbulence that act on the vessel wall was developed and evaluated using simulated flow data in Paper III, and in Paper V this method was utilized to examine the wall stresses of the carotid artery. The

Those following the profession of radiographer mainly work in the healthcare sector, with image production in medical imaging or with radiotherapy treatments. Radiographers are responsible for patient care and handling technology in this profession al field. Radiographers’ practice is interesting to study in relation to technical developments and changing conditions for performing professional work. The general aim of this thesis was to empirically explore the main features of radiographers’ work, how advances in tech n ology affect radiographers’ practice, interconnections with other practices and students learn in g in practice on the way to becoming professionals. Methods: Data was collected using interviews and observations (Papers I, II & IV). For Paper III, individual interviews were conducted. Data was analysed using a phenomenological interpretative method (Paper I) and practice theory perspective (Papers II–IV). Findings: Radiographers’ professional work with image production was seen as a process comprising three phases: planning the examination, producing the images, and evaluating the images. During this process, radiographers make judgements to ensure patient safety and adapt the technology in use to the individual patient. When conventional imaging techniques are converted into examinations performed by Computer Tomography, the planning phase of radiographers’ work process becomes more important. Technology improvements also mean that the technical aspects of radiographers’ work with image production are easier to foresee in scheduling examinations. The caring aspects however are difficult to plan for because of little information about the patient before the examination. The professional practices involved in medical imaging interconnect to ensure patient safety through materiality and common tasks and/ or projects. The content and quality of two artefacts, the referral and the image, in these interconnections are important in collaborative work t

BackgroundCore outcome sets (COS) prioritise outcomes based on their importance to key stakeholders, reduce reporting bias and increase comparability across studies. The first phase of a COS study is to form a long-list of outcomes. Key stakeholders then decide on their importance. COS reporting is described as suboptimal and this first phase is often under-reported. Our objective was to develop a long-list of outcome items for non-pharmacological interventions for people with dementia living at home.MethodsThree iterative phases were conducted. First, people living with dementia, care partners, health and social care professionals, policymakers and researchers (n=55) took part in interviews or focus groups and were asked which outcomes were important. Second, existing dementia trials were identified from the ALOIS database. 248 of 1009 pharmacological studies met the inclusion criteria. Primary and secondary outcomes were extracted from a 50% random sample (n=124) along with eight key reviews/qualitative papers and 38 policy documents. Third, extracted outcome items were translated onto an existing qualitative framework and mapped into domains. The research team removed areas of duplication and refined the long-list in eight workshops.ResultsOne hundred seventy outcome items were extracted from the qualitative data and literature. The 170 outcome items were consolidated to 54 in four domains (Self-Managing Dementia Symptoms, Quality of Life, Friendly Neighbourhood amp; Home, Independence).ConclusionsThis paper presents a transparent blueprint for long-list development. Though a useful resource in their own right, the 54 outcome items will be distilled further in a modified Delphi survey and consensus meeting to identify core outcomes., Funding Agencies|Economic and Social Research Council (ESRC); National Institute for Health Research (NIHR) [ES/L001772/1]

Based largely on the so-called problem of asymmetry in concept application, philosopher Murat Aydede has argued for a non-perceptual view of pain. Aydede is of course not denying basic neurobiological facts about neurons, action potentials, and the like, but he nonetheless makes a strong philosophical case for pain not being the perception of something extramental. In the present paper, after having stated some of the presuppositions I hold as a physician and pain researcher, and after having shortly described Aydedes critique of perceptual theories of pain, I make a constructive proposal centred around the concept of pain as the perception of some-one, not some-thing. In doing so, I propose that there often is a problematic duality at work when we think about pain, namely the mental/extramental duality. This pre-reflective mindset creates difficulties when reflecting over pain. Instead, I propose the body/world duality as being more helpful. Two neologisms, cosmoception and egoception, are presented as an alternative to the twin concepts of exteroception and interoception. It is argued that the new concepts have the advantage of not pushing our thought into a mental/extra-mental dichotomy. Hence, when in pain (which is an instance of egoception), I get epistemic access to the body that is I, to how I fare in this world. From that perspective, pain is not the perception of something, but of someone-namely, the self. In the final part of the paper, this proposal is discussed in dialogue with a paper from phenomenological thinker Jennifer Bullington.

Purpose: The purpose of this paper is to explore the embedding of hospital-based medication review attending to the conflictual and developmental nature of practice. Specifically, this paper examines manifestations of contradictions and how they play out in professional practices and local embedding processes. Design/methodology/approach: Using ethnographic methods, this paper employs the activity-theoretic notion of contradictions for analyzing the embedding of medication review. Data from participant observation (in total 290?h over 48 different workdays) and 31 semi-structured interviews with different healthcare professionals in two Swedish hospital-based settings (emergency department, department of surgery) are utilized. Findings: The conflictual and developmental potential related to three interrelated characteristics (contested, fragmented and distributed) of the activity object is shown. The contested nature is illustrated showing different conceptualizations, interests and positions both within and across different professional groups. The fragmented character of medication review is shown by tensions related to the appraisal of the utility of the newly introduced practice. Finally, the distributed character is exemplified through tensions between individual and collective responsibility when engaging in multi-site work. Overall, the need for ongoing ￜrepairￜ work is demonstrated. Originality/value: By using a practice-theoretical approach and ethnographic methods, this paper presents a novel perspective for studying local embedding processes. Following the day-to-day work of frontline clinicians captures the ongoing processes of embedding medication review and highlights the opportunities to learn from contradictions inherent in routine work practices., Funding agencies: Swedish Research Council for Health, Working Life and Welfare (Forte) [2014-4657]; Medical Research Council of Southeast Sweden (FORSS) [FORSS-476971, FORSS-568651]; County Council of ostergotland patient safety research fund (Region ostergotlands Medel f

Introduction Even though medical improvements have reduced the mortality rates for patients afflicted by stroke, mortality during the first few days at hospital is significant. Today, there is an increasing recognition that the principles of palliative and supportive care are important components of meeting the needs of patients severely afflicted by stroke even in acute settings. However, there is limited knowledge about which factors have an impact on the end-of-life care (EoLC) for these patients or about how these last days of life are experienced from the family members’ perspective. Aim The overall aim of this thesis was to describe the EoLC of patients severely afflicted by stroke and to identify factors impacting upon EoLC for the patients and their family members in Sweden out of various contexts and methods. Design and Methods This thesis is based upon four papers employing qualitative, quantitative and mixed-method designs. Paper I is a qualitative study based on focus-group interviews with 41 health-care professionals (HCPs) in different professions related to stroke care at three stroke units. The aim was to study ethical dilemmas, different approaches and what consequences they had among health HCPs; the data was analysed using content analysis. The result inspired the design and conduct of the following studies. Paper II is a quantitative comparative study based on a retrospectively registered questionnaire from the Swedish Registry of Palliative Care (SRPC). Patients dying of stroke (n =1626) were compared with patients dying from cancer (n=1626), according to symptoms, symptom management and communication with the patient and family members during the last week of life. Data was statistically calculated using OR. Paper III is a mixed-method study employing a sequential explanatory design. In the first, quantitative, part, 995 stroke patients who died in hospital were compared with 631 stroke patients who died at nursing homes, according to symptoms

