1. Abstract 1.1. Background It is uncertain whether 1) patient’s characteristics (e.g., age, weight, height, and sex) influence anti-Xa heparin levels (hereafter referred to as "heparin levels"), or 2) if heparin levels influence recurrent venous thromboembolism (VTE) or bleeding events, in patients with acute VTE treated with weight-adjusted therapeutic-dose subcutaneous (SC) unfractionated heparin (UFH) or SC low-molecular weight heparin (LMWH). To determine if either association exist, we analyzed data from the Fixed-Dose Heparin (FIDO) study, in which patients were randomized to either SC UFH or SC LMWH, each given in fixed weight-adjusted doses and overlapped with 3 month of warfarin therapy for treatment of acute VTE. 1.2. Methods During the original study, 708 patients were asked to participate in a sub-study that would measure peak heparin levels while they were treated with heparin. 408 patients provided blood samples and met the eligibility criteria for the analyses in this thesis. Linear regression was used to examine the influence of patients’ baseline characteristics (e.g., age, weight, height, body mass index [BMI], sex) on heparin levels. The influence of other factors (e.g., type of heparin [UFH or LMWH]) on heparin levels was also assessed. Logistic regression was used to examine the association of heparin levels with the outcomes of 1) recurrent VTE during 3 months of follow up, and 2) bleeding events in the first 10 days of follow up. 1.3. Results: Mean heparin levels were 0.695 in patients treated with UFH, 0.698 in those treated with dalteparin and 1.034 in those treated with enoxaparin (p<0.001; R2=0.08 for variability accounted for by type of heparin). In a univariable analysis, heparin levels increase by 0.04 IU/ml (95% CI 0.02-0.07; p=0.001; R2=0.03) for every 10-kg increment in weight, by 0.02 IU/ml (95% CI 0.01-0.03; p<0.001; R2=0.04) for each unit of BMI, and by 0.03 IU/ml (95% CI 0.01-0.05; p=0.001; R2=0.03) for every 10 mol/l increment in creatinine. In a multivariable analysis, weight, BMI, and creatinine still influenced heparin levels, after adjusting for type of heparin and timing of blood sample withdrawal. Although heparin levels increased with weight, the magnitude was not large enough to suggest altering the current weight-based dosing method for LMWH. Other baseline factors such as age, height, type of VTE, creatinine clearance and hospitalization status did not influence heparin levels in patients treated with UFH or LMWH. In a univariable analysis, when heparin levels were treated as a continuous variable, higher heparin levels were associated with a lower risk of recurrent VTE at 90-days in patients treated with LMWH (OR 0.04, 95% CI 0.003-0.550, for each 1.0 IU/ml increase in heparin levels), but not in patients treated with UFH (OR 1.46, 95% CI 0.37-5.58, for each 1.0 IU/ml increase in heparin levels). In addition, higher heparin levels were associated with a higher risk of bleeding at 10-days in patients treated with UFH (OR 3.32, 95% CI 1.30-8.46 for each 1 IU/ml increase in heparin levels) but not in patients treated with LMWH (OR 3.77, 95% CI 0.42-33.92, for each 1.0 IU/ml increase in heparin levels). In a multivariable analysis, the association of heparin levels with VTE at 90-days in patients receiving LMWH (lower VTE events) and with bleeding events at 10-days in patients receiving UFH (higher bleeding events) persisted after adjusting for antiplatelet use at baseline and diagnosis of cancer at baseline. When heparin levels were treated as a dichotomous variable (subtherapeutic vs. non-subtherapeutic levels and supratherapeutic vs. non-supratherapeutic levels), the proportion of patient with recurrent VTE was significantly higher in patients with subtherapeutic levels compared with non-subtherapeutic levels in patients receiving LMWH (8.6% vs. 1.3%, p = 0.01). No significant difference was found in the proportion of patients with subtherapeutic levels and non-subtherapeutic levels in patients receiving UFH (0% vs. 3.4%, χ2=0.15, p= 0.70). The test of interaction supported the decision to analyze LMWH and UFH groups separately (p=0.02). Finally, the proportion of patient with bleeding was higher in patients with supratherapeutic compared with non-supratherapeutic heparin levels (6.5% vs. 1.5%, χ2=7.65, p=0.01). The test of interaction did not support the decision to analyze LMWH and UFH groups separately (p=0.13). 1.4. Conclusions Although it was possible to identify factors that were associated with heparin levels in patients who had been treated with weight-adjusted UFH or LMWH, none of these associations were strong enough to suggest that variables other than weight should influence SC heparin dosing. Subtherapeutic heparin levels were associated with a higher risk of recurrent VTE in patients treated with LWMH but not UFH, and supratherapeutic heparin levels were associated with a higher risk of bleeding in patients treated with UFH but not LMWH. Indirectly, these findings suggest that adjusting UFH or LMWH dose in response to heparin levels might improve clinical outcomes. / Thesis / Master of Science (MSc)

