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  • Public defence: 2017-08-31 10:15 Auditorium Minus, Uppsala
    Galazka, Martyna A.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala Child & Babylab.
    Social causality in motion: Visual bias and categorization of social interactions during the observation of chasing in infancy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the seminal work of Fritz Heider and Marienne Simmel (1944) the study of animacy perception, or the perception and attribution of life from the motion of simple geometrical shapes has intrigued researchers. The intrigue for psychologists and vision scientists then and today centered on the stark disconnect between the simplicity of the visual input and the universal richness of the resulting percept.

    Infant research in this domain has become critical in examining the ontological processes behind the formation of animated percepts. To date, little is known about how infants process these kinds of stimuli. While numerous habituation studies have shown sensitivity to animate motion in general, none to date has examined whether infants actually perceive animate displays as social interactions.

    The overarching goal of the present thesis is to answer this question and further augment knowledge about the mechanisms behind the formation of animated percepts in infancy. I, along with my collaborators, do so in three ways, in three separate studies. First, we examined visual attention during online observation of randomly moving geometrical shapes in adults and infants (Study I, using eye tracking). Second, we examine distribution of visual attention in infancy during online observation of non-contact causal interactions, focusing on the most ubiquitous, fitness relevant of interactions – chasing (Study II, using eye tracking). Third, we answer the question whether infants perceive social content in chasing displays by measuring the neural correlates in response to chasing (Study III, using EEG).

    The collective contribution of the present work is also three fold. First, it demonstrates that starting at the end of the first year of life, human visual system is sensitive to cues that efficiently predict an interaction. Second, at 5-months infants begins allocating attention differently across agents within interactions. Finally, attention to specific objects is not due to low-level saliency but the social nature of the interaction. Subsequently, I present the case that perception of social agents is fast, direct, and reflects the workings of a specialized learning mechanisms whose function is the detection of heat-seeking animates in motion. 

    List of papers
    1. Visual Attention to Dynamic Spatial Relations in Infants and Adults
    Open this publication in new window or tab >>Visual Attention to Dynamic Spatial Relations in Infants and Adults
    2016 (English)In: Infancy, ISSN 1525-0008, E-ISSN 1532-7078, Vol. 21, no 1, 90-103 p.Article in journal (Refereed) Published
    Abstract [en]

    Previous research has found that kinematic features of interactions, such as spatial proximity, capture adult visual attention. The current research uses online measures of gaze behavior to determine attentional capture to objects with reduced interobject spacing in adults as well as infants at 5 and 12months. The three age groups observed three identical geometrical shapes that moved randomly. Relative distance between the objects was mapped and intervals of high and low spatial proximity were identified. Findings demonstrate that only adults and 12-month-olds look significantly more at the objects that are close during instances of high spatial proximity, while 5-month-olds look at chance. The findings speak for a developmental trend in oculomotor processes, where a bias to look at objects with high spatial proximity develops within the first year of life.

    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-268915 (URN)10.1111/infa.12091 (DOI)000368719000005 ()
    Funder
    Swedish Research Council, VR-2011-1528
    Available from: 2015-12-11 Created: 2015-12-11 Last updated: 2017-05-12Bibliographically approved
    2. Infants' preference for individual agents within chasing interactions
    Open this publication in new window or tab >>Infants' preference for individual agents within chasing interactions
    2016 (English)In: Journal of experimental child psychology (Print), ISSN 0022-0965, E-ISSN 1096-0457, Vol. 147, 53-70 p.Article in journal (Refereed) Published
    Abstract [en]

    Infants, like adults, are able to discriminate between chasing and non-chasing interactions when watching animations with simple geometric shapes. But where infants derive the necessary information for discrimination and how chasing detection influences later visual attention has been previously unexplored. Here, using eye tracking, we investigated how 5- and 12-month-old infants (N = 94) distribute their visual attention among individual members within different interactions depending on a type of interaction. Infant gaze was examined when observing animations depicting chasing and following interactions compared with animations displaying randomly moving shapes. Results demonstrate that when observing chasing and following interactions, all infants strongly preferred to attend to the agent that initiates an interaction and trails behind another. Low-level features, such as changes in agent-specific velocity profiles, could not account for this preference (Study 2). Rather, the strong preference for the agent going behind seems to be dependent on the initial goal-directed or "heat-seeking" motion of one agent toward another (Study 3). The current set of experiments suggests that, similar to adults, 5 months-olds' visual attention depends on the motion features of an individual agent within the interaction and is fine-tuned to agents that display goal-directed motion toward other agents.

    Keyword
    Visual attention, Social interactions, Social perception, Infant, Eye tracking, Chasing
    National Category
    Psychology (excluding Applied Psychology)
    Identifiers
    urn:nbn:se:uu:diva-298836 (URN)10.1016/j.jecp.2016.02.010 (DOI)000376698100004 ()27017143 (PubMedID)
    Funder
    Swedish Research Council, VR-2011-1528
    Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2017-05-12Bibliographically approved
    3. How social is the chaser?: Neural correlates of chasing perception in 9-month-old infants
    Open this publication in new window or tab >>How social is the chaser?: Neural correlates of chasing perception in 9-month-old infants
    2016 (English)In: Developmental Cognitive Neuroscience, ISSN 1878-9293, E-ISSN 1878-9307, Vol. 19, 270-278 p.Article in journal (Refereed) Published
    Abstract [en]

    We investigated the neural correlates of chasing perception in infancy to determine whether animated interactions are processed as social events. By using EEG and an ERP design with animations of simple geometric shapes, we examined whether the positive posterior (P400) component, previously found in response to social stimuli, as well as the attention related negative fronto-central component (Nc), differs when infants observed a chaser versus a non-chaser. In Study 1, the chaser was compared to an inanimate object. In Study 2, the chaser was compared to an animate but not chasing agent (randomly moving agent). Results demonstrate no difference in the Nc component, but statistically higher P400 amplitude when the chasing agent was compared to either an inanimate object or a random object. We also find a difference in the N290 component in both studies and in the P200 component in Study 2, when the chasing agent is compared to the randomly moving agent. The present studies demonstrate for the first time that infants' process correlated motion such as chasing as a social interaction. The perception of the chasing agent elicits stronger time-locked responses, denoting a link between motion perception and social cognition.

    Keyword
    P400, Animacy perception, Chasing
    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-299733 (URN)10.1016/j.dcn.2016.05.0051878 (DOI)000378032000027 ()27258722 (PubMedID)
    Funder
    Swedish Research Council, VR-2011-1528EU, European Research Council, 312292
    Available from: 2016-07-26 Created: 2016-07-26 Last updated: 2017-05-12Bibliographically approved
  • Public defence: 2017-09-01 09:15 Enghoffsalen, Uppsala
    Rosenqvist, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Transjugular intrahepatic portosystemic shunt in the treatment of symptomatic portal hypertension2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Portal hypertension (PHT) is a condition with serious complications, such as variceal bleeding, refractory ascites and bowel ischemia. The cause of PHT may be pre-, intra- or post-hepatic. Initial treatment is pressure-reducing drugs and the treatment of acute symptoms.

    Ten patients presented with severe abdominal pain and acute portomesenteric venous thrombosis. Their response to systemic anticoagulation was insufficient. Treatment with primary continuous thrombolysis by a transhepatic or transjugular approach in four patients resulted in major complications, incomplete recanalization and a 75% survival rate. Treatment with repeated transjugular thrombectomy (TT) combined with the creation of a transjugular intrahepatic portosystemic shunt (TIPS) achieved near complete recanalization, prompt symptom relief and 100% survival in five patients treated with this method as the primary intervention. In one patient, treated with TT and TIPS secondary to surgical thrombectomy and bowel resection, the outcome was fatal.

    Nineteen patients with portal vein thrombosis presented with acute or threatening variceal bleeding or refractory ascites. TIPS was feasible in 16 of the 18 patients in whom it was attempted and symptom relief was achieved in the majority of them.

    In 14 patients with Budd-Chiari syndrome, 13 patients were treated with TIPS, four of them after previous liver vein angioplasty. The 5-year transplantation-free survival rate was 100% in patients treated with primary TIPS.

    In 131 patients with variceal bleeding treated with TIPS, the survival at 12 months in patients with and without cirrhosis was 70% and 100% respectively and in accordance with previous studies. A high Child-Pugh score prior to TIPS and severe HE within 12 months after TIPS was related to an increased mortality. The occurrence of HE after TIPS did not correlate with the PSG after TIPS. Re-bleeding within 12 months after TIPS occurred in 10 patients and was associated with TIPS dysfunction.

    In conclusion, endovascular intervention, mainly TIPS, seems to be safe and effective for treating patients with complications of PHT, regardless of the underlying cause of disease and site of venous blood flow obstruction. HE may occur more frequently after TIPS than medical and endoscopic treatment, but is often mild and easily treated. In selected patients with PHT, TIPS may improve survival.

    List of papers
    1. Endovascular treatment of acute and chronic portal vein thrombosis in patients with cirrhotic and non-cirrhotic liver
    Open this publication in new window or tab >>Endovascular treatment of acute and chronic portal vein thrombosis in patients with cirrhotic and non-cirrhotic liver
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    2016 (English)In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 57, no 5, 572-579 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Treatment of patients with portal vein thrombosis (PVT) differs due to different etiology and wide range of symptoms but certain patients seems to benefit from endovascular intervention.

    PURPOSE: To assess the safety and efficiency of endovascular treatment of acute and chronic PVT in patients with cirrhotic and non-cirrhotic liver.

    MATERIAL AND METHODS: Twenty-one patients with PVT treated with an endovascular procedure in 2002-2013 were studied retrospectively. Data on etiology, onset and extension of thrombus, presenting symptoms, methods of intervention, portal pressure gradients, complications, recurrence of symptoms, re-interventions, clinical status at latest follow-up, and survival were collected.

    RESULTS: Four non-cirrhotic patients with acute extensive PVT and bowel ischemia were treated with local thrombolysis, in three combined with placement of a transjugular intrahepatic portosystemic shunt (TIPS) placement. Three recovered and have survived more than 6 years. In six non-cirrhotic patients with chronic PVT and acute or threatening variceal bleeding recanalization and TIPS were successful in three and failed in three. Eleven cirrhotic patients with PVT and variceal bleeding or refractory ascites were successfully treated with recanalization and TIPS. Re-intervention was performed in five of these patients and five patients died, three within 12 months of intervention. Four cirrhotic patients had episodes of shunt-related encephalopathy and three had variceal re-bleeding.

    CONCLUSION: TIPS was found to be effective in reducing portal hypertension in patients with PVT. In patients with extensive PVT and bowel ischemia treatment with TIPS combined with thrombolysis should be considered.

    Keyword
    Portal vein; thrombosis; liver cirrhosis; endovascular procedure; retrospective study
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-261206 (URN)10.1177/0284185115595060 (DOI)000374327600010 ()26253926 (PubMedID)
    Available from: 2015-08-31 Created: 2015-08-31 Last updated: 2017-05-10Bibliographically approved
    2. Endovascular treatment of symptomatic Budd-Chiari syndrome - in favour of early transjugular intrahepatic portosystemic shunt.
    Open this publication in new window or tab >>Endovascular treatment of symptomatic Budd-Chiari syndrome - in favour of early transjugular intrahepatic portosystemic shunt.
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    2016 (English)In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 28, no 6, 656-660 p.Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Treatment of Budd-Chiari syndrome (BCS) has shifted from mainly medical treatment, with surgical shunt and orthotopic liver transplantation (OLT) as rescue, to medical treatment combined with an early endovascular intervention in the past two decades.

