Warfarin is the most widely used oral anticoagulant and is indicated for many clinical conditions. Levofloxacin, a fluoroquinolone, is one of the most commonly prescribed antibiotics in clinical practice and is effective against Gram-positive, Gram-negative, and atypical bacteria. While small prospective studies have not revealed any significant drug-drug interaction between warfarin and levofloxacin, several case reports have indicated that levofloxacin may significantly potentiate the anticoagulation effect of warfarin. We report 3 cases of serious bleeding complications that appear to be the result of the interaction between warfarin and levofloxacin. Physicians should be aware of this potential interaction and use caution when prescribing levofloxacin to patients taking warfarin.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21621号 / 医博第4427号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 湊谷 謙司, 教授 佐藤 俊哉, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

OBJECTIVE: Diverticular bleeding is the most common cause of lower gastrointestinal bleeding. Arteriovascular disease, metabolic syndromes, non-steroidal anti-inflammatory drugs (NSAIDs), anti-thrombotics, and anticoagulants have been suggested as risk factors. There is a paucity of studies addressing factors associated with diverticular re-bleeding, especially in the United States. The aim of this study is to evaluate factors associated with colonic diverticular bleeding and re-bleeding in a US community-based hospital. METHODS: We conducted a retrospective case-control study to analyze the factors associated with diverticular bleeding. Between January 2010 and July 2011, 93 patients were admitted to our hospital with a primary diagnosis of acute diverticular bleeding. We compared them to 152 patients who were admitted with a primary diagnosis of diverticulitis in the same period. We collected data from the medical records of each patient in relation to the demographics, comorbidities, medications, social habits, location of diverticulosis, length of stay in the hospital, and re-bleeding rate within 2 years of the first bleeding episode. RESULTS: Factors such as cerebrovascular accident (p=0.009), coronary artery disease (p=0.037), diabetes mellitus (p=0.046), obstructive sleep apnea (p=0.033), NSAIDs (p=0.038), use of anti-thrombotics (p=0.001), anticoagulants (p=0.002) or calcium channel blockers (p=0.009), and bilateral diverticulosis (p=0.001) were significantly associated with diverticular bleeding as compared to diverticulitis. Recurrence of bleeding was noted in 26 out of 93 patients (28%) within 2 years of the first bleeding episode (p=0.001). Bilateral colonic involvement, anticoagulants, and elderly age (≥65 years) were found to have a closer relationship to diverticular re-bleeding, although it was not statistically significant. CONCLUSION: This study reveals that arteriovascular disease, diabetes mellitus, NSAIDs, the use of anti-thrombotics, anticoagulants or calcium channel blockers, and obstructive sleep apnea are factors that are significantly associated with diverticular bleeding. It also shows that bilateral colonic involvement, elderly age, and anticoagulants have a closer relationship to diverticular re-bleeding. More prospective studies in patients with diverticular bleeding should be conducted to shed light on the causality of these factors and the prevalence of diverticulitis.

Rare bleeding disorders are a group of inherited conditions caused by a deficiency of blood coagulation factors. Due to the low prevalence of these conditions in the general population, there is a scarcity of data to make informed, evidence-based clinical decisions. In this population who are highly susceptible to excessive bleeding, surgeries and invasive procedures pose an additional level of risk for bleeding-related and non-bleeding-related complications, especially in the perioperative period. The data scarcity in patients with rare bleeding disorders is further compounded by an infrequent rate of invasive procedures, sometimes attributed to the hemostatic challenges faced by such interventions among other factors. To address the problem of insufficient data for healthcare decision-making, as well as the assessment of perioperative outcomes in this population, this thesis explores the use of routinely collected data for the creation of a novel surgical database used for the assessment of perioperative hemostasis, complications, and initial surgical plan deviations in patients with rare bleeding disorders. Across five chapters, this thesis provides the methodology for the creation of the Indiana Hemostasis and Thrombosis Center (IHTC) Surgical Database, a descriptive analysis of the population and procedures, and assessment of perioperative outcomes. Approaches to ensure the validity of study results including confounder adjustment by variable selection methods, data quality improvement, missing data description, and imputation methods, were explored. Evidence from randomized controlled was also reviewed using Cochrane methodology to summarize the efficacy of clotting factor concentrates for the prevention of bleeds and bleeding-related complications in patients with hemophilia. Based on findings from the different approaches (observational study designs, randomized controlled trials, and systematic review methodology), recommendations were made regarding methodological and analytical considerations required to ensure valid and reliable perioperative outcome assessment in patients with rare bleeding disorders. The following provides a brief outline of each chapter. Chapter 1 is an introduction that outlines each of the studies in this thesis. Chapter 2 is a descriptive overview of the design, structure, and exploratory analysis of data captured in the IHTC-Surgical Database over a 21-year period. Chapter 3 is a retrospective cohort study that assessed the association between inhibitor status and perioperative hemostasis, complications, and initial surgical plan deviations in patients with hemophilia A and B. Chapter 4 is a systematic review that examined the efficacy of clotting factor concentrates for the prevention of bleeds and bleeding-related complications in patients with hemophilia. Chapter 5 outlines key findings, limitations, implications of the research in this thesis, and methodological considerations for the assessment of perioperative outcomes in patients with bleeding disorders. / Thesis / Doctor of Philosophy (PhD)