Persons with severe hemophilia A exhibit significant variations in clinical phenotype; approximately 10% are milder bleeders. This study explored factors that might contribute to this inter-patient heterogeneity. Using a multi-center prospective study following boys with severe hemophilia A on a tailored primary prophylaxis regimen, age at first joint bleed, body mass index, protocol adherence and family activity level were modeled on the age at escalation from once-weekly to twice-weekly and alternate day infusions. Escalation, based on bleeding frequency, served as a surrogate marker of bleeding severity. We also assessed the roles of clinical and hemostatic parameters in predicting age at first joint bleed using a cross-sectional study. Results suggest that a delayed first joint bleed indicates later escalation (milder bleeding pattern) and that a longer lag time is associated with an earlier onset of joint bleeding. Larger studies are needed to definitively identify predictors of clinical heterogeneity in these patients.

Persons with severe hemophilia A exhibit significant variations in clinical phenotype; approximately 10% are milder bleeders. This study explored factors that might contribute to this inter-patient heterogeneity. Using a multi-center prospective study following boys with severe hemophilia A on a tailored primary prophylaxis regimen, age at first joint bleed, body mass index, protocol adherence and family activity level were modeled on the age at escalation from once-weekly to twice-weekly and alternate day infusions. Escalation, based on bleeding frequency, served as a surrogate marker of bleeding severity. We also assessed the roles of clinical and hemostatic parameters in predicting age at first joint bleed using a cross-sectional study. Results suggest that a delayed first joint bleed indicates later escalation (milder bleeding pattern) and that a longer lag time is associated with an earlier onset of joint bleeding. Larger studies are needed to definitively identify predictors of clinical heterogeneity in these patients.

In this thesis, we discuss three image processing topics: High Dynamic Range (HDR) image creation in scenes with motion, Tone Mapping (TM), and Demosaicking. The first part of this thesis focuses on the creation of HDR images using gradient fusion techniques, and proposes a method that deals with motion and avoids bleeding and ghost artifacts. In the second part, we tackle the TM problem, whose goal is to produce a low dynamic range picture from an HDR image that reproduces the sensation of an observer in the scene. We review the perceptual principles that we find important for TM purposes and present a new method that compares well to the state of the art. Finally, we propose a new method to reconstruct the three color channels of a picture taken with a Bayer filter. This problem is called Demosaicking and will be presented in the third part of this thesis. / En esta tesis tratamos tres temas de procesamiento de imagen: creación de imágenes de alto rango dinámico o HDR, Tone Mapping (TM) y Demosaicking. En la primera parte proponemos un método para la creación de imágenes HDR con movimiento que permite generar resultados sin artefactos de tipo bleeding y ghosting. En la segunda parte de la tesis tratamos el problema de TM cuyo objetivo es comprimir el rango dinámico de una imagen HDR para ser mostrada en una pantalla o impresa, simulando lo mejor posible la percepción de un sujeto en la escena. Presentaremos los principios sicofísicos que consideramos relevantes para TM y propondremos un método nuevo que mejora los resultados del estado del arte. Finalmente, en la tercera parte presentamos un método de Demosaicking o reconstrucción de los tres canales de color de una imagen tomada con un filtro de Bayer.

This diploma thesis is divided into two parts, the theoretical and practical part. The theoretical part is to study of factors influencing the workability and bleeding of concrete. There is mentioned the production of cement and standard requirement. The task of the practical part is to assess the cements produced by the cement works Hranice and Prachovice. These cements test in terms of water separation. In combination with these cements use superplasticizing admixtures from Mapei and Stachema and determine the impact of water separation on cement pastes. Determine rheology on the cement pastes. Define influence of variations in cement composition affect the stability of cement mixtures.