    PURPOSE: To assess the safety and efficiency of endovascular treatment of symptomatic patients with BCS and to compare mortality with symptomatic BCS patients in the same region treated with only sporadic endovascular techniques.

    METHODS: This was a retrospective review of clinical data, treatment and survival in 14 patients diagnosed with BCS and treated with endovascular methods from 2003 to 2015. A national epidemiology study of BCS from 1986 to 2003 was used for comparison.

    RESULTS: Thirteen of the 14 patients eventually had transjugular intrahepatic portosystemic shunt (TIPS), four after previous liver vein angioplasty. TIPS were performed with polytetrafluoroethylene-covered stents and technical success was 100%. Calculated preinterventional prognostic indices indicated a high risk of TIPS dysfunction, OLT and death. However, only one patient died and one had an OLT, and the 1- and 2-year primary TIPS-patency was 85 and 67%, respectively. Episodes of de-novo hepatic encephalopathy occurred in three patients. Overall 1- and 5-year transplantation-free survival was 100 and 93% compared with 47 and 28%, respectively, in 1986 to 2003.

    CONCLUSION: TIPS seems to be a safe and effective treatment for symptomatic BCS and there is an obvious improvement in transplantation-free survival compared with conservatory medical treatment. It should, therefore, be considered early, as first-line intervention, in patients with insufficient response to medical treatment.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-285913 (URN)10.1097/MEG.0000000000000621 (DOI)000375147100008 ()26958788 (PubMedID)
    Available from: 2016-04-20 Created: 2016-04-20 Last updated: 2017-05-10Bibliographically approved
    3. Repeated thrombectomy through a transjugular intrahepatic portosystemic shunt. An effective and safe way to treat acute portomesenteric venous thrombosis.
    Open this publication in new window or tab >>Repeated thrombectomy through a transjugular intrahepatic portosystemic shunt. An effective and safe way to treat acute portomesenteric venous thrombosis.
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-321534 (URN)
    Available from: 2017-05-08 Created: 2017-05-08 Last updated: 2017-05-10
    4. Transjugular intrahepatic portosystemic shunt treatment of variceal bleeding in an unselected patient population
    Open this publication in new window or tab >>Transjugular intrahepatic portosystemic shunt treatment of variceal bleeding in an unselected patient population
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-321536 (URN)
    Available from: 2017-05-08 Created: 2017-05-08 Last updated: 2017-05-18
  • Public defence: 2017-09-01 13:00 Hedstrandsalen, Uppsala
    Strandberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Experimental Studies on Diagnostic and Therapeutic Aspects of Intraosseous Access2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Reliable access to the circulation is paramount in most medical and surgical emergencies. When venous access cannot be expediently established, intraosseous (IO) access is indicated. This method has a high success rate even in relatively inexperienced hands and there is considerable clinical experience of IO administration of drugs and fluids. There is however limited evidence on the use of IO samples for laboratory analysis. Also, uptake of drugs during shock has not been extensively studied. Further, there have been concerns that analysis of IO samples may damage laboratory equipment. We have studied, in a porcine model, the use of IO samples for point of care analysis of blood gases, acid base parameters and blood chemistries in stable circulation, in experimental septic shock, and in hypovolemia after major hemorrhage, comparing IO samples with arterial and venous samples, and comparing IO samples from different sites. We have also studied coagulation assays on IO samples in stable circulation and after major hemorrhage. Furthermore, we have compared IO and intravenous administration of antibiotics in experimental sepsis.

    Average differences between IO and arterial/venous samples varied between the studied analytes. During stable circulation, average IO levels of blood gases, acid-base parameters, hemoglobin/hematocrit and several blood chemistries approximated venous levels relatively well. Differences in acid-base and blood gas parameters, and lactate, were more pronounced in hypovolemia, as well as in sepsis. The dispersion of the differences was often relatively large, indicating limited precision. Average differences between two intraosseous sites were small.

    Intraosseous samples were clinically hypercoagulable with a strong tendency to clot in vitro, and thromboelastography demonstrated shortened reaction times compared with venous samples. Major bleeding and hemodilution moderately affected the studied coagulation parameters.

    In endotoxemic animals with circulatory instability, concentrations of cefotaxime and gentamicin in samples from the pulmonary artery were comparable at 5 minutes after intraosseous and intravenous administration, and during a 3 hour observation period.

    In summary, agreement between analytes in intraosseous and conventional blood samples was variable and often unpredictable, especially during circulatory compromise. Intraosseous samples clinically appeared hypercoagulable, and thromboelastography confirmed this. High and comparable concentrations of cefotaxime and gentamicin were found after intraosseous and intravenous administration of equivalent doses, suggesting that uptake is acceptable during septic instability.  

    List of papers
    1. Analysis of intraosseous samples using point of care technology: an experimental study in the anaesthetised pig
    Open this publication in new window or tab >>Analysis of intraosseous samples using point of care technology: an experimental study in the anaesthetised pig
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    2012 (English)In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 83, no 11, 1381-1385 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Intraosseous access is an essential method in emergency medicine when other forms of vascular access are unavailable and there is an urgent need for fluid or drug therapy. A number of publications have discussed the suitability of using intraosseous access for laboratory testing. We aimed to further evaluate this issue and to study the accuracy and precision of intraosseous measurements.

    METHODS:

    Five healthy, anaesthetised pigs were instrumented with bilateral tibial intraosseous cannulae and an arterial catheter. Samples were collected hourly for 6h and analysed for blood gases, acid base status, haemoglobin and electrolytes using an I-Stat(®) point of care analyser.

    RESULTS:

    There was no clinically relevant difference between results from left and right intraosseous sites. The variability of the intraosseous sample values, measured as the coefficient of variance (CV), was maximally 11%, and smaller than for the arterial sample values for all variables except SO(2). For most variables, there seems to be some degree of systematic difference between intraosseous and arterial results. However, the direction of this difference seems to be predictable.

    CONCLUSION:

    Based on our findings in this animal model, cartridge based point of care instruments appear suitable for the analysis of intraosseous samples. The agreement between intraosseous and arterial analysis seems to be good enough for the method to be clinically useful. The precision, quantified in terms of CV, is at least as good for intraosseous as for arterial analysis. There is no clinically important difference between samples from left and right tibia, indicating a good reproducibility.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-181455 (URN)10.1016/j.resuscitation.2012.04.007 (DOI)000311793100023 ()22542768 (PubMedID)
    Available from: 2012-09-24 Created: 2012-09-24 Last updated: 2017-05-08Bibliographically approved
    2. Analysis of intraosseous samples in endotoxemic shock: an experimental study in the anaesthetised pig
    Open this publication in new window or tab >>Analysis of intraosseous samples in endotoxemic shock: an experimental study in the anaesthetised pig
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    2014 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 58, no 3, 337-344 p.Article in journal (Refereed) Published
    Abstract [en]

    Background

    Intraosseous (IO) access is used in emergency situations to allow rapid initiation of treatment. IO access is also sometimes used for blood sampling, although data on accuracy of such sampling in critical illness are limited. There is also a potential risk that bone marrow fragments in IO samples may damage laboratory equipment. It is ethically questionable to perform a simultaneous comparison between IO and arterial/venous sampling in critically ill humans. We have, thus, studied the analytical performance of IO sampling in a porcine septic shock model using a cartridge-based analyser.

    Methods

    Eight pigs with endotoxin-induced septic shock were sampled hourly for 6 h, and analysed for blood gases, acid base status, haemoglobin, glucose and lactate using point of care instruments. Samples were taken from three IO cannulae (tibia bilaterally, one with infusion, and humerus), one arterial and one venous. An interaction test was used to assess changes in agreement between methods over time. Bland–Altman plots were constructed to study bias between methods.

    Results

    There were, to a varying extent, differences between IO and arterial/venous levels for all studied variables, but agreement did not change significantly during the experiment. A general finding was a large dispersion of differences between methods.

    Conclusions

    IO sample values should be treated with caution in this setting but may add useful information to the clinical picture. The tibia or humerus may be used for sampling. IO infusion decreases agreement, thus sampling during infusion should be avoided.

    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-220973 (URN)10.1111/aas.12274 (DOI)000331406500011 ()
    Available from: 2014-03-25 Created: 2014-03-24 Last updated: 2017-05-08Bibliographically approved
    3. Intraosseous and intravenous administration of antibiotics yields comparable plasma concentrations during experimental septic shock
    Open this publication in new window or tab >>Intraosseous and intravenous administration of antibiotics yields comparable plasma concentrations during experimental septic shock
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    2015 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, no 3, 346-353 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: We aimed to investigate whether comparable antibiotic concentrations could be reached with intraosseous and intravenous administration during septic shock.

    METHODS: In this randomized, prospective experimental study conducted at an animal research laboratory at the University Hospital of Uppsala, eight anesthetized pigs, weighing 21.2 to 29.1 kg (mean: 25.2 ± 2.3 kg), received endotoxin infusion at 4 μg/kg/h for 6 h. At the onset of clinical shock, alternatively after 3 h of endotoxemia, they received 75 mg/kg of cefotaxime and 7 mg/kg of gentamicin either in a proximal tibial intraosseous catheter or in a peripheral intravenous catheter. Mixed venous samples were taken after 5, 15, 30, 60, 120 and 180 min and analyzed for antibiotic concentrations.

    RESULTS: For both antibiotics, plasma concentrations after intraosseous and intravenous administration followed similar curves throughout the observation period, and peak concentrations were comparable. Mean concentration area under the curve (AUC mg × h/l) for cefotaxime was 108.1 ± 19.5 after intraosseous and 116.5 ± 11.1 after intravenous administration; ratio 0.93, (95% CI 0.71-1.19). Mean AUC for gentamicin was 28.1 ± 6.8 for intraosseous and 32.2 ± 3.5 for intravenous administration; ratio 0.87 (95% CI 0.62-1.19).

    CONCLUSIONS: In this porcine septic shock model, intraosseous and intravenous administration of gentamicin and cefotaxime yielded comparable concentrations. In an emergency, intraosseous administration of these antibiotics may be considered in severe infections when venous access is difficult.

    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-240273 (URN)10.1111/aas.12454 (DOI)000349604000009 ()25557933 (PubMedID)
    Available from: 2015-01-06 Created: 2015-01-06 Last updated: 2017-05-08Bibliographically approved
    4. Analysis of Thromboelastography, PT, APTT and Fibrinogen in Intraosseous and Venous Samples: An Experimental Study
    Open this publication in new window or tab >>Analysis of Thromboelastography, PT, APTT and Fibrinogen in Intraosseous and Venous Samples: An Experimental Study
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    2016 (English)In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 24, 131Article in journal (Refereed) Published
    Abstract [en]

    Background:Laboratory analysis of coagulation is often important in emergencies. If vascular access is challenging,intraosseous catheterization may be necessary for treatment. We studied the analysis of coagulation parameters inintraosseous aspirate during stable conditions and after major haemorrhage in a porcine model.Methods:Ten anesthetized pigs received central venous and intraosseous catheters and samples were taken foranalysis of thromboelastography (TEG), prothrombin time (PT), activated partial thromboplastin time (APTT) andfibrinogen concentration. Analyses were repeated after removal of 50 % of the calculated blood volume andresuscitation with crystalloid. Intraosseous and venous values were compared.Results:Bleeding and resuscitation resulted in haemodilution and hypotension. Median TEG reaction time wasshorter in intraosseous than in venous samples before (1.6 vs 4.6 min) and after (1.6 vs 4.7 min) haemodilution.Median maximal amplitude was smaller in intraosseous samples at baseline (68.3 vs 76.4 mm). No major differenceswere demonstrated for the other TEG parameters. The intraosseous samples often coagulated in vitro, makinganalysis of PT, APTT and fibrinogen difficult. After haemodilution, TEG maximal amplitude andα-angle, andfibrinogen concentration, were decreased and PT increased.Discussion:The intraosseous samples were clinically hypercoagulable and the TEG demonstrated a shortenedreaction time. The reason for this may hypothetically be found in the composition of the IO aspirate or in thesampling technique. After 50 % haemorrhage and haemodilution, a clinically relevant decrease in fibrinogenconcentration and a lower TEG maximal amplitude were observed.Conclusions:Although the sample is small, these data indicate that intraosseous samples are hypercoagulable,which may limit their usefulness for coagulation studies. Major haemodilution only moderately affected the studied parameters.