Background: Cholecystectomy is a common surgical procedure and incidental gallbladder cancer is a rare and unexpected finding at a cholecystectomy performed upon benign indications. Whether to perform routine or selective histopathology of the gallbladder specimen is still a subject for discussion. The prognosis of gallbladder cancer is largely affected by tumour stage and treatment. Aims: The overall aim was to study whether routine histological examination of the gallbladder specimen is of clinical and health economic value; determine if there are any predictive factors of incidental gallbladder cancer at benign cholecystectomy and compare the management and outcome of incidental gallbladder cancer patients in Sweden. Methods: All studies were based on registry data from GallRiks (The Swedish Registry for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography) between 2007 and 2016, with some modifications between studies. Complemental cross-linkage was made to national registries, and medical records were reviewed. Papers I, II and III were population-based observational studies with prospectively and retrospectively collected data. Paper IV was a health economic evaluation based on the results from papers I and III. Results and conclusions: Hospitals submitting >75 per cent of gallbladder specimens diagnosed a higher proportion of incidental gallbladder cancer than did hospitals submitting ≤25 per cent of samples (paper I). Incidental gallbladder cancer was more prevalent in older patients, women and patients with acute or previous cholecystitis, as well as ongoing jaundice. The risk model based on predictive preoperative factors was further improved by adding a macroscopic assessment of the gallbladder (paper II). Predictive factors for gallbladder cancer appeared to have an impact on which specimens were submitted in hospitals with a selective approach of histopathology (paper I). For pT2 and pT3 patients, re-resection improved diseasespecific

Approximately 20-30% of all road fatalities are related to driver sleepiness. A long-lasting goal in driver state research has therefore been to develop a robust sleepiness detection system. Since the alertness level is reflected in autonomous nervous system activity, it has been suggested that various heart rate variability (HRV) metrics can be used as features for driver sleepiness classification. Since the heart rate is modulated by many different factors, and not just by sleepiness, it is relevant to question the high driver sleepiness classification accuracies that have occasionally been presented in the literature. The main objective of this paper is thus to test how well a sleepiness classification system based on HRV features really is. A unique data set with 86 drivers, obtained while driving on real roads in real traffic, both in alert and sleep deprived conditions, was used to train and test a support vector machine (SVM) classifier. Subjective ratings based on the Karolinska sleepiness scale (KSS) was used as ground truth to divide the data into three classes (alert, somewhat sleepy and severely sleepy). Even though nearly all the 24 investigated HRV metrics showed significant differences between sleepiness levels, the SVM results only reached a mean accuracy of 61 %, with the worst results originating from the severely sleepy cases. In summary, the high classification performance that may arise in studies with high experimental control could not be replicated under realistic driving conditions. Future works should focus on how various confounding factors should be accounted for when using HRV based metrics as input to a driver sleepiness detection system., Funding Agencies|ADAS&ME project - European Unions Horizon 2020 research and innovation programme [688900]

Initiatives with mobile phone dispatched volunteers to out-of-hospital cardiac arrest (OHCA) cases, can be found today in some countries, e.g. Sweden, the Netherlands, Switzerland and Italy. When an OHCA case is reported, an alarm is sent to the registered volunteers’ phones. However, the allocation of which volunteers to send to the automatic external defibrillator (AED) and who to send directly to the patient, is today based on simple rules of thumb. In this paper, we propose a model to optimally select how many and which volunteers to send directly to the patient, and who should pick up and deliver an AED. The results show that the model can help increase the survivability of the patients, compared to simple decision rules.

Inductively powered 99% accurate implantable temperature sensor is designed, characterized and the findings are presented in this paper. The implantable sensors deliver a continuous temperature reading to external storage or readout devices via Near Field Communication interface. A 2.76 mu H rectangular inductive coil printed on a thin biocompatible plastic substrate is designed to establish the coupling link through NFC interface with external readout devices. A commercially available wide range temperature sensor chip is mounted along with the developed inductive coil on the same plastic substrate. For 50 samples, the received signal strength indicator, temperature accuracy and statistical distribution of measurement levels is investigated. Comparison of predetermined temperature in a controlled temperature and humidity chamber versus the temperature reading from the developed sensors proves a 99% accuracy., Funding Agencies|Swedish Foundation for Strategic Research (SSF)Swedish Foundation for Strategic Research

Motion imaging phantoms are expensive, bulky and difficult to transport and set-up. The purpose of this paper is to demonstrate a simple approach to the design of multi-modality motion imaging phantoms that use mechanically stored energy to produce motion. We propose two phantom designs that use mainsprings and elastic bands to store energy. A rectangular piece was attached to an axle at the end of the transmission chain of each phantom, and underwent a rotary motion upon release of the mechanical motor. The phantoms were imaged with MRI and US, and the image sequences were embedded in a 1D non linear manifold (Laplacian Eigenmap) and the spectrogram of the embedding was used to derive the angular velocity over time. The derived velocities were consistent and reproducible within a small error. The proposed motion phantom concept showed great potential for the construction of simple and affordable motion phantoms., Funding Agencies|Wellcome Trust IEH Award [102431]; Wellcome/EPSRC Centre for Medical Engineering at Kings College London [WT 203148/Z/16/Z]; National Institute for Health Research (NIHR) comprehensive Biomedical Research CentreNational Institute for Health Research (NIHR); Kings College London

Purpose Comprehensive geriatric assessment (CGA) is a widely used approach in geriatric care and involves multidisciplinary assessments focused on determining a frail elderly persons medical, psychological and functional capability to develop an integrated plan for treatment. The purpose of this paper is to describe and scrutinize the CGA implementation process at six acute geriatric departments in three county councils and to study the outcome by the documentation in the patient medical records, and the staff perceptions using CGA. Design/methodology/approach The paper describes the implementation process stages. Outcome measures were based on patient medical records reviews at baseline and follow-ups at year 1 and year 2. Staff perceptions of using CGA were gathered by a questionnaire at the second follow-up. Findings The implementation had not yet reached sustainability so the implementation process must continue. Results show that documentation on the different areas increased in year 1, as well as the use of standardized assessment tools. However, results from the reviews for year 2 showed some decrease. Staff considered CGA to have high value for the geriatric patient but pointed out the need for continuing education. Originality/value Successful strategies for this implementation were strong support from the managers, small seminars, CGA rounds, good introduction routines for new staff and the use of reminders such as pocket-sized focus cards. A high staff turnover occurred during the study, which probably had a significant negative impact on the results., Funding Agencies|Medical Research Council, south-east Sweden

Purpose The purpose of this paper is to reflect on carers’ experiences of being involved in the development of a web-based support programme for carers of people with heart failure (CPwHF), and discuss the challenges related to their involvement in the development process. The focus was on the different phases in the project as well as the methodological challenges and opportunities that occurred in the user group sessions conducted. Design/methodology/approach This research adopt an explorative design studying a co-design process to develop an information and communication technology based support programme for and with CPwHF. Habermas’ concepts of lifeworld and system are used as a theoretical framework to analyse the co-design process employed in the study. Findings Reflecting on the co-design approach adopted, the findings highlight the methodological challenges that arise with carer involvement and the possible tensions that occur between researchers’ ambitions to include users in the design process, and the goal of developing a product or service, in the different phases of the design process. Originality/value Findings highlight that there is a tension between the system and lifeworld in the co-design process which are not totally compatible. The paper highlights that there is a need to develop flexible and reflexive human-centred design methodologies, able to meet carers’ needs and ideas, and at the same time balance this with proposed research outcomes., Funding Agencies|Swedish National Science Council; Swedish Research Council for Health, Working life and Welfare (VR-FORTE) [2014-4100]