Background: The specific clinical impact of delays to hemostatic intervention in trauma is under-explored. Objectives: Investigate the current understanding of the impact of increasing time to hemostasis and assess its relationship with clinical outcomes. Methods: We conducted a systematic review to characterize existing definitions of delayed hemostasis and its clinical sequelae. We conducted a cohort study of 147 trauma patients to investigate the impact of increased time to hemostasis. Results: Most studies demonstrated significant relationships between time to hemostasis and mortality, despite heterogeneity. The cohort study failed to demonstrate a significant association between time to hemostasis and mortality. Discussion: The thesis has taken steps to investigate time to hemostasis with appropriate methodology. The findings are limited by sample size and confounding by indication. Conclusions: There remains a substantial gap in the literature with respect to understanding the impact of increasing time to hemostasis in trauma and larger studies are needed.

O ato cirúrgico sempre deve ser precedido de uma avaliação das condições de saúde local e sistêmica do paciente, sendo os exames complementares, o subsídio utilizado para avaliar e confirmar as suspeitas clínicas e hipóteses diagnósticas, adequando o paciente à terapêutica proposta. A literatura é ampla no que diz respeito a testes de hemostasia por meio de diferentes métodos, contudo, não há estudos na literatura revisada que comparem o tempo de sangramento pelo método de Ivy com o tempo de sangramento aferido na mucosa bucal. A proposta deste estudo é de avaliar a técnica de aferição do tempo de sangramento da mucosa bucal e comparar com o tempo de sangramento pelo método de Ivy convencional, em pacientes com história de diátese hemorrágica relacionada a procedimentos cirúrgicos anteriores. Tais pacientes apresentaramse no ambulatório de Cirurgia da Faculdade de Odontologia da Universidade de São Paulo com necessidade de procedimentos relacionados à cirurgia oral menor. Foi realizado o tempo de sangramento pelo método de Ivy previamente ao teste do tempo de sangramento da mucosa bucal em 30 pacientes. O tempo de sangramento da mucosa bucal não apresentou diferença estatística quando comparado ao tempo de sangramento de Ivy (p=0,755). Os resultados avaliados pelo método de KOLMOGOROV-SMIRNOV seguiram uma distribuição normal em ambas amostras (p>0,15) sendo que o tempo médio de sangramento na pele e na mucosa bucal foi de 295 segundos e 291 segundos respectivamente, demonstrando semelhança entre os tempos aferidos. / Surgical procedures must be preceded by an accurate evaluation of the local and systemic health status and complementary exams can confirm or not clinical suspect and diagnosis hypothesis in order to adequate the patient to the proposed surgical treatment. The world literature is generous with respect of hemostasia tests employing several methodologies although there are not studies that compare the bleeding time test by Ivy?s method with bleeding time accessed at the oral mucosa. We propose at this study the evaluation of a bleeding time method in the oral mucosa comparing the results with the conventional Ivy?s test in patients with bleeding disorders history in past oral minor surgical procedures. The patients were those selected in the Oral Surgery Clinic of the Dental School of University of São Paulo that underwent to oral minor surgery. The Ivy?s bleeding time test were previously obtained before bleeding time of the mucosa in 30 patients and it was concluded that the bleeding time of the mucosa did not present statistically difference significant comparing the Ivy?s test (p=0,755). The results evaluated by KOLMOGOROV-SMIRNOV?s method followed a normal distribution in both samples (p>0,15) and that the mean bleeding time at the skin and at the oral mucosa was 295 seconds and 291 seconds respectively showing similarity between the groups.