    Keyword
    Blood coagulation; Haemorrhage; Infusions; Intraosseous; Thrombelastography
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-306587 (URN)10.1186/s13049-016-0318-0 (DOI)000386860300001 ()
    Available from: 2016-10-29 Created: 2016-10-29 Last updated: 2017-05-08Bibliographically approved
    5. Comparison of Intraosseous, Arterial and Venous Blood Sampling for Laboratory Analysis in Haemorrhagic Shock
    Open this publication in new window or tab >>Comparison of Intraosseous, Arterial and Venous Blood Sampling for Laboratory Analysis in Haemorrhagic Shock
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Abstract

    Introduction Intraosseous (IO) access is often indicated for administration of drugs and fluids in emergencies when venous access is challenging. There is no consensus regarding which laboratory analyses may be performed on IO aspirates, and research on hemodynamically unstable subjects is limited.

    Methods 12 anaesthetised pigs were sampled from IO, venous and arterial accesses during stable circulation and after haemorrhage corresponding to 20% and 40% of the blood volume. Samples were analysed for blood gases and acid-base status, electrolytes, haematocrit, creatinine, glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP) and creatine kinase (CK).

    Results Average differences of blood gases and acid-base parameters, sodium, creatinine, haematocrit, ALT and γ-GT and between IO and venous samples were small at baseline and after haemorrhage while differences for lactate and glucose increased with hypovolaemia. Both IO-arterial and venoarterial differences in acid-base parameters increased with hypovolaemia. Dispersions of differences were often large.

    Conclusions Average levels of blood gases, acid base parameters, haematocrit, creatinine and ALT, but not lactate and glucose, were similar in IO and venous samples in hypovolaemia. However, precision was limited, indicating that IO test results should be confirmed when other vascular access is established, and that analysis of IO samples should be limited to acute situations and not used for detailed diagnostics in this setting.

    Keyword
    Intraosseous access, shock
    National Category
    Anesthesiology and Intensive Care
    Research subject
    Anaesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-321402 (URN)
    Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2017-05-04
  • Public defence: 2017-09-01 13:15 Polhemsalen, Uppsala
    Wang, Liguo
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Electricity.
    Modelling and Advanced Control of Fully Coupled Wave Energy Converters Subject to Constraints: the Wave-to-wire Approach2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ocean wave energy is a promising renewable source to contribute to supplying the world’s energy demand. The Division of Electricity at Uppsala University is developing a technology to capture energy from ocean waves with a wave energy converter (WEC) consisting of a linear permanent magnet generator and a point absorber. The linear generator is placed on sea bed and is driven directly by the floating absorber. Since March 2006, multiple wave energy converters have been deployed on the Swedish west coast outside the town of Lysekil. The technology is verified by long-term operation during at sea and satisfactory reliability of the electricity generation.

    This thesis focuses on developing advanced control strategies for fully coupled wave energy converters subject to constraints. A nonlinear control strategy is studied in detail for a single WEC subject to constraints under regular and irregular waves. Besides, two coordinated control strategies are developed to investigate the performance of a wave energy farm subject to constraints. The performance of the WECs using these control strategies are investigated in case studies, and optimal PTO damping coefficients are found to maximize the output power. The results show that these control strategies can significantly improve the performance of the WECs, in terms of mean power, compared to a conventional control.

    Besides these control strategies, a wave-to-wire simulation platform is built to study the power generation control of the WEC subject to constraints.  The wave-to-wire simulation platform allows both nonlinear and linear control force. The results show that there is a good agreement between the desired value and the actual value after advanced control.

    List of papers
    1. Constrained optimal control of a point absorber wave energy converter with linear generator
    Open this publication in new window or tab >>Constrained optimal control of a point absorber wave energy converter with linear generator
    2015 (English)In: Journal of Renewable and Sustainable Energy, ISSN 1941-7012, E-ISSN 1941-7012, Vol. 7, 043127Article in journal (Refereed) Published
    Abstract [en]

    This paper investigates a method for optimal control of a point absorbing wave energy converter by considering the constraints on motions and forces in the time domain. The problem is converted to an optimization problem with the cost function being convex quadratic and the constraints being nonlinear. The influence of the constraints on the converter is studied, and the results are compared with uncontrolled cases and established theoretical bounds. Since this method is based on the knowledge of the future sea state or the excitation force, the influence of the prediction horizon is indicated. The resulting performance of the wave energy converter under different regular waves shows that this method leads to a substantial increase in conversion efficiency.

    Keyword
    wave energy
    National Category
    Environmental Engineering
    Research subject
    Engineering Science
    Identifiers
    urn:nbn:se:uu:diva-263980 (URN)10.1063/1.4928677 (DOI)000360655500046 ()
    Funder
    Swedish Energy Agency
    Available from: 2015-10-05 Created: 2015-10-05 Last updated: 2017-04-26Bibliographically approved
    2. Nonlinear Passive Control of a Wave Energy Converter Subject to Constraints in Irregular Waves
    Open this publication in new window or tab >>Nonlinear Passive Control of a Wave Energy Converter Subject to Constraints in Irregular Waves
    2015 (English)In: Energies, ISSN 1996-1073, Vol. 8, no 7, 6528-6542 p.Article in journal (Refereed) Published
    National Category
    Other Engineering and Technologies
    Identifiers
    urn:nbn:se:uu:diva-258502 (URN)10.3390/en8076528 (DOI)000359897800015 ()
    Funder
    Swedish Energy Agency
    Available from: 2015-07-14 Created: 2015-07-14 Last updated: 2017-04-26Bibliographically approved
    3. Constrained Optimal Control of Single and Arrays of Point-Absorbing Wave Energy Converters
    Open this publication in new window or tab >>Constrained Optimal Control of Single and Arrays of Point-Absorbing Wave Energy Converters
    Show others...
    2016 (English)Conference paper, (Refereed)
    National Category
    Ocean and River Engineering
    Identifiers
    urn:nbn:se:uu:diva-297190 (URN)
    Conference
    Marine Energy Technology Symposium
    Available from: 2016-06-21 Created: 2016-06-21 Last updated: 2017-04-26Bibliographically approved
    4. Coordinated Control of Wave Energy Converters Subject to Motion Constraints
    Open this publication in new window or tab >>Coordinated Control of Wave Energy Converters Subject to Motion Constraints
    2016 (English)In: Energies, ISSN 1996-1073, E-ISSN 1996-1073, Vol. 9, no 6, 475Article in journal (Refereed) Published
    Abstract [en]

    In this paper, a generic coordinated control method for wave energy converters is proposed, and the constraints on motion amplitudes and the hydrodynamic interaction between converters are considered. The objective of the control problem is to maximize the energy converted from ocean waves, and this is achieved by coordinating the power take-off (PTO) damping of each wave energy converter in the frequency domain in each sea state. In a case study, a wave energy farm consisting of four converters based on the concept developed by Uppsala University is studied. In the solution, motion constraints, including constraints on the amplitudes of displacement and velocity, are included. Twelve months of sea states, based on measured wave data at the Lysekil test site on the Swedish west coast, are used in the simulation to evaluate the performance of the wave energy farm using the new method. Results from the new coordinated control method and traditional control method are compared, indicating that the coordinated control of wave energy converters is an effective way to improve the energy production of wave energy farm in harmonic waves.

    Place, publisher, year, edition, pages
    MDPI: , 2016
    Keyword
    wave energy farm; coordinated control; optimal damping; motion constraints; frequency domain
    National Category
    Ocean and River Engineering
    Identifiers
    urn:nbn:se:uu:diva-297187 (URN)10.3390/en9060475 (DOI)000378854400088 ()
    Funder
    Swedish Energy AgencyStandUpSwedish National Infrastructure for Computing (SNIC)
    Available from: 2016-06-21 Created: 2016-06-21 Last updated: 2017-04-26Bibliographically approved
    5. Performance of arrays of direct-driven wave energy converters under optimal power take-off damping
    Open this publication in new window or tab >>Performance of arrays of direct-driven wave energy converters under optimal power take-off damping
    2016 (English)In: AIP Advances, ISSN 2158-3226, E-ISSN 2158-3226, Vol. 6, 085313Article in journal (Refereed) Published
    Abstract [en]

    It is well known that the total power converted by a wave energy farm is influenced by the hydrodynamic interactions between wave energy converters, especially when they are close to each other. Therefore, to improve the performance of a wave energy farm, the hydrodynamic interaction between converters must be considered, which can be influenced by the power take-off damping of individual converters. In this paper, the performance of arrays of wave energy converters under optimal hydrodynamic interaction and power take-off damping is investigated. This is achieved by coordinating the power take-off damping of individual converters, resulting in optimal hydrodynamic interaction as well as higher production of time-averaged power converted by the farm. Physical constraints on motion amplitudes are considered in the solution, which is required for the practical implementation of wave energy converters. Results indicate that the natural frequency of a wave energy converter under optimal damping will not vary with sea states, but the production performance of a wave energy farm can be improved significantly while satisfying the motion constraints.

    National Category
    Water Engineering
    Identifiers
    urn:nbn:se:uu:diva-301092 (URN)10.1063/1.4961498 (DOI)000383909100078 ()
    Projects
    Performance and Survivability of Wave power Farm
    Funder
    Swedish Energy Agency, 40421-1
    Available from: 2016-08-17 Created: 2016-08-17 Last updated: 2017-04-26Bibliographically approved
    6. Review of control strategies for wave energy conversion systems and their validation: the wave-to-wire approach
    Open this publication in new window or tab >>Review of control strategies for wave energy conversion systems and their validation: the wave-to-wire approach
    (English)Article in journal, Editorial material (Refereed) Submitted
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-320904 (URN)
    Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2017-04-26
  • Public defence: 2017-09-01 13:15 Room C8:305, Uppsala
    Inturi, Raviteja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Functional characterization of the human adenovirus pVII protein and non-coding VA RNAI2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human adenovirus (HAdV) is a common pathogen causing a broad spectrum of diseases. HAdV encodes the pVII protein, which is involved in nuclear delivery, protection and expression of viral DNA. To suppress the cellular interferon (IFN) and RNA interference (RNAi) systems, HAdVs encode non-coding virus-associated (VA) RNAs. In this thesis we have investigated the functional significance of the pVII protein and VA RNAI in HAdV-5 infected cells.

    We report that the propeptide module is the destabilizing element targeting the precursor pVII protein for proteasomal degradation. We also found that the Cul3-based E3 ubiquitin ligase complex alter the precursor pVII protein stability via binding to the propeptide sequence. In addition, we show that inhibition of the Cul3 protein reduces HAdV-5 E1A gene expression. Collectively, our results suggest a novel function for the pVII propeptide module and involvement of Cul3 in viral E1A gene expression.