School attendance problems (SAPs) are heterogeneous with respect to etiology and presentation. The long history of conceptualizing SAPs has led to a vast array of terms and definitions as well as different perspectives on the most helpful approach to classification. For educators, practitioners, researchers, and policymakers, this presents a challenge in understanding, assessing, and intervening with SAPs. This paper outlines evolution in the conceptualization of SAPs, focusing on two contemporary approaches to differentiating between them. One approach draws on the longstanding differentiation between SAP types labeled school refusal, truancy, and school withdrawal. A fourth type of SAP, labeled school exclusion, is also considered. The other approach focuses on the function of absenteeism, measured via the School Refusal Assessment Scale (SRAS). Anecdotal and scientific support for the SAP typology is presented, along with the benefits and shortcomings of the SRAS approach to differentiation. The paper offers suggestions for how to differentiate between SAPs and introduces the SNACK, a brief screening measure that permits differentiation by SAP type.

Self-care is important for heart failure patients. However, what are the views of patients on their situation when it comes to realizing self-care? The aim of the paper is to investigate the self-care needs of HF patients, by understanding the issues they embrace in their self-care processes. In this paper we make a review of 17 interviews and make a classification of what the needs are for possible information technology support systems. Based on the analysis of these interviews, we identify the diversity of needs in support of activities related to different background conditions and the dynamics of change of learning and changes in the heart failure condition. The contribution of the paper is a framework for understanding the diversity of needs and the specific situations of this group of patients.

Platelets are important players in the hemostatic system, acting as guardians of vessel integrity. When they come across a breach in the vessel wall, they quickly adhere to the damaged surface, secrete activating and adhesive compounds from their secretory granules, recruit additional platelets into a growing platelet plug and support the action of the coagulation system. In the past decades, it has become clear that platelets form functionally different platelet subpopulations. The aggregatory platelets build the platelet plug, whereas the procoagulant subpopulation support and direct the actions of the coagulation system. The aim of this thesis was to examine the formation and features of the different platelet subpopulations, and elucidate their respective roles in hemostasis. Platelet lysosomal secretion is not well characterized. In Paper I, we found that lysosomal secretion, detected as LAMP-1 surface exposure, occur upon potent platelet stimulation including secondary activation by ADP. This is regulated by the endothelial platelet inhibitors nitric oxide and prostacyclin. As observed in Paper II, lysosomal secretion might also be of clinical relevance as a quality indicator for platelet concentrates used for transfusion, an area were quality control may become increasingly important in the future. Among several evaluated platelet activation markers, platelet LAMP-1 exposure and the ability to form procoagulant platelets may be useful as novel indicators of platelet responsiveness. Moreover, the ability to form procoagulant platelets varies extensively between individuals, something we established in Paper III. Here we also present a novel flow cytometry protocol enabling the simultaneous investigation of 6 different platelet activation markers. Using this protocol we investigate the formation of procoagulant platelets and reveal that only a subpopulation of platelets may become procoagulant. Further we show that this is dependent on the agonist stimulation a

The purpose of this thesis is to explore the institutionally shaped response to the introduction of the national guidelines on the Swedish regional health policy arena. The thesis consists of two case studies. Adapting a qualitative approach, the data is based on individual interviews and these were analysed thematically. The first paper explores the response by four Swedish regional health authorities to the introduction of the National Guidelines for Cardiac Care, while the second paper aims to broaden the understanding of how the national guidelines are used for strategic purposes among politicians. As illustrated in this thesis, organizations will respond, adjust and react to external pressure according to conditions shaped by the institutional context. Key findings here are that the national guidelines are a complex policy instrument that, beyond being able to be used in an instrumental fashion by the medical managment, can also serve a legitimizing function for political decision-makers. The goals of the national guidelines, i.e. equal and efficient care, and the uncertainty about who, among multiple stakeholders, is responsible for the guidelines in the regional health authority, is a source of ambiguity and potential conflict. Those who are potentially responsible represent different rationales – a political rationale and a scientific rationale. The dominating scientific rationale of the national guidelines can create instability, when pushing towards the use of explicit priority-setting. Priority-setting in the institutional setting of a regional health authority has strong elements of becoming “wicked problems” since the dilemma of prioritization remains regardless of ambitions to apply a “technocratic fix”. A wicked problem is characterized by high complexity and being persistently hard to solve (Williams et al. 2012). A recurring dilemma is that priority-setting still contains many wicked problems, as social values and political considerations remain imp

Scoliosis is a complex three-dimensional deformity of the spine. Even though it has been known for centuries, treatment of the deformity has focused on correcting only in the frontal plane. In the last decades, the need for three-dimensional assessment regarding scoliosis has been highlighted to better understand the cause and the principles of treating scoliosis. The overall aim of this dissertation is to provide knowledge to assess scoliosis as a three-dimensional problem. The severity of scoliosis is measured with the Cobb angle from standing radiographs. Computed tomography (CT) examinations are used throughout this thesis. The first paper investigates the difference in Cobb angle measured from standing radiographs and supine CT examinations. The standing radiographs had larger Cobb angles with a mean difference of 11° and a linear correlation between the two examinations from 128 consecutive patients with adolescent idiopathic scoliosis (AIS) planned for surgery. The second paper compares the axial shape of vertebrae in 20 patients with AIS with a reference group. Clear asymmetry was observed in all vertebrae – superior and inferior end vertebrae as well as the apical vertebra – compared with corresponding vertebrae among the reference group. The asymmetry was most pronounced in the apical vertebra. A novel parameter, frontal vertebral body rotation (FVBR), was introduced to describe the internal rotation of the vertebrae in the axial plane. Pelvic incidence (PI) is a measurement of the position of the sacrum in relation to the femoral heads. This is relevant in scoliosis because PI determines the pelvic configuration acting as a foundation to the spine. PI has traditionally been measured from standing radiographs. The third study investigates PI three-dimensionally, based on low-dose CT examinations, in 37 patients with Lenke type 1 or 5 curves compared with a reference group. A significantly higher PI was observed in patients with Lenke type 5 curves compared

It is not unusual for patients with head and neck cancer (HNC) to suffer from both tumor and treatment-related pain that is difficult to alleviate despite individualized pharmacological treatment. The presence of concomitant various dimensions of pain in patients during the often difficult period following radiotherapy (RT) has not been elucidated. Several aspects concerning the importance of relatives for HNC patients have been addressed. However, little attention has been given to how relatives perceive patients with HNC pain and it is important to further elucidate this sparsely studied topic. Knowledge about health-related quality of life (HR-QoL) in this patient group during early RT is limited and needs to be assessed in relation to diagnosis and treatment. Self-care (SC) refers to what patients do on their own to achieve, maintain, and promote optimal health and may help reduce pain for several pain conditions. The impact of patient education and SC on pain and other common HNC symptoms need further clarification. The aims of this thesis were: to describe experiences and perceptions of pain in patients with HNC shortly after RT to describe how relatives perceived the patient’s situation, especially concerning pain, and how they experienced their own situation to identify factors that impact HR-QoL during early RT to develop effective pain management strategies, maintain activities of daily living, and promote HR-QoL in patients with HNC undergoing RT using patient education and SC instruction. In paper I patients with HNC described existential pain – expressed as fear of death, meaninglessness and guilt – already during and shortly after RT. Physical pain, psychological distress and social withdrawal played a significant role. Patients with HNC who were treated with RT should also proactively be offered treatment for the various dimensions of pain. In paper II relatives described their mental stress in response to a challenging situation that required their a, Korrigeringar är gjorda i den elektroniska versionen utifrån publicerad erratalista / The corrections in the published errata list are implemented in the electronic version.