<p> Inherited bleeding disorders can be caused by mutations affecting platelet, coagulation, or fibrinolytic proteins. Quebec platelet disorder (QPD) is a rare, autosomal dominant disorder associated with increased expression of the fibrinolytic enzyme urokinase plasminogen activator (uPA) in platelets. Individuals with QPD experience delayed-onset bleeding after hemostatic challenges that is attenuated with fibrinolytic inhibitor therapy. The aims of this thesis were to: 1) determine if increased platelet uPA contributes to QPD clot lysis in vitro; 2) investigate whether QPD individuals have increased urinary uPA, as some individuals experience hematuria; and 3) map the genetic locus of QPD, and look for the putative mutation. Studies of clot lysis indicated that QPD platelets induce a gain-of-function defect in fibrinolysis when platelets are incorporated into clots. This suggests that accelerated fibrinolysis may contribute to QPD bleeding. Studies of urinary uPA in QPD showed that uPA is not increased, indicating that hematuria in QPD is likely a consequence of increased platelet uPA. This finding also suggests that uPA overexpression in QPD may be megakaryocyte-specific. Linkage studies showed that QPD is strongly linked to a 2 megabase region on chromosome 10 that harbors the uPA gene, PLA U. No mutations in PLA U or its regulatory regions were identified; however, a common haplotype for a 32.5 kilobase region around PLA U, including inheritance of a rare, linked polymorphism, suggests this is the most likely locus for QPD. mRNA studies in QPD platelets showed that QPD selectively increases expression of the linked PLAU allele, without similar increases in megakaryocyte progenitors or in saliva. These findings implicate a cis-mutation near PLA U as the cause of QPD. This thesis provides novel insights on the fibrinolytic abnormality in QPD blood, and on the QPD genetic locus. which will be important for identifying the precise mutation that converts normally prohemostatic platelets to profibrinolytic cells. </p> / Thesis / Doctor of Philosophy (PhD)

Haematological malignancies and their treatment lead to prolonged periods of severe thrombocytopenia (platelet count ≤ 50 x 10⁹/l). Despite the use of prophylactic platelet transfusions, haemorrhage remains an important complication during this thrombocytopenic period. Within a 30 day period up to 70% of patients have clinically significant haemorrhage (World Health Organization (WHO) grade 2 or above bleeding) and up to 10% have severe or life-threatening haemorrhage (WHO grade 3 or 4 bleeding). Hence our current management of these patients to prevent haemorrhage is sub-optimal. The aim of this thesis was to identify clinical and laboratory factors that may predict the risk of haemorrhage in patients with haematological malignancies and severe thrombocytopenia. This was achieved via several different study designs and assessed the effect of clinical and laboratory factors on any or clinically significant haemorrhage and their effect on intracranial haemorrhage. This thesis has demonstrated that there is no consensus on how bleeding is assessed and graded in this patient group. Also it showed that the absolute immature platelet number may be a better alternative to the total platelet count to guide administration of platelet transfusions. Female sex, a previous history of a fungal infection, a high C-reactive protein, a high white cell count, a low platelet count, anaemia, impaired renal function, and recent clinically significant haemorrhage were all found to be independent risk factors for haemorrhage. Patients who were in complete remission from their haematological malignancy had a much lower risk of bleeding.

Acute Upper Gastrointestinal Bleeding (AUGIB) accounts for 7000 deaths in the UK annually and is the single leading indication for transfusion of blood components. A large UK audit in 2007 reported high case fatality and rates of further bleeding. Since many deaths are determined by pre-existing co-morbidity, strategies to improve outcome should be targeted at preventable deaths and therefore focus upon improved control of haemorrhage and prevention of further bleeding, which are investigated in this thesis. Data for the analyses presented originate from the UK national audit of AUGIB, a laboratory study and a cross sectional survey. Five broad themes were investigated including service provision and timing of endoscopy, the use of transcatheter arterial embolisation (TAE) or surgery for refractory bleeding, the impact of coagulopathy on outcome, management of acute variceal haemorrhage (AVH) and haemostatic derangements after AVH, and the use of red blood cells (RBCs). Although there was no evidence of a “weekend effect” for mortality, earlier endoscopy (<12 hours) was associated with improved control of haemorrhage in higher risk patients compared to later endoscopy (>24 hours). TAE was an effective and safe modality for refractory bleeding, but the high post-surgical mortality (29%) raises questions about the appropriateness of case selection for surgery. Coagulopathy after non-variceal haemorrhage was associated with a 5-fold increase in risk-adjusted mortality. Further bleeding after AVH was strikingly high (26%) with notable deficiencies in the use of vasopressors, antibiotics and endotherapy. Global assessments of coagulation demonstrated that thrombin generation after AVH was normal, but clot strength was poor with excessive fibrinolysis. Platelets, fibrinogen and antifibrinolytics improved haemostasis ex vivo but coagulation factor transfusion had no effect. RBC transfusion practice is variable. This work on AUGIB provides new data highlighting areas of sub-optimal care, and informs both current practice and research questions for new interventional trials.