    Our studies show that the cellular E3 ubiquitin ligase MKRN1 is a novel pVII interacting protein in HAdV-5 infected cells. MKRN1 expression reduced the pVII protein accumulation in virus-infected cells and affected infectious virus formation. Surprisingly, the endogenous MKRN1 protein underwent proteasomal degradation during the prolonged HAdV-5 infection. Furthermore, the precursor pVII protein enhanced MKRN1 self-ubiquitination, suggesting the direct involvement of pVII in the initiation of MKRN1 degradation. Hence, we propose that the MKRN1 is a novel antiviral protein and that HAdV-5 infection counteracts its antiviral activity.

    In papers III and IV, we tested the ability of various plant and animal virus encoded RNAi/miRNA and IFN suppressor proteins to functionally substitute for the HAdV-5 VA RNAI. Our results revealed that the Vaccinia virus E3L protein was able to partially substitute for the HAdV-5 VA RNAI functions in virus-infected cells. Interestingly, the E3L protein rescued the translational defect but did not stimulate viral capsid mRNA accumulation observed with VA RNA. Additionally, we show that the HAdV-4 and HAdV-37 VA RNAI are more effective in virus replication compared to HAdV-5 and HAdV-12 VA RNAI. In paper IV, we employed a novel triplex-specific probing assay, based on the intercalating and cleaving agent benzoquinoquinaxline 1,10-phenanthroline (BQQ-OP), to unravel triplex structure formation in 
VA RNAI. The BQQ-OP cleavage of HAdV-4 VA RNAI indicates that a potential 
triplex is formed involving the highly conserved stem 4 of the central domain and side 
stem 7. Further, the integrity of HAdV-4 VA RNAI stem 7 contributes to the virus growth in vivo.

    List of papers
    1. Adenovirus Precursor pVII Protein Stability Is Regulated By Its Propeptide Sequence
    Open this publication in new window or tab >>Adenovirus Precursor pVII Protein Stability Is Regulated By Its Propeptide Sequence
    2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 11, e80617- p.Article in journal (Refereed) Published
    Abstract [en]

    Adenovirus encodes for the pVII protein, which interacts and modulates virus DNA structure in the infected cells. The pVII protein is synthesized as the precursor protein and undergoes proteolytic processing by viral proteinase Avp, leading to release of a propeptide sequence and accumulation of the mature VII protein. Here we elucidate the molecular functions of the propeptide sequence present in the precursor pVII protein. The results show that the propeptide is the destabilizing element targeting the precursor pVII protein for proteasomal degradation. Our data further indicate that the propeptide sequence and the lysine residues K26 and K27 regulate the precursor pVII protein stability in a co-dependent manner. We also provide evidence that the Cullin-3 E3 ubiquitin ligase complex alters the precursor pVII protein stability by association with the propeptide sequence. In addition, we show that inactivation of the Cullin-3 protein activity reduces adenovirus E1A gene expression during early phase of virus infection. Collectively, our results indicate a novel function of the adenovirus propeptide sequence and involvement of Cullin-3 in adenovirus gene expression.

    Keyword
    Adenovirus, pro-peptide, pVII, cullin3, protein stability
    National Category
    Microbiology
    Research subject
    Microbiology; Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-212439 (URN)10.1371/journal.pone.0080617 (DOI)000327258600074 ()
    Funder
    Swedish Research Council, K2012-99X-21959-01-3, 2006-5038-36531-16Swedish Cancer Society, 12 0504
    Available from: 2013-12-10 Created: 2013-12-10 Last updated: 2017-05-09Bibliographically approved
    2. Human adenovirus infection counteracts the anti-viral activity of the cellular MKRN1 E3 ubiquitin ligase
    Open this publication in new window or tab >>Human adenovirus infection counteracts the anti-viral activity of the cellular MKRN1 E3 ubiquitin ligase
    Show others...
    (English)Article in journal (Refereed) Submitted
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-321638 (URN)
    Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-05-09
    3. Complementation of the human adenovirus type 5 VA RNAI defect by the Vaccinia virus E3L protein and serotype-specific VA RNAIs
    Open this publication in new window or tab >>Complementation of the human adenovirus type 5 VA RNAI defect by the Vaccinia virus E3L protein and serotype-specific VA RNAIs
    2015 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 485, 25-35 p.Article in journal (Refereed) Published
    Abstract [en]

    Human adenoviruses (HAdVs) encode for multifunctional non-coding virus-associated (VA) RNAs, which function as powerful suppressors of the cellular interferon (IFN) and RNA interference (RNAi) systems. In this study we tested the ability of various plant and animal virus encoded RNAi and IFN suppressor proteins to functionally substitute for the HAdV-5 VA RNAI. Our results revealed that only the Vaccinia virus (VACV) E3L protein was able to substitute for the HAdV-5 VA RNAI functions in virus-infected cells. Interestingly, the E3L protein rescues the translational defect but does not stimulate viral capsid mRNA accumulation observed with VA RNA. We further show that the E3L C-terminal region containing the dsRNA-binding domain is needed to enhance VA RNAI mutant virus replication. Additionally, we show that the HAdV-4 and HAdV-37 VA RNAI are more effective than the HAdV-5 VA RNAI in rescuing virus replication.

    Keyword
    Adenovirus, Vaccinia virus, interferon, PKR, RNAi
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Medical Virology
    Identifiers
    urn:nbn:se:uu:diva-258879 (URN)10.1016/j.virol.2015.07.002 (DOI)000363993100003 ()
    Funder
    Swedish Cancer Society, 12 0504, 13 0469Swedish Research Council, K2012–999X-21959-01-301–3Åke Wiberg Foundation, M14-01555
    Available from: 2015-07-21 Created: 2015-07-21 Last updated: 2017-05-09Bibliographically approved
    4. RNA triplex formation in human adenovirus type 4 VA RNAI and its implication on virus growth
    Open this publication in new window or tab >>RNA triplex formation in human adenovirus type 4 VA RNAI and its implication on virus growth
    (English)Article in journal (Refereed) Submitted
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-321639 (URN)
    Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-05-09
  • Public defence: 2017-09-04 13:30 room 132:028, Stockholm
    Chen-Lin, Xinyi
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Physics. Nordita.
    Non-conformal gauge/string duality: A rigorous case study2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The gauge/string duality, a.k.a. the holographic principle is a profound assertion that emerged from string theory. It relates strongly-coupled gauge theories to weakly coupled string theories living in a higher-dimensional curved geometry. Nevertheless, it is a conjecture, and only a few instances of its more concrete form, the AdS/CFT correspondence, are well-understood. The most well-studied example is the duality between N=4 SYM, which is a CFT, and type IIB string theory in AdS5xS5 background. Generalization to less symmetric cases is a must, and the next logical step is to add a mass scale to N=4 SYM, therefore breaking its conformal symmetry and leading to N=2* SYM, the theory we study in this thesis. It is supersymmetric enough to employ the powerful localization method that reduces its partition function to a matrix model. We will see that the mass scale causes non-trivial phase structures in its vacuum configuration, visible in the holographic regime. We will probe them using Wilson loops in different representations of the gauge group. On the other hand, the dual supergravity background was derived by Pilch-Warner, making N=2* theory an explicitly testable non-conformal holographic case, which is a rare example. We will prove that the duality works for the dual observables (string action, D-branes) we managed to compute, even at a quantum-level.

    List of papers
    1. Quantum String Test of Nonconformal Holography
    Open this publication in new window or tab >>Quantum String Test of Nonconformal Holography
    2017 (English)In: Journal of High Energy Physics (JHEP), ISSN 1126-6708, E-ISSN 1029-8479, Vol. 04, 95Article in journal (Refereed) Published
    Abstract [en]

    We compute Lüscher corrections to the effective string tension in the PilchWarner background, holographically dual to N" style="position: relative;" tabindex="0" id="MathJax-Element-1-Frame" class="MathJax">N = 2 supersymmetric Yang-Mills theory. The same quantity can be calculated directly from field theory by solving the localization matrix model at large-N . We find complete agreement between the field-theory predictions and explicit string-theory calculation at strong coupling.

    National Category
    Subatomic Physics
    Identifiers
    urn:nbn:se:uu:diva-321871 (URN)10.1007/JHEP04(2017)095 (DOI)000402858600004 ()
    Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2017-08-03Bibliographically approved
    2. Symmetric Wilson Loops beyond leading order
    Open this publication in new window or tab >>Symmetric Wilson Loops beyond leading order
    2016 (English)In: SciPost Physics, ISSN 2542-4653, Vol. 1, no 2, 013Article in journal (Refereed) Published
    Abstract [en]

    We study the circular Wilson loop in the symmetric representation of U(N) in N=4 super-Yang-Mills (SYM). In the large N limit, we computed the exponentially-suppressed corrections for strong coupling, which suggests non-perturbative physics in the dual holographic theory. We also computed the next-to-leading order term in 1/N, and the result matches with the exact result from the k-fundamental representation.

    National Category
    Other Physics Topics
    Identifiers
    urn:nbn:se:uu:diva-321872 (URN)10.21468/SciPostPhys.1.2.013 (DOI)
    Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2017-05-14Bibliographically approved
    3. Holographic Wilson loops in symmetric representations in N=2*super-Yang-Mills theory
    Open this publication in new window or tab >>Holographic Wilson loops in symmetric representations in N=2*super-Yang-Mills theory
    2016 (English)In: Journal of High Energy Physics (JHEP), ISSN 1126-6708, E-ISSN 1029-8479, no 2, 109Article in journal (Refereed) Published
    Abstract [en]

    We construct the D3-brane solution in the holographic dual of the N = 2* theory that describes Wilson lines in symmetric representations of the gauge group. The results perfectly agree with the direct field-theory predictions based on localization.

    Keyword
    Gauge-gravity correspondence, D-branes, AdS-CFT Correspondence
    National Category
    Other Physics Topics
    Identifiers
    urn:nbn:se:uu:diva-282320 (URN)10.1007/JHEP02(2016)109 (DOI)000370849500001 ()
    Funder
    EU, FP7, Seventh Framework Programme, 317089EU, European Research Council, 341222Swedish Research Council, 2013-4329
    Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2017-05-14Bibliographically approved
    4. Higher rank Wilson loops in N=2*super-Yang-Mills theory
    Open this publication in new window or tab >>Higher rank Wilson loops in N=2*super-Yang-Mills theory
    2015 (English)In: Journal of High Energy Physics (JHEP), ISSN 1029-8479, E-ISSN 1126-6708, no 3, 147Article in journal (Refereed) Published
    Abstract [en]

    The N = 2* Super-Yang-Mills theory (SYM*) undergoes an infinite sequence of large-N quantum phase transitions. We compute expectation values of Wilson loops in k-symmetric and antisymmetric representations of the SU(N) gauge group in this theory and show that the same phenomenon that causes the phase transitions at finite coupling leads to a non-analytic dependence of Wilson loops on k/N when the coupling is strictly infinite, thus making the higher-representation Wilson loops ideal holographic probes of the non-trivial phase structure of SYM*.

    Keyword
    Matrix Models, Wilson, 't Hooft and Polyakov loops, AdS-CFT Correspondence, Strong Coupling Expansion
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-252000 (URN)10.1007/JHEP03(2015)147 (DOI)000351751200007 ()
    Funder
    Swedish Research Council, 2013-4329
    Available from: 2015-05-08 Created: 2015-04-28 Last updated: 2017-05-14Bibliographically approved
    5. N=2*super-Yang-Mills theory at strong coupling
    Open this publication in new window or tab >>N=2*super-Yang-Mills theory at strong coupling
    2014 (English)In: Journal of High Energy Physics (JHEP), ISSN 1029-8479, E-ISSN 1126-6708, no 11, 057- p.Article in journal (Refereed) Published
    Abstract [en]

    The planar N = 2* Super-Yang-Mills (SYM) theory is solved at large 't Hooft coupling using localization on S-4. The solution permits detailed investigation of the resonance phenomena responsible for quantum phase transitions in infinite volume, and leads to quantitative predictions for the semiclassical string dual of the N = 2* theory.