The prevalence of obesity has over the last 40 years nearly tripled and obesity is one of the major risk factors of developing type 2 diabetes. Type 2 diabetes was formerly called adultonset diabetes but today, probably due to the rise in childhood obesity, it is also seen in children and adolescents. Type 2 diabetes is diagnosed when the body no longer can control the glucose levels in the blood. This is due to an insulin resistant state in the insulin responding tissues, liver, adipose and muscle and insufficient production of insulin in the pancreas. However, in spite of extensive research the mechanisms behind insulin resistance is still not known. The adipose tissue is believed to play a major role in the development of whole body insulin resistance. Adipocytes are the most important sites for storage of the high energy containing triacylglycerols. Insulin stimulation causes the adipocyte to increase the uptake of glucose and to reduce lipolysis: the hydrolysis of triacylglycerol and release of glycerol and fatty acids. The insulin signalling network is complex with numerous proteins involved. These signaling proteins not only transmit the insulin signal but also create negative and positive feedbackloops and induce cross talk between different parts of the network and with the signalling of other hormones. One important positive feedback in insulin signalling is the mTORC1 mediated feedback to phosphorylation of IRS1 at serine 307. In paper I we found that in human adipocytes this feedback is not likely catalysed by the assumed kinase S6K1. However we find an immunoprecipitate of mTOR to contain a ser307 phosphorylating kinase. Scaffolding proteins serve as docking sites for several proteins to promote protein-protein interactions that facilitate signal transduction. In paper II we demonstrate the existence of the scaffolding protein IQGAP1 in human adipocytes and that the expression of IQGAP1 is downregulated in type 2 diabetes. We reveal that IQGAP1 co-local

Many children with developmental language disorder (DLD) exhibit difficulties with phonology, i.e. the sounds of language. Children with any degree of hearing impairment (HI) are at an increased risk of problems with spoken language, including phonology. The cause of these difficulties is unknown in children with DLD, and is often assumed to result from reduced hearing acuity in children with HI. Variability in terms of language outcomes is large in both groups, and determining if a child’s language ability is within normal limits or not is problematic. A task that has proven useful in differentiating typical from atypical language development is nonword repetition, in which the child listens to a word form without meaning and repeats it back immediately. Performance in nonword repetition tasks is a potential indicator of language ability in both children with DLD and children with HI. However, it has not been established exactly what the task measures. In the present thesis, the ability to repeat prosodic and segmental features of real words and nonwords was investigated in Swedish-speaking four- to six-year-old children with DLD and HI, as well as in children with normal hearing and typical language development (TLD) (papers I, II and III). Further, relations of word and nonword repetition ability to language and hearing were explored (papers II and III), along with comparisons of phonological and grammatical production between the groups (paper IV). The findings indicated that the prosodic features stress and tonal word accent affect repetition performance in children with DLD, HI, and TLD. In general, the children with DLD and HI achieved lower results than the children with TLD on repetition of segments (consonants and vowels) and prosodic features, but tonal word accent was repeated with relatively high accuracy. Tonal word accent 1 was more accurately repeated than tonal word accent 2 by the DLD and HI children. The children with TLD repeated tonal word accen

In cardiovascular disease, which is the most common cause of death in the world, early diagnosis is crucial for disease outcome. Diagnosis of cardiovascular disease can be challenging, though. Quantification of myocardial T1 and T2 relaxation times with MRI has demonstrated to be a promising method for characterizing myocardial tissue, but long measurement times have hampered clinical use. The overall aim of this doctoral thesis was to develop, validate and, in patient studies, evaluate a very fast three-dimensional method for simultaneous quantification of myocardial T1 and T2 relaxation times with whole coverage of the left ventricle. The 3D-QALAS method is presented in Paper I of this thesis. It is a method that simultaneous measures both T1 and T2 relaxation times in a three-dimensional volume of the heart. The method requires 15 heartbeats, to produce 13 short-axis slices of the left ventricle with voxelwise information of both T1 and T2 relaxation times. The 3D-QALAS method was validated in phantoms and in 10 healthy volunteers by comparing the method with reference methods and demonstrated good accuracy and robustness both in-vitro and in-vivo. In Paper II, the 3D-QALAS method was carefully validated in-vivo by investigating accuracy and precision in 10 healthy volunteers, while the clinical feasibility of the method was investigated in 23 patients with various cardiac pathologies. Repeated independent and dependent scans together with the intra-scan repeatability, demonstrated all a very good precision for the 3D-QALAS method in healthy volunteers. In Paper III and IV, the 3D-QALAS method was applied and evaluated in patient cohorts where the heart muscle alters over time. In Paper III, patients with severe aortic stenosis underwent MRI examinations with 3D-QALAS before, 3 months after and 12 months after aortic valve surgery. Changes in T1 and T2 were observed, which might be used as markers of myocardial changes with respect to edema and fibrosis, which ma

Background: Subsyndromal depression (SSD) or subthreshold depression is a common affective condition that can be described as depressiveness below the threshold of what is called a syndromal or a major depressive episode. The point prevalence for SSD has been reported to be about 10% in the community, or about two or three times higher than the prevalence for syndromal depression. In elderly persons, SSD compared to non-depression (ND) is associated with impaired activities of daily living, lower cognitive function, lower self-perceived health, worse psychiatric outcomes and higher mortality. However, most studies on SSD in elderly persons have been done in the young old age group (age 60-80 years), while few studies have investigated SSD in very old persons (age 80+). As many aspects (e.g. multimorbidity, frailty, functional decline and social dependence) change between the young old and the very old ages, there is a need for more knowledge about SSD in the very old. The overall aim of this doctoral thesis was to describe SSD, or the complex area between syndromal depression and normal aging, in very old persons. Method: Paper 1 was based on qualitative interviews (n=27), while papers 2-4 were based largely on data from a prospective observational cohort study “Elderly in Linköping Screening Assessment” (ELSA85), with a population-based design following the participants from the age of 85 in three waves of follow-up. The 15-item Geriatric Depression Scale (GDS-15) was used for measuring depressiveness and to define SSD in the studies. Results: The analysis of the qualitative interviews (paper 1) resulted in four themes (life curve and the body go down, to manage on one’s own, to keep up with life, and taking one day at a time), giving a comprehensive picture of SSD in very old age. In a comparison among SSD, ND and syndromal depression, SSD differed qualitatively from syndromal depression, but not clearly from ND. A cross-sectional analysis of data from baseline (p