Systematic reviews and meta-analyses have been a central pillar of evidence-based practice and policy-making in healthcare over recent years. Traditionally, this has focused on effectiveness evidence from trials.. There is increasing understanding, however, that other study designs also provide essential information and this has led to interest in developing ways to review and synthesis such evidence. Qualitative research has unique potential to illuminate the patient experience. This research has three aims: 1) To review and compare the proposed methods of systematic review and synthesis of qualitative research. 2) To develop and assess two methods of systematic review and synthesis of qualitative research. 3) To compare these two methods and suggest how they might be used in a policy-making context. In addressing these aims, this thesis substantially contributes to debates about the purpose and practice of systematic review and synthesis of qualitative research, particularly in the context of health technology assessment and related pOlicy-making. I undertake a unique critical comparison of the methods suggested for reviewing and synthesising qualitative research, based on their approach to key stages of systematic review. This is used to produce a comprehensive framework for good practice~ I use the framework in two systematic reviews, one about heavy menstrual bleeding using meta-ethnography, and one about hysterectomy using meta-study. These two reviews allow a comparison of the two methods, and in particular explore the impact of expanding the meta-ethnography approach through meta-study, which adds explicit steps to assess the impact of study methodology and theory on findings. The ability of meta-study to unpack the procedures and theories that produce particular findings is key and illuminates the importance of theory in systematic reviews of qualitative research. Through the two systematic reviews, my thesis also contributes to understanding of these reproductive health topic areas through the creation of new insights and concepts from the synthesis. The synthesis of heavy menstrual bleeding studies produced a detailed patient illness model based on women's experiences. In addition, it allowed an understanding of elements that contribute to women's certainty or uncertainty about whether or not their periods could be seen as problematic and requiring medical help. This helps to establish the limitations of the medical model for doctors, as well as women who suffer from heavy menstrual bleeding. The synthesis of hysterectomy studies produced a detailed description of the journey that women make to, and through, hysterectomy, based on their experiences. I also created a theoretical framework, which shows that hysterectomy needs to be understood in the context of personal, physical experiences, together with sociocultural forces that affect the way in which hysterectomy is experienced, and that the interaction of these micro- and macro-concerns mediate through, and affect, relationships with key other people. Methodology affected the research questions posed and the conclusions of research. Comparing the two methods of review and synthesis showed the importance of taking account of the methods and theories that produce research findings. However this additional detail may be at the expense of certainty and requires additional resources.

The thesis is focused on the specifics of care for women with postpartum bleeding in intensive care. Part of this work are two segments, theoretical and empirical. The first segment focuses on the theoretical part, which lists the existing knowledge from literature approaching the issue of bleeding complications accompanying childbirth, especially postpartum period, when the lack of timely solution can endanger the woman's life. This section defines the terms postpartum bleeding, hemorrhagic shock, DIC, intensive care and severe postpartum bleeding complications. The work also focuses on nursing care for women with postpartum bleeding. The theoretical part is concluded postoperative nursing care. The second segment of the work is of empirical character. The main objective of this thesis was to investigate how the care provided to the ARO / ICU for women with problems postpartum bleeding. This part of the non-standardized using an anonymous questionnaire identifies issues of bleeding complications in postpartum period. The work deals with the level of care provided in intensive care for women with severe postpartum bleeding complications, knowledge of the healthcare paramedical personnel in the care of patients with postpartum bleeding and acquiring new information on nursing care in case postpartum...