    Keyword
    Matrix Models, Gauge-gravity correspondence, AdS-CFT Correspondence, 1/N Expansion
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-245554 (URN)10.1007/JHEP11(2014)057 (DOI)000347908000004 ()
    Available from: 2015-02-27 Created: 2015-02-26 Last updated: 2017-05-14Bibliographically approved
  • Public defence: 2017-09-08 09:00 Sal IX, Gamla universitetshuset, Uppsala
    Thorsell Cederberg, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Acceptance for persons suffering from pain: Evaluation of acceptance-based interventions for adults with chronic pain and children with cancer experiencing acute pain2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    It is increasingly clear that pain and emotions are closely interconnected. Pain does not only cause psychological distress, but psychological distress also amplifies pain through neurological mechanisms. Treatment of both chronic and acute pain would benefit from acknowledging the psychological mechanisms of pain neurophysiology. Psychological acceptance predicts increased pain tolerance and decreased pain intensity and discomfort in experimentally induced pain and improved physical and psychosocial functioning for persons with chronic pain.

    The overall aim of this thesis was to evaluate acceptance-based interventions for persons suffering from pain.

    In Study I the effect of a manualised ACT-based self-help intervention for adults with chronic pain was evaluated in an RCT (n=90). The results showed improvements in satisfaction with life, physical functioning and pain intensity for the ACT group. Both the ACT and the control group improved regarding depression and anxiety. In Study II the mediating effect of acceptance for treatment change was evaluated, using data from Study I (n=64). The results showed indirect effects of treatment via acceptance for physical functioning but not for satisfaction with life. In Studies III and IV, instruments to measure psychological flexibility in relation to pain were developed for children with cancer, and their parents respectively, using factor analysis. The results showed that a two-factor solution for the child scale (n=61) and a three-factor solution for the parent scale (n=243), best represented the data. In Study V, an acceptance-based intervention was preliminarily evaluated in a single-subject study (n=5) for children reporting pain during cancer treatment. The intervention consisted of an approximately 15-minute long pain exposure exercise. All participants reported reduced discomfort of pain, and three of the participants reported reduced pain intensity.

    The results suggest that a manualised ACT-based self-help intervention is a valuable addition to the treatment repertoire for persons with chronic pain and that acceptance may mediate the effect of treatment on physical functioning. Furthermore, instruments to measure acceptance in the context of acute pain in children with cancer are now available, although further validation is needed. Lastly, the results indicate that an acceptance-based intervention may help children undergoing cancer treatment to cope with pain.

    List of papers
    1. A Comparative Study of 2 Manual-based Self-Help Interventions, Acceptance and Commitment Therapy and Applied Relaxation, for Persons With Chronic Pain
    Open this publication in new window or tab >>A Comparative Study of 2 Manual-based Self-Help Interventions, Acceptance and Commitment Therapy and Applied Relaxation, for Persons With Chronic Pain
    Show others...
    2011 (English)In: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 27, no 8, 716-723 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective: The aim of this study was to compare 2 self-help-based interventions; a coping-oriented approach, applied relaxation (AR) and an acceptance-oriented approach, acceptance and commitment therapy (ACT), for persons with chronic pain. Method: This study is a randomized control trial (N = 90) with a mixed between-within participants design with repeated measures. Interventions in both conditions comprised an initial face-to-face session, a 7-week manual-based self-help intervention including weekly therapist telephone support and a concluding face-to-face session. Outcome measures included satisfaction with life, depression, anxiety, acceptance of chronic pain, level of function, and pain intensity. Effects were measured at preintervention and postintervention and at 6 and 12 months after the end of intervention. Results: The results show that the ACT condition increased their level of acceptance significantly compared with the AR condition. There was also a marginally significant interaction effect regarding satisfaction with life in which the ACT condition had improved in comparison to the AR condition. Further, the ACT condition reported a higher level of function and decreased pain intensity compared with the AR condition. Both conditions improved significantly regarding depression and anxiety. Conclusions: A manual-based self-help intervention with weekly therapist support in an ACT format adds value to the treatment repertoire for persons suffering with chronic pain.

    Keyword
    chronic pain, manual-based, self-help, acceptance and commitment therapy, acceptance, satisfaction with life
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-159223 (URN)10.1097/AJP.0b013e318219a933 (DOI)000294709700009 ()
    Available from: 2011-09-27 Created: 2011-09-26 Last updated: 2017-08-15Bibliographically approved
    2. Acceptance as a Mediator for Change in Acceptance and Commitment Therapy for Persons with Chronic Pain?
    Open this publication in new window or tab >>Acceptance as a Mediator for Change in Acceptance and Commitment Therapy for Persons with Chronic Pain?
    Show others...
    2016 (English)In: International Journal of Behavioral Medicine, ISSN 1070-5503, E-ISSN 1532-7558, Vol. 23, no 1, 21-29 p.Article in journal (Refereed) Published
    Abstract [en]

    Background Cognitive behavior therapy (CBT) is considered effective for chronic pain, but little is known about active treatment components. Although acceptance correlates with better health outcomes in chronic pain patients, no study has examined its mediating effect in an experimental design. Purpose The aim of the present study is to investigate acceptance as a mediator in acceptance and commitment therapy (ACT), a third wave CBT intervention, for chronic pain. Method A bootstrapped cross product of coefficients approach was used on data from a previously published RCT evaluating ACT for chronic pain. To address the specificity of acceptance as a mediator, anxiety and depression were also tested as mediators. Outcome variables were satisfaction with life and physical functioning. Two change scores, preassessment to 6-month follow-up (n=53) and pre-assessment to 12-month follow-up (n=32), were used. Results Acceptance was found to mediate the effect of treatment on change in physical functioning from pre-assessment to follow-up at 6 months. Further, a trend was shown from pre-assessment to follow-up at 12 months. No indirect effect of treatment via acceptance was found for change in satisfaction with life. Conclusion This study adds to a small but growing body of research using mediation analysis to investigate mediating factors in the treatment of chronic pain. In summary, the results suggest that acceptance may have a mediating effect on change in physical functioning in ACT for persons with chronic pain. However, given the small sample size of the study, these findings need to be replicated.

    Keyword
    Acceptance, Acceptance and commitment therapy, Chronic pain, Mediation analysis, Physical functioning, Satisfaction with life
    National Category
    Medical and Health Sciences Applied Psychology
    Identifiers
    urn:nbn:se:uu:diva-256448 (URN)10.1007/s12529-015-9494-y (DOI)000370243400003 ()26041582 (PubMedID)
    Available from: 2015-06-23 Created: 2015-06-23 Last updated: 2017-08-15Bibliographically approved
    3. Parents’ relationship to pain during children's cancer treatment – a preliminary validation of the Pain Flexibility Scale for Parents
    Open this publication in new window or tab >>Parents’ relationship to pain during children's cancer treatment – a preliminary validation of the Pain Flexibility Scale for Parents
    2017 (English)In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 10, 507-514 p.Article in journal (Refereed) Published
    Abstract [en]

    Objectives: Pain is one of the most frequent and burdensome symptoms for children with cancer. Psychological acceptance has been shown to be beneficial in chronic pain. Acceptance-based interventions for experimentally induced pain have been shown to predict increased pain tolerance and decreased pain intensity. An acceptance-based pilot study for children with cancer experiencing pain has shown promising results. Further, parental acceptance has been shown to predict decreased child distress. To date, no instruments measuring acceptance in the context of acute pain in children are available. The aim of this study was to develop and evaluate an instrument to measure acceptance in parents of children experiencing pain during cancer treatment. Methods: A test version of the Pain Flexibility Scale for Parents (PFS-P) was sent to parents of all children undergoing cancer treatment in Sweden at the time of the study. Exploratory factor analysis (n=243) examined numerous solutions. Internal consistency, test-retest reliability and convergent validity were calculated. Results: A three-factor Promax solution best represented the data. The subscales were pain resistance, valued action and pain fusion. Internal consistency was good (alpha=0.81-0.93), and the total scale and the subscales demonstrated temporal stability (r=0.76-0.87) and good convergent validity (-0.40 to -0.84). Discussion: The PFS-P measuring acceptance in parents of children experiencing pain during cancer treatment is now available, enabling evaluation of acceptance in the context of acute pain in children. The scale shows good psychometric properties but needs further validation.

    Place, publisher, year, edition, pages
    Dovepress, 2017
    Keyword
    acute pain, children, parents, acceptance, psychological flexibility, factor analysis
    National Category
    Psychology Neurology
    Identifiers
    urn:nbn:se:uu:diva-316716 (URN)10.2147/JPR.S127019 (DOI)000396320600001 ()
    Funder
    Swedish Childhood Cancer Foundation, PR2013-0058Swedish Cancer Society, CAN2013/749
    Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2017-08-15Bibliographically approved
    4. Children’s and adolescents’ relationship to pain during cancer treatment: a preliminary validation of the Pain Flexibility Scale for Children
    Open this publication in new window or tab >>Children’s and adolescents’ relationship to pain during cancer treatment: a preliminary validation of the Pain Flexibility Scale for Children
    2017 (English)In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 10, 1171-1178 p.Article in journal (Refereed) Published
    Abstract [en]

    Objectives: Children with cancer often suffer from pain. Pain is associated with psychological distress, which may amplify the pain experience. In chronic pain, it has been shown that psychological acceptance is helpful for both adults and children. For experimentally induced pain, interventions fostering psychological acceptance have been shown to predict increases in pain tolerance and reductions in pain intensity and discomfort of pain. A single subject study aiming to nurture psychological acceptance for children with cancer experiencing pain has shown promising results. No instruments measuring psychological acceptance in acute pain are yet available. The aim of the current study was to develop and preliminarily evaluate an instrument to measure psychological acceptance in children experiencing pain during cancer treatment.

    Methods: A test version of the Pain Flexibility Scale for Children was sent to all children aged 7–18 years undergoing cancer treatment in Sweden at the time of the study. Exploratory factor analysis was used. Internal consistency, test–retest reliability, and convergent validity were examined.

    Results: Sixty-one children participated in the study. A two-factor solution with Promax rotation was found to best represent the data. Internal consistency was good to excellent (a =0.87–0.91). The total scale and the subscales demonstrated temporal stability (Intraclass correlation coefficient =0.56–0.61) and satisfactory convergent validity (r=−0.27 to −0.68).

    Discussion: The Pain Flexibility Scale for Children measuring psychological acceptance in children with cancer experiencing pain is now available for use. This enables the evaluation of acceptance as a mediator for treatment change in the context of acute pain in children with cancer, which in turn is a step forward in the development of psychological treatments to help children cope with the pain during these difficult circumstances. The scale shows good psychometric properties but needs further validation, particularly considering the small sample size.