The breast cancer survival in Sweden is good (almost 90 % 5-year relative survival) and has increased over time. For women with hormone receptor negative tumors, most relapses occur within the first 5 years after diagnosis. Thereafter the recurrence risk decreases rapidly. For women with estrogen receptor positive (ER+) tumors the annual risk for late recurrences is 1 – 2 %, even after 5 years of endocrine therapy. This risk accumulates so that approximately 25 % of the patients that are recurrence-free after five years from diagnosis may experience a relapse within further 15 years of follow-up. The relatively high long-term risk calls for identification of prognostic and predictive markers with long-term effect. Though, the number of such markers with proven significance is limited. Of the clinical characteristics, only nodal status and to some extent tumor size and tumor grade have been shown to have long-term prognostic value. In this thesis, we propose long-term prognostic and predictive markers for breast cancer. In paper I, we suggest the protein v-akt murine thymoma viral oncogene homologue 2 (AKT2) as a long-term prognostic marker among patients with ER+ tumors. In our study, besides nodal status, AKT2 was the only factor with long-term prognostic value. This is in accordance with some other studies, though we also showed that the significance of AKT2 was limited to ER+ tumors and that the impact increased with higher ER expression. Approximately 75 – 85 % of the ER+ tumors are also progesterone receptor positive (PR+). ER+/progesterone receptor negative (PR-) tumors are considered to be more aggressive and patients with such tumors are often treated with chemotherapy. In this group, more specific subgroups for targeted therapy are needed. Whereas ER has long been established as a predictive factor regarding tamoxifen benefit, the role of PR has not been clarified to date. In paper II, we showed that PR status adds predictive value to ER considering the lon

This thesis focuses on interventional aspects of spasticity, but has a very holistic approach, grounded in the specialty of Rehabilitation medicine. This means capturing the effects of spasticity, on such a complex biological system as the human being, living in a psychosocial context affecting the situation. When evaluating spasticity there are a number of levels of evidence. The first of course, understanding what we mean with spasticity, where there unfortunately is no consensus. The second level is to study if our treatments affect spasticity in a positive direction. The third is to grasp if a decrease in spasticity improve or normalize patient’s movement patterns. The fourth level investigates if improvement in movement patterns improve patient’s ability to perform activities; and the fifth level, comprising whether this intervention improves life satisfaction. Finally, on a societal level, we wish to investigate whether the improvement in life satisfaction or health related quality of life would motivate society to fund the intervention. Paper I on Goal Attainment Scaling pointed out necessary aspects to consider when using this instrument. This relates, among other things, to the need of learning (“the art of”) goal setting and deciding the purpose of the measurements. Research and clinical use puts different demands on the instrument, for the latter time-efficiency and simplicity to use being most important. For research, it is important to be able to register deterioration, and this can be achieved using the 6-step version. In paper II, concerning validation of the portable motion system, we showed this system to be valid for short-term measurements and that the use of Exposure Variation Analysis (EVA) seems to be a valuable tool for graphically elucidating different movements. The equipment needs further development in handling long-term measurements (which is effectuated), and norms for normal movements in different activities has to be produced. The disc

Current diagnostic tools for assessing cardiovascular disease mostly focus on measuring a given biomarker at a specific spatial location where an abnormality is suspected. However, as a result of the dynamic and complex nature of the cardiovascular system, the analysis of isolated biomarkers is generally not sufficient to characterize the pathological mechanisms behind a disease. Model-based approaches that integrate the mechanisms through which different components interact, and present possibilities for system-level analyses, give us a better picture of a patient’s overall health status. One of the main goals of cardiovascular modelling is the development of personalized models based on clinical measurements. Recent years have seen remarkable advances in medical imaging and the use of personalized models is slowly becoming a reality. Modern imaging techniques can provide an unprecedented amount of anatomical and functional information about the heart and vessels. In this context, three-dimensional, three-directional, cine phase-contrast (PC) magnetic resonance imaging (MRI), commonly referred to as 4D Flow MRI, arises as a powerful tool for creating personalized models. 4D Flow MRI enables the measurement of time-resolved velocity information with volumetric coverage. Besides providing a rich dataset within a single acquisition, the technique permits retrospective analysis of the data at any location within the acquired volume. This thesis focuses on improving subject-specific assessment of cardiovascular function through model-based analysis of 4D Flow MRI data. By using computational models, we aimed to provide mechanistic explanations of the underlying physiological processes, derive novel or improved hemodynamic markers, and estimate quantities that typically require invasive measurements. Paper I presents an evaluation of current markers of stenosis severity using advanced models to simulate flow through a stenosis. Paper II presents a framework to personaliz

The debate on the use and misuse of P values has risen and fallen throughout their almost century-long existence in scientific discovery. Over the past few years, the debate has again received front-page attention, particularly through the public reminder by the American Statistical Association on how P values should be used and interpreted. At the core of the issue lies a fault in the way that scientific evidence is dichotomized and research is subsequently reported, and this fault is exacerbated by researchers giving license to statistical models to do scientific inference. This paper highlights a different approach to handling the evidence collected during a randomized controlled trial, one that does not dichotomize, but rather reports the evidence collected. Through the use of a coin flipping experiment and reanalysis of real-world data, the traditional approach of testing null hypothesis significance is contrasted with a Bayesian approach. This paper is meant to be understood by those who rely on statistical models to draw conclusions from data, but are not statisticians and may therefore not be able to grasp the debate that is primarily led by statisticians.

Ziconotide is a selective and potent blocker of N-type voltage-gated calcium channels. It was approved by the Food and Drug Administration in 2004 and by the European Medicines Agency in 2005 for the treatment of severe chronic pain in patients needing intrathecal analgesia (ITA). The aim of this paper is to provide a practitioner-oriented, educational, narrative, up-to-date review on the use of ziconotide in clinical pain medicine. Of special concern regarding safety is the partial incongruity between dosing statements in the Summary ofProduct Characteristics and novel low-dosage, slow uptitration recommendations. Even though ziconotide has obvious advantages compared to opioids, pain practitioners pondering the use of ziconotide nonetheless have to balance its proved potential analgesic effect against its neurological side effects, with special consideration being given to dosing and neuropsychiatric dangers. Using a seesaw analogy, the paper discusses what factors pain physicians should weigh in when considering ziconotide as ITA drug, the non-opioid advantages of ziconotide being counterbalanced by its potential psychiatric side effects. Ziconotide is an important part of the armamentarium of modern interventional pain medicine. If ITA is deemed necessary, ziconotide is a rational alternative, at least in chronic (neuropathic) non-cancer pain. However, in many European countries, ziconotide treatment is only available in a few (if any) centres. The safety profile of ziconotide is not fundamentally more worrying than that of opioids or cannabinoids; it is just different. This paper provides a concise, up-to-date and clinically-oriented summary of the use of ziconotide in clinical practice, not least concerning safety and dosage issues., Funding Agencies|Region Ostergotland (Sinnescentrum), Sweden; Lions Postdoc Research Fund, Linkoping, Sweden

This paper presents a conceptual framework to analyse the design of the cost‐effectiveness appraisal process of new healthcare technologies. The frameworkcharacterises the appraisal processes as a diagnostic test aimed at identifyingcost‐effective (true positive) and non‐cost‐effective (true negative) technologies.Using the framework, factors that influence the value of operating an appraisalprocess, in terms of net gain to popula tion health, are identified. The frame-work is used to gain insight into current policy questions including (a) howrigorous the process should be, (b) who should have the burden of proof, and(c) how optimal design changes when allowing for appeals, price reductions,resubmissions, and re‐evaluations.The paper demonstrates that there is no one optimal appraisal process and theprocess should be adapted over time and to the specific technology underassessment. Optimal design depends on country‐specific features of (future)technologies, for example, effect, price, and size of the patient population,which might explain the difference in appraisal processes across countries. Itis shown that burden of pro of should be placed on the producers and that theimpact of price reductions and patient access schemes on the producer's pricesetting should be considered when designing the appraisal process.