    Place, publisher, year, edition, pages
    Dove Medical Press, 2017
    Keyword
    Acute pain, children, acceptance, psychological flexibility, factor analysis, Akut smärta, barn och ungdomar, acceptans, psykologisk flexibilitet, faktoranalys
    National Category
    Applied Psychology Medical and Health Sciences
    Research subject
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-322391 (URN)10.2147/JPR.S137871 (DOI)000401610300001 ()
    Funder
    Swedish Childhood Cancer Foundation, FTJH11/002 och PR2013/0058Swedish Cancer Society, CAN2013/749
    Available from: 2017-05-22 Created: 2017-05-22 Last updated: 2017-08-15Bibliographically approved
    5. An acceptance-based intervention for children and adolescents with cancer experiencing pain – a single subject study
    Open this publication in new window or tab >>An acceptance-based intervention for children and adolescents with cancer experiencing pain – a single subject study
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Children and adolescents with cancer report pain as one of their most recurrent and troublesome symptoms throughout the cancer trajectory. Pain evokes psychological distress, which in turn, has an amplifying effect on the pain experience. Acceptance-based interventions for experimentally induced acute pain predict increased pain tolerance, decreased pain intensity and decreased discomfort of pain. The aim of this study was to preliminarily evaluate an acceptance-based intervention for children and adolescents with cancer experiencing acute pain, with regards to feasibility and effect on pain intensity and discomfort of pain.

    Methods: The study is a single subject study with an AB design with a non-concurrent multiple baseline. Children and adolescents aged 4-18 years undergoing cancer treatment at the Children’s University Hospital, Uppsala, Sweden, reporting sustained acute pain were offered participation. Pain intensity and discomfort of pain were measured during baseline and at post intervention. The intervention consisted of a pain exposure exercise lasting approximately 15 minutes.

    Results: Five children participated in the study. All participants completed the intervention and reported that it had helped them to cope with the pain in the moment. All participants reported decreased discomfort of pain at post measurement, three of whom also reported decreased pain intensity.

    Discussion: The results suggest that an acceptance-based intervention may help children and adolescents with cancer to cope with the pain that is often associated with cancer treatment in spite of pharmacological pain management. The results are tentative but promising and warrant further investigation.  

    Keyword
    Acute pain, children, cancer, acceptance, pain intensity, discomfort of pain
    National Category
    Applied Psychology Other Medical Sciences not elsewhere specified
    Research subject
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-322400 (URN)
    Funder
    Swedish Childhood Cancer Foundation, FTJH11/002 och PR2013/0058Swedish Cancer Society, CAN2013/749
    Available from: 2017-05-22 Created: 2017-05-22 Last updated: 2017-08-15Bibliographically approved
  • Public defence: 2017-09-08 13:15 Hörsal 2, Uppsala
    Molinder, Jakob
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economic History.
    Interregional Migration, Wages and Labor Market Policy: Essays on the Swedish Model in the Postwar Period2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The Swedish model is perceived as a successful framework for combining rapid labor market adjustment with low inequality. Formulated by Gösta Rehn and Rudolf Meidner and implemented from the 1950s, it has been associated with the peak in economic restructuring and interregional migration during the 1960s. However, there is little empirical evidence for this. This thesis consists of an introduction and four essays. It explores three aspects of the model from a long-run perspective: interregional migration, wage dispersion and labor market policy.

    Essay I uses new data to track interregional migration rates in the postwar period (1945-1985). The results show that the responsiveness of interregional migration to local labor market conditions remained stable over time; it was neither higher during the 1960s nor lower when migration declined after 1970.

    Essay II employs a regression-decomposition framework to analyze the evolution of wage dispersion. The results suggest that wage dispersion was stable from centralized bargaining’s introduction in 1956 to the late 1960s. Afterwards, there was a rapid decline, likely because of solidaristic bargaining.

    Essay III contrasts the implementation of the active labor market policy to regional policy. Following a decisive shift around 1970, the focus on north to south mobility was replaced with policies to stimulate northern employment. Declining rural support for the Social Democrats and electoral competition from the Center Party caused this shift.

    Finally, Essay IV is a case study about mobility subsidy usage in Västernorrland County using sources on relocation allowances from 1965, 1970 and 1975. The results indicate that in the 1960s there was strong selection into the program by young persons with good labor market prospects. However, the program’s use did not change after the regional policy shift in the early 1970s.

    The collective results suggest that the policies associated with the Swedish model were minor for economic restructuring patterns. The migrations of the 1960s and the decline in regional disruptions after 1970 should instead be explained by studying the consequences of structural changes, how regions were progressively affected differently and the possible role that government policies played in directing demand for labor across space.

    List of papers
    1. Local Labor Markets and Regional Mobility in Sweden: Evidence from New County Level Data, 1945–1985
    Open this publication in new window or tab >>Local Labor Markets and Regional Mobility in Sweden: Evidence from New County Level Data, 1945–1985
    2017 (English)Article in journal (Refereed) Submitted
    National Category
    Economic History
    Research subject
    Economic History
    Identifiers
    urn:nbn:se:uu:diva-322610 (URN)
    Funder
    The Jan Wallander and Tom Hedelius Foundation, P2013-0274:1
    Available from: 2017-05-27 Created: 2017-05-27 Last updated: 2017-06-15
    2. Regional Wages, Economic Restructuring and the Solidaristic Wage Policy in Sweden
    Open this publication in new window or tab >>Regional Wages, Economic Restructuring and the Solidaristic Wage Policy in Sweden
    2017 (English)Article in journal (Refereed) Submitted
    Abstract [en]

    The solidaristic wage policy in Sweden, negotiated by peak organizations on the labor market between 1956 and 1983, has been associated with a decrease in wage differences across regions, leading to the interregional migration flows that culminated during the 1960s. While the effects of the solidaristic wage policy have been widely discussed, there is little evidence on the actual evolution of regional wages and its effect on economic restructuring, especially before the 1970s. Using new regional wage data, I examine the evolution of wage dispersion and analyze the changes using a regression-decomposition framework. The results show that wage inequality was stable before 1968, then it rapidly declined. According to the decomposition, this decline was also likely the result of deliberate union policy. However, the wage policy cannot explain the height of regional restructuring in the 1960s since it is unlikely to have affected the wage structure at the time.

    National Category
    Economic History
    Research subject
    Economic History
    Identifiers
    urn:nbn:se:uu:diva-324440 (URN)
    Funder
    The Jan Wallander and Tom Hedelius Foundation, P2013-0274:1
    Available from: 2017-06-15 Created: 2017-06-15 Last updated: 2017-06-15
    3. What can the State do for you?: Relocation Allowances and Regional Subsidies in Post-War Sweden
    Open this publication in new window or tab >>What can the State do for you?: Relocation Allowances and Regional Subsidies in Post-War Sweden
    2017 (English)In: Scandinavian Journal of History, ISSN 0346-8755, E-ISSN 1502-7716, Vol. 42, no 3, 273-298 p.Article in journal (Refereed) Published
    Abstract [en]

    It has been suggested that Swedish policy during the early postwar period was strongly directed towards mobility increasing expenditures, most notably relocation allowances, aimed at moving labor from north to south. While this view has dominated the academic discussion on labor market policy there is little direct evidence. We make three claims. First, the relocation allowances have to be evaluated against the regional policy. Second, by doing so we show that the mobility oriented policy was predominant only for a short period of time. In the early 1970s, there was a decisive shift towards a policy directed at stimulating employment in the north. Third, drawing on this, we reevaluate the previous view on policy making in Sweden. Our analysis suggests that the Social Democratic government acted in a voter maximizing way. The relocation allowances were introduced at the behest of the Trade Union Confederation (LO). The regional subsidies were expanded when voter sentiment turned against the perceived depletion of rural regions. However, this strategy interacted with the political and institutional environment. The new election law in 1970 and political competition from the Center Party pushed the Social Democrats to shift their policies on regional subsidies.

    Place, publisher, year, edition, pages
    Taylor & Francis Group, 2017
    Keyword
    ‘Swedish model’, subsidies, relocation allowances, regional policy, post-war period, economic history
    National Category
    Economic History
    Research subject
    Economic History
    Identifiers
    urn:nbn:se:uu:diva-321047 (URN)10.1080/03468755.2017.1318337 (DOI)
    Funder
    The Jan Wallander and Tom Hedelius Foundation, P2013-0274:1
    Available from: 2017-04-28 Created: 2017-04-28 Last updated: 2017-06-15
    4. Implementing National Structural Change at the Local Level: The Case of Relocation Allowances in Västernorrland, 1965–1975
    Open this publication in new window or tab >>Implementing National Structural Change at the Local Level: The Case of Relocation Allowances in Västernorrland, 1965–1975
    2017 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The Swedish model was built on the notion that mobility from high- to low-unemployment areas could be achieved without large wage differentials if active labor market policy was used to aid in the movements across places. While Sweden pioneered the use of relocation allowances on a large scale in the late 1950s, very little is known about the actual implementation of this program. Its role during the large out-migrations from northern Sweden during the 1960s is especially underresearched. In this essay, I study the usage of the program through a case study of  Västernorrland county from 1965 to 1975. The analysis shows that in the 1960s there was a strong selection into the program by younger persons, newly examined students and from certain sectors. After 1970, there was a shift in government policy with the aim of reducing the outflow of migrants from the northern counties and to keep allowance migration within counties. Between 1970 and 1975 there was also a drop in both regular and allowance out-migration by 20 %. Within the group of allowance migrants, however, there was no change in the likelihood of staying within Västernorrland after controlling for age, sex and occupation. The share of out-migrations that took place with support from the program also remained constant at 20 %. This suggests that the decline in out-migration was probably not caused by lower mobility but was rather more likely the consequence of structural change and alterations to public policy after 1970, which improved the labor market situation in the northern counties. 

    National Category
    Economic History
    Research subject
    Economic History
    Identifiers
    urn:nbn:se:uu:diva-324441 (URN)
    Funder
    The Jan Wallander and Tom Hedelius Foundation, P2013-0274:1
    Available from: 2017-06-15 Created: 2017-06-15 Last updated: 2017-06-15
  • Public defence: 2017-09-08 13:15 Sal IV, Universitetshuset, Uppsala
    Larsson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Treatment for childbirth fear with a focus on midwife-led counselling: A national overview, women’s birth preferences and experiences of counselling2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Many women experience childbirth fear to such an extent that it seriously interferes with the woman’s daily life and affects her mental well-being.

    Aim: The overall aim was to conduct an overview of the midwife-led counselling for childbirth fear in Sweden, to investigate women’s birth preferences and to describe their experiences of treatment on childbirth fear, with focus on midwife-led counselling.

    Methods: Study I is a cross-sectional study where 43 out of 45 maternity clinics responded to a questionnaire regarding midwife-led counselling. Study II is a longitudinal survey where 889 women participated of whom 70 received counselling. Data were collected by questionnaires in mid-pregnancy, two months and finally, one year after birth. Study III is a randomised controlled study with 258 participating women assessed with childbirth fear. It compares Internet-based cognitive behaviour therapy (ICBT) with midwife-led counselling. Data were collected by questionnaires twice during pregnancy and two months after birth. Study IV is a qualitative interview study using thematic analysis, including 27 women who received midwife-led counselling during pregnancy.

    Results: Overall, midwife-led counselling was perceived as empowering by the women and increased their confidence when facing birth. The preference for a caesarean section decreased during pregnancy and the majority had a normal vaginal birth but an increase in preference for caesarean section appeared after birth. Half of the women who received treatment for childbirth fear experienced a less than positive birth. Women who had a positive birth experience voiced that the contributing factors were the self-confidence received from counselling and the support from the midwife during birth. Decreased or manageable fear was expressed by the women after counselling and birth, which in turn brought a strengthened confidence for a future pregnancy and birth. Furthermore, major differences exist in counselling for childbirth fear throughout the clinics in Sweden.

    Conclusion: Midwife-led counselling improved women’s confidence toward giving birth and fear was perceived as manageable. Continuous support is crucial to experience birth as positive. Although women’s preferences for caesarean section did not change over time, few women gave birth with a caesarean section without medial reason.  

    List of papers
    1. Counseling for childbirth fear: a national survey
    Open this publication in new window or tab >>Counseling for childbirth fear: a national survey
    2016 (English)In: Sexual & Reproductive HealthCare, ISSN 1877-5756, E-ISSN 1877-5764, Vol. 8, 82-87 p.Article in journal (Refereed) Published
    Abstract [en]

    Background

    Counseling by experienced midwives is offered to women with childbirth fear in most obstetric clinics in Sweden, but information about the content of such counseling is lacking. Aim To study comprehensiveness, content and organization of the midwife-led counseling for childbirth fear in all obstetric clinics in Sweden.

    Methods

    In this cross-sectional study, data were collected using a questionnaire sent to all obstetric clinics in Sweden (n = 45); a total of 43 clinics responded. Descriptive and one-way ANOVA was used in the analysis.

    Results

    All responding obstetric clinics in Sweden offer midwife-led counseling to women with childbirth fear. Major differences were found regarding the time allocated to counseling, with a range between 5.7 and 47.6 minutes per childbirth. Supplementary education for midwives and the availability of treatment options varied at the different clinics and were not associated with the size of the clinic.

    Conclusion

    The midwife-led counseling conducted at the different Swedish obstetric clinics showed considerable disparities. Women with childbirth fear would benefit from care on equal terms irrespective of place of residence. Consequently, it would be valuable to develop a national healthcare program for childbirth fear.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-289181 (URN)10.1016/j.srhc.2016.02.008 (DOI)000376839500013 ()27179382 (PubMedID)
    External cooperation:
    Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2017-06-29Bibliographically approved
    2. The effects of counseling on fear of childbirth
    Open this publication in new window or tab >>The effects of counseling on fear of childbirth
    2015 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 94, no 6, 629-636 p.Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:

    To investigate women's experiences of attending existing counseling programs for childbirth-related fear and the effect of this counseling over time.

    DESIGN:

    A longitudinal survey.

    SETTING:

    Three hospitals in the central north of Sweden.

    SAMPLE:

    A selected sample of 936 women. Of these, 70 received counseling due to fear of childbirth (study-group).

    METHODS:

    Data were collected with questionnaires 2 months and 1 year after giving birth with background data collected during midpregnancy. Comparisons were made between women with or without counseling. Crude and adjusted odds ratios (OR) were calculated.

    MAIN OUTCOME MEASURES:

    Self-reported childbirth fear, experience of counseling, birth experience and preferred mode of birth.

    RESULTS:

    Women in the counseling group reported higher childbirth fear 1 year after giving birth (OR 5.0, 95% confidence interval (95% CI) 2.6-9.3), they had a more negative birth experience that did not change over time (OR 2.1, 95% CI 1.2-3.9) and they preferred cesarean section to a greater extent (OR 12.0, 95% CI 5.1-28.1) in the case of another birth. Also, they were more often delivered by planned cesarean section (OR 4.7, 95% CI 2.4-9.1). However, 80% were satisfied with the given support.

    CONCLUSION:

    Although women were satisfied with the treatment, this study shows that counseling had a minor effect on fear of childbirth, birth experiences or cesarean section rates. To help women with their fear of childbirth, more effective methods of treatment are needed.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-254711 (URN)10.1111/aogs.12634 (DOI)000354398300012 ()25772528 (PubMedID)
    Available from: 2015-06-10 Created: 2015-06-10 Last updated: 2017-06-29Bibliographically approved
    3. Birth preference in women undergoing treatment for childbirth fear: A randomised controlled trial
    Open this publication in new window or tab >>Birth preference in women undergoing treatment for childbirth fear: A randomised controlled trial
    Show others...
    (English)In: Women and Birth, ISSN 1871-5192, E-ISSN 1878-1799Article in journal (Refereed) In press
    Abstract [en]

    Background: Childbirth fear is the most common underlying reason for requesting a caesarean section without medical reason.  The aim of this randomised controlled study was to investigate birth preferences in women undergoing treatment for childbirth fear, and to investigate birth experience and satisfaction with the allocated treatment.

    Methods: Pregnant women classified with childbirth fear (≥60 on the Fear Of Birth Scale) (n=258) were recruited at one university hospital and two regional hospitals over one year.  The participants were randomised (1:1) to intervention (Internet-based Cognitive Behaviour Therapy (ICBT)) (n=127) or standard care (face-to-face counselling) (n=131). Data were collected by questionnaires in pregnancy week 20-25 (baseline), week 36 and two months after birth.

    Results: Caesarean section preference decreased from 34% to 12% in the ICBT group and from 24% to 20% in the counselling group. Two months after birth, the preference for caesarean increased to 20% in the ICBT group and to 29% in the counselling group, and there was no statistically significant change over time. Women in the ICBT group were less satisfied with the treatment (OR 4.5). The treatment had no impact on or worsened their childbirth fear (OR 5.5). There were no differences between the groups regarding birth experience.

    Conclusion: Women’s birth preferences fluctuated over the course of pregnancy and after birth regardless of treatment method. Women felt their fear was reduced and were more satisfied with face-to-face counselling compared to ICBT. A higher percentage were lost to follow-up in ICBT group suggesting a need for further research.  

    Keyword
    caesarean section, childbirth fear, counselling, internet based cognitive behavioural therapy, randomised controlled trial
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-325923 (URN)10.1016/j.wombi.2017.04.004 (DOI)
    Available from: 2017-06-29 Created: 2017-06-29 Last updated: 2017-06-29
    4. Women’s experience of midwife-led counselling and its influence on childbirth fear
    Open this publication in new window or tab >>Women’s experience of midwife-led counselling and its influence on childbirth fear
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-325924 (URN)
    Available from: 2017-06-29 Created: 2017-06-29 Last updated: 2017-06-29
  • Public defence: 2017-09-13 09:00 A1:111 BMC, Uppsala
    Bauer, Paul
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Computational modelling of enzyme selectivity2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enantioselective reactions are one of the ways to produce pure chiral compounds. Understanding the basis of this selectivity makes it possible to guide enzyme design towards more efficient catalysts. One approach to study enzymes involved in chiral chemistry is through the use of computational models that are able to simulate the chemical reaction taking place. The potato epoxide hydrolase is one enzyme that is known to be both highly enantioselective, while still being robust upon mutation of residues to change substrate scope. The enzyme was used to investigate the epoxide hydrolysis mechanism for a number of different substrates, using the EVB approach to the reaction both in solution and in several enzyme variants. In addition to this, work has been performed on new ways of performing simulations of divalent transition metals, as well as development of new simulation software.

    List of papers
    1. Force Field Independent Metal Parameters Using a Nonbonded Dummy Model
    Open this publication in new window or tab >>Force Field Independent Metal Parameters Using a Nonbonded Dummy Model
    Show others...
    2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 16, 4351-4362 p.Article in journal (Refereed) Published
    Abstract [en]

    The cationic dummy atom approach provides a powerful nonbonded description for a range of alkaline-earth and transition-metal centers, capturing both structural and electrostatic effects. In this work we refine existing literature parameters for octahedrally coordinated Mn2+, Zn2+, Mg2+, and Ca2+, as well as providing new parameters for Ni2+, Co2+, and Fe2+. In all the cases, we are able to reproduce both M2+-O distances and experimental solvation free energies, which has not been achieved to date for transition metals using any other model. The parameters have also been tested using two different water models and show consistent performance. Therefore, our parameters are easily transferable to any force field that describes nonbonded interactions using Coulomb and Lennard-Jones potentials. Finally, we demonstrate the stability of our parameters in both the human and Escherichia coli variants of the enzyme glyoxalase 1 as showcase systems, as both enzymes are active with a range of transition metals. The parameters presented in this work provide a valuable resource for the molecular simulation community, as they extend the range of metal ions that can be studied using classical approaches, while also providing a starting point for subsequent parametrization of new metal centers.

    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-225523 (URN)10.1021/jp501737x (DOI)000335113600010 ()
    Funder
    Swedish National Infrastructure for Computing (SNIC), 2013/26-1
    Available from: 2014-06-23 Created: 2014-06-04 Last updated: 2017-07-02
    2. Expanding the catalytic triad in epoxide hydrolases and related enzymes
    Open this publication in new window or tab >>Expanding the catalytic triad in epoxide hydrolases and related enzymes
    Show others...
    2015 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 5, no 10, 5702-5713 p.Article in journal (Refereed) Published
    Abstract [en]

    Potato epoxide hydrolase 1 exhibits rich enantio- and regioselectivity in the hydrolysis of a broadrange of substrates. The enzyme can be engineered to increase the yield of optically pureproducts, as a result of changes in both enantio- and regioselectivity. It is thus highly attractive inbiocatalysis, particularly for the generation of enantiopure fine chemicals and pharmaceuticals.The present work aims to establish the principles underlying the activity and selectivity of theenzyme through a combined computational, structural, and kinetic study, using the substratetrans-stilbene oxide as a model system. Extensive empirical valence bond simulations have beenperformed on the wild-type enzyme together with several experimentally characterized mutants.We are able to computationally reproduce the differences in activities between differentstereoisomers of the substrate, and the effects of mutations in several active-site residues. Inaddition, our results indicate the involvement of a previously neglected residue, H104, which iselectrostatically linked to the general base, H300. We find that this residue, which is highlyconserved in epoxide hydrolases and related hydrolytic enzymes, needs to be in its protonatedform in order to provide charge balance in an otherwise negatively-charged active site. Our datashow that unless the active-site charge balance is correctly treated in simulations, it is notpossible to generate a physically meaningful model for the enzyme that can accurately reproduceactivity and selectivity trends. We also expand our understanding of other catalytic residues,demonstrating in particular the role of a non-canonical residue, E35, as a “backup-base” in theabsence of H300. Our results provide a detailed view of the main factors driving catalysis andregioselectivity in this enzyme, and identify targets for subsequent enzyme design efforts.

    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-260232 (URN)10.1021/acscatal.5b01639 (DOI)000362391500006 ()
    Funder
    EU, FP7, Seventh Framework Programme, 306474Swedish Research Council, 621-2011-6055, 621-2010-5145Swedish National Infrastructure for Computing (SNIC), 2015/16-12
    Available from: 2015-08-18 Created: 2015-08-18 Last updated: 2017-07-02Bibliographically approved
    3. Conformational Diversity and Enantioconvergence in Potato Epoxide Hydrolase 1
    Open this publication in new window or tab >>Conformational Diversity and Enantioconvergence in Potato Epoxide Hydrolase 1
    Show others...
    2016 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 24, 5639-5651 p.Article in journal (Refereed) Published
    Abstract [en]