BACKGROUND: In this paper, we report progress on "Neighborhoods: our people, our places" an international study about how people living with dementia interact with their neighborhoods. The ideas of social health and citizenship are drawn upon to contextualize the data and make a case for recognizing and understanding the strengths and agency of people with dementia. In particular, we address the lived experience of the environment as a route to better understanding the capabilities, capacities, and competencies of people living with dementia. In doing this, our aim is to demonstrate the contribution of social engagement and environmental support to social health. METHODS: The study aims to "map" local spaces and networks across three field sites (Manchester, Central Scotland and Linkoping, Sweden). It employs a mix of qualitative and participatory approaches that include mobile and visual methods intended to create knowledge that will inform the design and piloting of a neighborhood-based intervention. RESULTS: Our research shows that the neighborhood plays an active role in the lives of people with dementia, setting limits, and constraints but also offering significant opportunities, encompassing forms of help and support as yet rarely discussed in the field of dementia studies. The paper presents new and distinctive insights into the relationship between neighborhoods and everyday life for people with dementia that have important implications for the debate on social health and policy concerning dementia friendly communities. CONCLUSION: We end by reflecting on the messages for policy and practice that are beginning to emerge from this on-going study., Funding agencies: Economic and Social Research Council (ESRC); National Institute for Health Research (NIHR)

Severe sepsis is characterized by acute organ dysfunction caused by an infection. Despite advanced treatment with antibiotics and organ support the mortality remains high. The epidemiological research on severe sepsis has expanded over the years but has led to conflicting results. In this thesis, we present evidence that some of these conflicting results may be explained by inappropriate methods used in epidemiological studies on severe sepsis. The definition of severe sepsis relies on consensus criteria including a number of clinical signs, parameters and laboratory findings. To facilitate large nation-wide studies on the incidence of severe sepsis in already existing administrative datasets, several investigators have attempted to mirror the clinical criteria by using combinations of the International Classification of Diseases (ICD) codes for infection and organ dysfunction. In paper I of this thesis, however, we found that three different ICD code abstraction strategies applied on the same dataset (the Swedish National Patient Register) generated three almost separate cohorts of patients. Furthermore, in paper II, where we followed intensive care unit (ICU)-treated patients with severe sepsis according to clinical consensus criteria to discharge, we observed that most patients did not meet any ICD code abstraction strategies for severe sepsis when reviewing their ICD codes registered at discharge from the hospital. In conclusion, the ICD code abstraction strategies previously used in the epidemiological research on sepsis seem to be inaccurate in the Swedish setting. Sepsis may also result in poor long-term outcomes, and contribute to an increased risk of late mortality. However, the actual causes of late mortality in sepsis remain unclear. In paper III, we investigated causes of death over 1 year after treatment of sepsis in the ICU. In this study, a matched control group consisting of ICU-treated patients without sepsis was included. The most common causes o

Recent natural and man-made disasters highlight that a more resilient approach to preparing for and dealing with such events is needed. To address this challenge, the main objective of the research and innovation H2020 project DARWIN is the development of European resilience management guidelines for Critical Infrastructures (CI). Based on a systematic literature survey with a world-wide scope and prioritization of resilience concepts, the guidelines have been developed taking into account everyday operations, contingency plans, training, etc. This paper describes insights gained from the adaptation of these guidelines in the domains of Air Traffic Management (ATM) and Healthcare (HC). A collaborative and iterative process has been defined involving relevant experts and practitioners. To ensure transnational, cross-sector applicability and uptake, a Community of Crisis and Resilience Practitioners (DARWIN DCoP) has been involved. The preliminary results indicate that a big step has been taken in moving from the resilience theory to practice

Introduction: Internet is an integral part of everyday life today. In Sweden 98% of adolescents are reported using internet. However, adolescents with intellectual disabilities are often excluded in national surveys, since questions are not adapted for the target group. Statistics remain therefore limited regarding internet-use among adolescents with intellectual disabilities. Objectives: To investigate and describe internet-use among adolescents with intellectual disabilities through an adapted version of a nationwide survey in Sweden. Method: A cross-sectional study was conducted using an adapted version of a survey from the Swedish Media Council on media-use among adolescents. Cognitive adaptations were included and it was accessible through the web and in paper. The sample was drawn from three municipalities using a total-selection of pupils in secondary- and upper secondary special schools. 265 surveys were sent out and the response rate was approximately 32%. Data was analyzed through descriptive statistics. Results: The result gives demographic data on the participants and descriptive statistics on the access to devices for internet-connection. Further, data are provided on activities done in leisure time and whether internet is used or not, together with perceptions of doings on internet from the participants. Conclusion: Stepwise adaptations of the survey with different levels of cognitive support enabled the participation of adolescents with intellectual disabilities and the result gives increased knowledge of internet-use among adolescents with intellectual disabilities. Finally, future comparative analysis are possible due to the national survey being used implying the voices of adolescents with intellectual disabilities being heard.

Functional Magnetic Resonance Imaging (fMRI) is a common technique for imaging brain activity in humans. However, the fMRI signal stems from local changes in oxygen level rather than from neuronal excitation. The change in oxygen level is referred to as the Blood Oxygen Level Dependent (BOLD) response, and is connected to neuronal excitation and the BOLD response are connected by the neurovascular coupling. The neurons affect the oxygen metabolism, blood volume and blood flow, and this in turn controls the shape of the BOLD response. This interplay is complex, and therefore fMRI analysis often relies on models. However, none of the previously existing models are based on the intracellular mechanisms of the neurovascular coupling. Systems biology is a relatively new field where mechanistic models are used to integrate data from many different parts of a system in order to holistically analyze and predict system properties. This thesis presents a new framework for analysis of fMRI data, based on mechanistic modelling of the neurovascular coupling, using systems biology methods. Paper I presents the development of the first intracellular signaling model of the neurovascular coupling. Using models, a feed-forward and a feedback hypothesis are tested against each other. The resulting model can mechanistically explain both the initial dip, the main response and the post-peak undershoot of the BOLD response. It is also fitted to estimation data from the visual cortex and validated against variations in frequency and intensity of the stimulus. In Paper II, I present a framework for separating activity from noise by investigating the influence of the astrocytes on the blood vessels via release of vasoactive sub- stances, using observability analysis. This new method can recognize activity in both measured and simulated data, and separate differences in stimulus strength in simulated data. Paper III investigates the effects of the positive allosteric GABA modulator diazepam

Squamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract. Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions. The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-tomesenchymal transition (EMT), and induction of cancer stem cells (CSC). In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Non-responders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two most promising proteins identified in papers I and II were analyzed in a study cohort of 149

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease. Clinically, the distinction between ongoing inflammation attributed to SLE, and organ damage due to medication or co-morbidities remains challenging. In addition, SLE is a heterogeneous disease where the various disease phenotypes complicate the search for biomarkers that adequately reflect disease activity and/or signs of increasing organ damage. The aim of the thesis was to investigate and evaluate potential new biomarkers of disease activity and/or organ damage in SLE patients. High mobility group box protein-1 (HMGB1) is a nuclear non-histone protein that can shuttle to the cytoplasm, become secreted extracellularly, and participate in systemic inflammation. Administration of monoclonal anti-HMGB1 antibodies has been reported both to attenuate and intensify disease in animal models of arthritis and lupus. In Paper I of the thesis, circulating anti-HMGB1 was found in 23% of the SLE patients and correlated with disease activity variables. The biological role of these autoantibodies remains to be elucidated. As a consequence of massive circulating levels of cellular debris and immune complexes, SLE patients have insufficient capacity to remove such material via the reticuloendothelial system. Pentraxin 3 (PTX3) may possibly protect against lupus flares due to classical complement activation, opsonization of apoptotic cells, and cytokine induction. In Paper II, circulating PTX3 was found to be inhibited or exhausted by interferon (IFN)-α, a key cytokine of SLE pathogenesis, and serum levels of PTX3 in SLE patients were inversely related to IFN-α levels. Suppressed PTX3 levels may contribute to a vicious circle resulting in impaired waste clearance, autoantigen exposure and autoantibody production, and sustained disease activity. Osteopontin (OPN), a protein known to influence cell signaling and apoptosis, has been proposed as a marker of organ damage in pediatric lupus. In a Swedish cross-section

Background: Despite the improvements in burn care during the last decades, burns remain catastrophic for the patients and a challenge for the care-givers. The early outcome of burn care is to assess its quality and to improve it, but the crucial outcome is mortality, which is the main focus of this thesis. In particular, I address questions about mortality that have arisen from working with burned patients and that can have clinical consequences: the impact of pre- existing medical conditions; long-term survival; the causes of unexpected deaths; and the possible differences between sexes in the provision of resources. Patients with burns share the fact that the time of their injury is known, its severity can be quantified from the size of the burn, and the care is relatively standardised. The analysis of outcome among burned patients treated at a single burn centre may therefore be of general value to others who treat burns. Methods: We retrospectively analysed data that had been collected prospectively (the burn unit database) from patients with burns admitted consecutively to a national burn centre in Sweden during the last 25 years. Results: Age and percentage of total body surface area burned (TBSA %) affected the in- hospital mortality, whereas pre-existing medical conditions did not influence the prediction of outcome (Paper I). After discharge, both age and the presence of full thickness burns reduced the long-term survival, whereas the extent of the burn (TBSA %) did not (Paper II). Most patients with moderate burns who die in hospital despite a good prognosis, die for reasons other than the burn (Paper III). Previously, it has been shown that sex is not an independent factor for mortality during burn care; in this thesis we show that the sex of the patients did not affect the number of medical interventions given either (Paper IV). Conclusion: The addition of “coexisting condition” to a mortality model based on age and size of burn does not improve, Questa tesi tratta del rischio di morte in seguito ad ustioni ed affronta, con approccio scientifico, alcune domande sollevate frequentemente da pazienti e da addetti ai lavori. In particolare:

a presenza di altre malattie a prescindere dall´ustione (diabete, nefropatie, alcolismo, etc.) peggiora la prognosi del paziente? L´essere sopravvissuto ad un´ustione riduce l´aspettativa di vita dopo la dimissione dall´ospedale? Qual è la causa di morte in quei (rari) pazienti che muoiono con ustioni di modesta entità? Il sesso del paziente influenza le cure prestate durante il ricovero ed, in tal caso, qual è l´effetto sulla prognosi? Spesso avevamo risposto a questi interrogativi di interesse clinico basandoci sull´esperienza o su luoghi comuni accettati acriticamente. Con questa tesi abbiamo cercato con metodo scientifico delle risposte di valore generale, analizzando i dati raccolti durante l´ultimo ventennio sui pazienti ricoverati a causa di traumi termici al Centro Nazionale Grandi Ustioni dell´Università di Linköping. In Svezia, come negli altri paesi a reddito medio-alto, il tasso di mortalità in seguito ad ustioni è diminuito notevolmente negli ultimi anni, tuttavia l´obbiettivo principale tra gli addetti ai lavori rimane quello di diminuire ulteriormente la mortalità. L´identificazione precoce di pazienti ad alto rischio di morte fornisce un mezzo utile per migliorarne la prognosi. A tale proposito sono stati sviluppati numerosi modelli matematici in grado di calcolare la probabilità di morte in seguito ad ustioni, basati principalmente sull`età del paziente e sull´ estensione dell´ustione. Infatti, è intuitivamente comprensibile che il rischio di morire aumenti con l´età del paziente e la gravità dell´ustione. Nel nostro primo studio abbiamo aggiunto ad un modello prognostico basato su età e superficie corporea ustionata informazioni sulle malattie già presenti nel paziente prima dell`ustione. Contrariamente a quanto ipotizzato, la presenza di altre, Dödligheten efter brännskador har minskat under de senaste årtiondena, likväl kvarstår målet att ytterligare minska risken att avlida. Syftet med denna avhandling var att studera prognosen efter brännskador, och i synnerhet att analysera dödligheten ur olika perspektiv. De modeller som brukar användas inom brännskadevård för att förutse dödlighet baseras framför allt på brännskadeyta och ålder. Det är emellertid oklart huruvida patientens samsjuklighet påverkar prognosen, och huruvida åldern kan ersätta uppgifter om samsjukligheten. I det första arbetet har detta undersökts genom analys av befintliga vårdregisterdata i Sverige. Att addera information om samsjukligheten till en modell baserat på ålder och brännskadeyta gav inte säkrare förutsägelser. En återkommande fråga inom brännskadevården har varit huruvida patienter som överlever tiden på sjukhus har förkortad långsiktig överlevnad. I det andra arbetet har detta undersökts genom en uppföljning av samtliga patienter som behandlats vid det nationella brännskadecentrat i Linköping. Resultaten visar att skadans svårighetsgrad (brännskadeytan) inte påverkar hur länge patienterna lever efter utskrivning, medan effekten av ålder är avgörande för överlevnaden på lång sikt. Det är ovanligt att patienter som vårdas på sjukhus för brännskador avlider. En viktig observation som gjorts i detta sammanhang är att bland dem som dör under dessa omständigheter återfinns individer vars dödsorsak inte är relaterad till själva brännskadan. Detta gäller särskilt för dem som dör trots att skadeutbredningen är relativt sett liten. Fokus för det tredje arbetet var att undersöka vilka dödsorsaker som är relevanta för gruppen i fråga. Resultaten visar att en inte oväsentlig del av dödsfallen var orsakade av andra faktorer än de som är direkt kopplade till själva brännskadan, exempelvis hjärnblödning eller hjärtinfarkt. Det är väl dokumenterat att ojämlikhet mellan könen ofta föreligger vid medicinsk vård med en diskriminering för kvinn