    Potato epoxide hydrolase 1 (StEH1) is a biocatalytically important enzyme that exhibits rich enantio-and regioselectivity in the hydrolysis of chiral epoxide substrates. In particular, StEH1 has been demonstrated to enantioconvergently hydrolyze racemic mixes of styrene oxide (SO) to yield (R)-1-phenylethanediol. This work combines computational, crystallographic and biochemical analyses to understand both the origins of the enantioconvergent behavior of the wild-type enzyme, as well as shifts in activities and substrate binding preferences in an engineered StEH1 variant, R-C1B1, which contains four active site substitutions (W106L, L109Y, V141K and I155V). Our calculations are able to reproduce both the enantio-and regioselectivities of StEH1, and demonstrate a clear link between different substrate binding modes and the corresponding selectivity, with the preferred binding modes being shifted between the wild-type enzyme and the R-C1B1 variant. Additionally, we demonstrate that the observed changes in selectivity and the corresponding enantioconvergent behavior are due to a combination of steric and electrostatic effects that modulate both the accessibility of the different carbon atoms to the nucleophilic side chain of D105, as well as the interactions between the substrate and protein amino acid side chains and active site water molecules. Being able to computationally predict such subtle effects for different substrate enantiomers, as well as to understand their origin and how they are affected by mutations, is an important advance towards the computational design of improved biocatalysts for enantioselective synthesis.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-282015 (URN)10.1039/C6OB00060F (DOI)000378933400042 ()27049844 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), 25/2-10EU, European Research Council, 306474;283570Swedish Research Council, 621-2011-6055Carl Tryggers foundation , CTS13:104
    Available from: 2016-04-01 Created: 2016-04-01 Last updated: 2017-07-02Bibliographically approved
    4. Laboratory evolved enzymes provide snapshots of the development of enantioconvergence in enzyme-catalyzed epoxide hydrolysis
    Open this publication in new window or tab >>Laboratory evolved enzymes provide snapshots of the development of enantioconvergence in enzyme-catalyzed epoxide hydrolysis
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    2016 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 17, no 18, 1693-1697 p.Article in journal (Refereed) Published
    Abstract [en]

    Engineered enzyme variants of potato epoxide hydrolase (StEH1) display varying degrees of enrichment of (2R)-3-phenylpropane-1,2-diol from racemic benzyloxirane. Curiously, the observed increase in the enantiomeric excess of the (R)-diol is not only due to changes in enantioselectivity for the preferred epoxide enantiomer, but also to changes in the regioselectivity of the epoxide ring opening of (S)-benzyloxirane. To probe the structural origin of these differences in substrate selectivities and catalytic regiopreferences, we have solved the crystal structures for the in-vitro evolved StEH1 variants. We have additionally used these structures as a starting point for docking the epoxide enantiomers into the respective active sites. Interestingly, despite the simplicity of our docking calculations, the apparent preferred binding modes obtained from the docking appears to rationalize the experimentally determined regioselectivities. These calculations could also identify an active site residue (F33) as a putatively important interaction partner, a role that could explain the high degree of conservation of this residue during evolution. Overall, our combined experimental, structural and computational studies of this system provide snapshots into the evolution of enantioconvergence in StEH1 catalyzed epoxide hydrolysis.

    Keyword
    enantioselectivity; epoxide hydrolysis; evolutionary snapshots; laboratory evolution; protein engineering
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-298675 (URN)10.1002/cbic.201600330 (DOI)000384425400004 ()27383542 (PubMedID)
    Funder
    Swedish Research CouncilEU, European Research Council, 306474Swedish National Infrastructure for Computing (SNIC), SNIC2015-16-12EU, FP7, Seventh Framework Programme, 283570
    Available from: 2016-07-06 Created: 2016-07-06 Last updated: 2017-07-02Bibliographically approved
    5. Epoxide Hydrolysis as a Model System for Understanding Flux Through a Branched Reaction Scheme
    Open this publication in new window or tab >>Epoxide Hydrolysis as a Model System for Understanding Flux Through a Branched Reaction Scheme
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    (English)Article in journal (Other academic) Submitted
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-325485 (URN)
    Available from: 2017-07-02 Created: 2017-07-02 Last updated: 2017-07-02
    6. Q Version 6, a comprehensive toolkit for empirical valence bond and related free energy calculations.
    Open this publication in new window or tab >>Q Version 6, a comprehensive toolkit for empirical valence bond and related free energy calculations.
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Chemistry Topics
    Identifiers
    urn:nbn:se:uu:diva-325490 (URN)
    Available from: 2017-07-02 Created: 2017-07-02 Last updated: 2017-07-03
  • Public defence: 2017-09-13 09:00 B7 111:a, BMC, Uppsala
    Zhao, Jin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sequence based identification of genetic variation associated with intellectual disability2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Intellectual disability (ID) is a common neurodevelopmental condition, often caused by genetic defects. De novo variation (DNV) is an important cause of ID, especially in severe or syndromic forms of the disorder. Next generation sequencing has been a successful application for finding pathogenic variation in ID patients. The main focus of this thesis is to use whole exome sequencing (WES) and whole genome sequencing (WGS) to identify pathogenic variants in undiagnosed ID patients. In Paper I, WES was used in family trios to identify pathogenic DNVs in patients diagnosed with ID in combination with epilepsy. This work led to the identification of several DNVs in both new and known disease genes, including the first report of variation in the HECW2 gene in association with neurodevelopmental disorder and epilepsy. Paper II is the first independent validation of PIGG as a disease-causing gene in patients with developmental disorder. We used WES to identify the homozygous variation in PIGG, and transcriptome analysis as well as flow-cytometry studies were used to validate the pathogenicity of the PIGG variation. We discovered that PIGG variation give different effects in different cell types, contributing new insights into the disease mechanism. Paper III is also an application of WES in trio families with patients diagnosed with ID in order to identify causal variants, a strategy similar to that of Paper I. Several pathogenic variants were identified in this study; in particular, the gene NAA15 is highlighted as a new disease gene, and was recently confirmed in independent studies. This study also adds evidence to support that variation in the PUF60 gene is causing the symptoms in patients with Verheij syndrome. In Paper IV, WGS was used to analyze families with consanguineous marriages. All families in this study had been previously analyzed with WES without finding a disease cause. A number of new disease-causing variants were identified in the study, including a first validation of FRMD4A as a disease-associated gene. This study also shows that WGS performs better than WES in finding variants, even for variants in coding parts of the genome.

    List of papers
    1. Mutations in HECW2 are associated with intellectual disability and epilepsy
    Open this publication in new window or tab >>Mutations in HECW2 are associated with intellectual disability and epilepsy
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    2016 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 53, no 10, 697-704 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.

    METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.

    RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.

    CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.

    Keyword
    Intellectual disability; Epilepsy; Exome sequencing; HECW2; ERC2
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-301393 (URN)10.1136/jmedgenet-2016-103814 (DOI)000385958500008 ()27334371 (PubMedID)
    Funder
    EU, European Research Council, 282330Swedish Society for Medical Research (SSMF)
    Available from: 2016-08-31 Created: 2016-08-22 Last updated: 2017-07-04Bibliographically approved
    2. Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function
    Open this publication in new window or tab >>Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function
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    (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004Article in journal (Refereed) Epub ahead of print
    Keyword
    PIGG, GPI deficiency, Intellectual disability, Exome sequencing
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-326282 (URN)
    Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-07-04
    3. Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
    Open this publication in new window or tab >>Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-326280 (URN)
    Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-07-04
    4. Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability
    Open this publication in new window or tab >>Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-326281 (URN)
    Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-07-04
  • Public defence: 2017-09-16 13:15 Fåhraeussalen, Rudbecklaboratoriet Hus 5, Uppsala
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    New Insights in Adrenal Tumourigenesis.2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Unilateral cortisol producing adenoma (CPA) is the most common cause of ACTH-independent Cushing’s syndrome and is surgically curable. On the other hand, adrenocortical carcinomas (ACCs) are rare and aggressive tumours. Although the overall survival of the patients with ACC is very poor, the outcome can be heterogeneous and vary significantly between the patients. This thesis comprises studies showing genetic and genomic events occurring in CPAs and ACCs, their functional impact and clinical correlations.

    The Wnt/β-catenin and cAMP/PKA signalling pathways are crucial in adrenal homeostasis and frequent mutations in members of these pathways (CTNNB1, GNAS, and PRKACA) are found in CPAs. Mutational analysis revealed that ~60% of the CPAs harboured mutations in either of these genes. Transcriptome signature exhibited increased expression of genes involved in steroidogenesis in PRKACA/GNAS mutated (Cluster1) tumours in comparison to CTNNB1 mutated /wildtype (Cluster2) tumours. In addition we have also observed that gain of chromosome arm 9q was the most frequent arm level copy number variation (CNV) occurring in CPAs and were exclusively present in Cluster2 tumours. We also discovered novel PRKACA mutations occurring in ACCs, causing activation of cAMP/signalling pathway.   

    Comprehensive analysis of Wnt/β-catenin signalling pathway in ACCs revealed novel interstitial deletions occurring in CTNNB1 leading to deletion of the N-terminus of β-catenin. This is a novel and yet another frequent event leading to activated Wnt/β-catenin signalling and downstream targets in ACCs. Both, mutations occurring in CTNNB1 and nuclear expression of its protein were associated with poor overall survival. Through multiregional sampling approach we discovered intra-tumour heterogeneity in ACC tumours. Although all the multiregions within a tumour showed presence of shared basal CNVs, they encompassed private CNVs, different ploidy levels and private mutations in known driver genes. We found intra-tumour heterogeneity in CTNNB1, PRKACA, TERT promoter and TP53 mutations as well as ZNRF3 and CDKN2A/2B homozygous deletions.

    List of papers
    1. Integrated Molecular Characterization of Benign Cortisol Producing Adenomas Defines Two Distinct Clusters.
    Open this publication in new window or tab >>Integrated Molecular Characterization of Benign Cortisol Producing Adenomas Defines Two Distinct Clusters.
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    (English)Manuscript (preprint) (Other academic)
    Keyword
    cortisol producing adenoma, mutation, expression, PRKACA, CTNNB1, GNAS
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
    Research subject
    Endocrinology and Diabetology
    Identifiers
    urn:nbn:se:uu:diva-325973 (URN)
    Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2017-07-05
    2. Identification and Characterization of Novel PRKACA Mutations in Adrenocortical Tumors.
    Open this publication in new window or tab >>Identification and Characterization of Novel PRKACA Mutations in Adrenocortical Tumors.
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    (English)Manuscript (preprint) (Other academic)
    Keyword
    PRKACA, Mutations, Adrenal
    National Category
    Cell and Molecular Biology Cancer and Oncology
    Research subject
    Molecular Genetics; Endocrinology and Diabetology
    Identifiers
    urn:nbn:se:uu:diva-325978 (URN)
    Funder
    Swedish Cancer Society
    Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2017-07-05
    3. Intratumoural Heterogeneity of TERT Promoter Mutations in Adrenocortical Carcinoma
    Open this publication in new window or tab >>Intratumoural Heterogeneity of TERT Promoter Mutations in Adrenocortical Carcinoma
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    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Keyword
    TERT, Adrenocortical Carcinoma, Mutation, Heterogeneity.
    National Category
    Cell and Molecular Biology Cancer and Oncology
    Research subject
    Molecular Genetics; Endocrinology and Diabetology
    Identifiers
    urn:nbn:se:uu:diva-325979 (URN)
    Funder
    Swedish Cancer Society
    Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2017-07-05
    4. Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival.
    Open this publication in new window or tab >>Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival.
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    (English)Manuscript (preprint) (Other academic)
    Keyword
    adrenocortical carcinomas, CTNNB1, mutation, β-Catenin, survival
    National Category
    Cell and Molecular Biology Cancer and Oncology
    Research subject
    Molecular Genetics; Endocrinology and Diabetology
    Identifiers
    urn:nbn:se:uu:diva-325980 (URN)
    Funder
    Swedish Cancer Society
    Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2017-07-05
    5. Multidimensional Genetic Analysis of Adrenocortical Cancers
    Open this publication in new window or tab >>Multidimensional Genetic Analysis of Adrenocortical Cancers
    (English)Manuscript (preprint) (Other academic)
    Keyword
    adrenocortical carcinoma, mutation, chromosomal aberration, CNV
    National Category
    Cancer and Oncology Endocrinology and Diabetes Cell and Molecular Biology
    Research subject
    Endocrinology and Diabetology; Molecular Genetics
    Identifiers
    urn:nbn:se:uu:diva-325981 (URN)
    Funder
    Swedish Cancer Society
    Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2017-07-05