This thesis focused on the acute management of patients with ST-segment elevation myocardial infarction (STEMI) in an effort to provide information that may improve outcome. The aim was to evaluate the efficacy and safety of bivalirudin versus unfractionated heparin (UFH) in STEMI patients during primary PCI. Furthermore, to provide pharmacodynamic data of novel ways of ticagrelor administration compared to standard tivcagrelor. Additionally, to identify subgroups of patients, such as women who may derive greater benefit from specific antithrombotic strategies due to their risk/benefit profile. Finally, to evaluate current formulas for estimation of renal function in the acute phase of STEMI. In Paper I, all STEMI patients in Sweden between 2008 and 2014, treated with primary PCI and UFH or bivalirudin were included in our analysis. Of the total population of 23 800 patients, 8 783 (36.9%) were included in the UFH group and 15 017 (63.1%) in the bivalirudin group. Concomitant GPI administration was 68.5% in the UFH arm compared to 3.5% in the bivalirudin arm (p<0.01).The adjusted incidence of 30-day mortality was not significant different between the two groups (UFH vs bivalirudin, adjusted HR 0.94; 95% CI 0.82 -1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between the two groups. In contrast, patients treated with UFH had a significantly higher incidence of major in-hospital bleeding (adjusted OR 1.62; 95%CI 1.30 -2.03). In Paper II pharmacodynamic data of chewed or crushed ticagrelor compared to standard ticagrelor loading dose (LD) was assessed in 99 patients with stable angina. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60 minutes after LD. High Residual platelet reactivity (HRPR) was defined as > 208 P2Y12 reaction units (PRU). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60 m

Background: The importance of the social environment and human life conditions for public health was early recognized in community medicine. Despite major reductions in recent decades, cardiovascular diseases (CVD) is one of the leading causes of mortality and morbidity for both genders in all European countries. Aim: The overall aim of this thesis was to increase our knowledge of factors in the social environment and of individual psychosocial factors that could explain why some women in working ages are affected by cardiovascular diseases. Methods: The Swedish sample comes from the urban population in two major cities in a region in the south-east of Sweden, the Twin cities. According to their social history they could be labelled a “blue-collar” and a “white-collar” city. Cardiovascular morbidity data in all papers for the Twin cities was derived from a computerized population-based administrative Health Care Register (HCR). In Paper IV, we made a comparative study between Sweden and Scotland, the Scottish data comes from the Scottish Health Survey. Results: In Paper I, the cumulative incidence of different cardiovascular diagnoses for younger and also elderly men and women were significantly higher in the population of the blue collar city in all ages and for both sexes. The qualitative interviews of women after an MI, in Paper II, the findings revealed a broad picture of social factors, life circumstances, personalities and, not least, psychosocial factors that are important to middle-aged women who have suffered an MI. Paper III demonstrated that women with a high level of the personality trait “being a Good Girl” reported significantly more psychosocial risk factors for CVD and more commonly report chest pain without seeking medical care, no increased incidence for various CVD-diagnoses were found. The comparative study (Paper IV) clearly showed that Scottish middle-aged women are – relative to Swedish women - particularly affected by a worse profile of CVD

Living with inflammatory bowel disease (IBD) affects physical, psychological and social dimensions, limiting the ability to engage in daily activities. Persons with IBD may need frequent and lifelong contacts with the healthcare (HC), highlighting the importance of quality care. High quality HC for persons with IBD involves a partnership between the HC professionals and the person living with the disease. Information is essential, the more a person knows about their disease, the more concordant and satisfied with their treatment they are likely to be. The overall aim of this thesis was to describe the knowledge need, life situation and perception of HC among persons living with IBD, in order to develop a questionnaire to evaluate the quality of HC. This thesis is based on three studies that are presented in four papers. Qualitative methods were used to describe aspects of life situation in relation to the disease, whereas quantitative method was used to develop a questionnaire measuring quality of care. Study I and II have an inductive qualitative design. In study I, qualitative interviews with 30 people were performed to describe the knowledge need and experience of critical incidents in daily life while living with IBD. The interviews in study I were analyzed using content analysis (results presented in Paper I) and critical incident technique (results presented in Paper II). In study II, the perceptions of HC among persons living with IBD was explored in five focus group interviews and two individual interviews, in total n=26. Study III aimed to develop and evaluate a questionnaire, measuring quality of care among persons with IBD, including 318 persons with IBD and 8 professionals. The knowledge need among persons with IBD focused on managing symptoms and course of the disease and learning to assimilate the information in order to manage everyday life. Losing bowel control was of great concern for most of the informants in the study. Many of the informants said

Triage, derived from the French word for sorting, aims to assess and prioritize injured patients, regardless of whether the injuries are sustained from everyday road traffic accident with few injured or a mass casualty incident. Triage seeks to provide the greatest benefit to the largest number of casualties in order to minimize morbidity and mortality. Triage in a pre-hospital setting entails management and sorting of patients according to an assessment of medical need, prioritization, and evacuation. In-hospital triage aims to rapidly identify the most injured and ensure timely and appropriate treatment according to the patient’s clinical urgency. A number of different systems for performing triage have been established and implemented globally. The methodology is recognized and utilized but there is still a need for an evidence-based strategy to optimize training and the efficacy of the different systems. The main aim of this thesis was to determine triage performance among prehospital personnel and investigate the potential advantage of a triage system for trauma patients. The papers included in this thesis evaluated the triage skills of physicians, pre-hospital personnel, and rescue services personnel by testing their performance before and after an educational intervention. The last paper evaluated potential benefits of using a triage system for trauma patients admitted to the emergency department at MOI Teaching and Referral Hospital in Eldoret, Kenya. The results presented in this thesis illustrate that triage skills are lacking among physicians. Experienced pre-hospital personnel are more skilled in performing triage than physicians. The triage skills of the rescue services personnel improved significantly after the educational intervention. Moreover, the potential benefit to trauma patients of implementing an in-hospital triage system in a resource-poor environment was shown. In conclusion, health care personnel, especially physicians without experience bu

Although improved treatments have reduced the rates of acute complications from myocardial infarction, sequelae such as heart failure and sudden death threaten the future wellbeing of those patients. Secondary prevention after myocardial infarction is related to cardiovascular risk factors and the effect of the infarct on left ventricular function. Cardiovascular magnetic resonance imaging (CMR) is necessary to determine the size of the infarct scar and can with great precision determine left ventricular volumes, left ventricular ejection fraction, and deformation (strain and torsion). The purpose of this thesis was to improve on CMR methods to facilitate image acquisition and post processing in patients with high risk of coronary artery disease (CAD). In Paper 1, a three-dimensional phase-sensitive inversion-recovery (3D PSIR) sequence was modified to measure T1 during a single breath hold. The measured T1 values were used to extrapolate a map of T1 relaxation, which avoided the time-consuming manual determination of the inversion time. The data collection consisted of phantom experiments, Monte Carlo simulations of the effect of various heart rates, and clinical investigation of 18 patients with myocardial infarction. Scar images created with the modified sequence were compared to those created with the standard sequence. The 3D PSIR sequence was able to measure T1 relaxation with a high accuracy up to 800 ms, which is in the suitable range for scar imaging. Simulated arrhythmias showed that the method was robust and able to tolerate some variation in heart rate. The modified sequence provides measurements of inversion time that can be used to facilitate standard scar imaging or to reconstruct synthetic scar images. Images of infarct scar obtained with the 3D PSIR sequence bore striking similarity to images obtained with the standard sequence. In Paper 2, 125 patients with high risk of CAD were investigated using the displacement encoding with stimulated echoes (D