OBJECTIVE: The objective of this study was to evaluate outcomes for women following endometrial ablations due to abnormal uterine bleeding (AUB). These outcomes included patient-reported quality of life, satisfaction with the procedure, and treatment failure. Women experiencing heavy/regular bleeding were compared with women experiencing heavy/irregular bleeding. DESIGN: The study was designed as a prospective cohort study of women aged 18-55 years presenting to Women and Infants Hospital (WIH) in Providence, Rhode Island, for endometrial ablations due to AUB. Sixty-three participants in the study completed the Baseline Health Form, the Short Form-36 Health Survey (SF-36), and the Menstrual Bleeding Questionnaire (MBQ) upon enrollment. At the 3-month, 6-month, and 1-year follow-ups participants completed the SF-36 and the MBQ. RESULTS: Baseline responses from the participants who were undergoing endometrial ablation found that 95.2% of women (n = 60) identified their periods as being heavy. From the total participants, 60.3% of women (n = 38) indicated their periods as being irregular. The SF-36 total score results demonstrate women with heavy/irregular bleeding experienced a greater negative impact in their quality of life. When broken down to the physical component score (PCS) and the mental component score (MCS) this difference, between women with heavy/regular bleeding and women with heavy/irregular bleeding, was minimized. Results from the MBQ revealed that women with heavy/irregular menstrual bleeding experienced a greater negative impact on their quality of life compared with women with heavy/regular bleeding. DISCUSSION: Heavy bleeding is one of the defining factors in determining whether women seek further treatment for their menstrual bleeding, and when they do, they will usually attempt other therapies before pursuing surgery. The MBQ revealed a difference in quality of life between women with heavy/irregular bleeding and women with heavy/regular bleeding because this questionnaire measures bleeding and its impact on a woman’s life. The SF-36 total scores also showed a difference between heavy/irregular bleeding and heavy/regular bleeding. Breaking down the total SF-36 total score into the PCS and MCS minimized this difference. This questionnaire focused more on overall general health rather than bleeding and this focus may account for the smaller scoring differences among bleeding patterns. CONCLUSION: Similar proportions of women experiencing heavy/regular and heavy/irregular bleeding pursue endometrial ablations as a treatment for AUB. The SF-36 demonstrated a greater burden on women’s general health when they have heavy/irregular bleeding. The MBQ provides a better measure to compare both bleeding patterns, aspects of bleeding, and demonstrates a more negative impact on quality of life for women with heavy/irregular bleeding.

O ato cirúrgico sempre deve ser precedido de uma avaliação das condições de saúde local e sistêmica do paciente, sendo os exames complementares, o subsídio utilizado para avaliar e confirmar as suspeitas clínicas e hipóteses diagnósticas, adequando o paciente à terapêutica proposta. A literatura é ampla no que diz respeito a testes de hemostasia por meio de diferentes métodos, contudo, não há estudos na literatura revisada que comparem o tempo de sangramento pelo método de Ivy com o tempo de sangramento aferido na mucosa bucal. A proposta deste estudo é de avaliar a técnica de aferição do tempo de sangramento da mucosa bucal e comparar com o tempo de sangramento pelo método de Ivy convencional, em pacientes com história de diátese hemorrágica relacionada a procedimentos cirúrgicos anteriores. Tais pacientes apresentaramse no ambulatório de Cirurgia da Faculdade de Odontologia da Universidade de São Paulo com necessidade de procedimentos relacionados à cirurgia oral menor. Foi realizado o tempo de sangramento pelo método de Ivy previamente ao teste do tempo de sangramento da mucosa bucal em 30 pacientes. O tempo de sangramento da mucosa bucal não apresentou diferença estatística quando comparado ao tempo de sangramento de Ivy (p=0,755). Os resultados avaliados pelo método de KOLMOGOROV-SMIRNOV seguiram uma distribuição normal em ambas amostras (p>0,15) sendo que o tempo médio de sangramento na pele e na mucosa bucal foi de 295 segundos e 291 segundos respectivamente, demonstrando semelhança entre os tempos aferidos. / Surgical procedures must be preceded by an accurate evaluation of the local and systemic health status and complementary exams can confirm or not clinical suspect and diagnosis hypothesis in order to adequate the patient to the proposed surgical treatment. The world literature is generous with respect of hemostasia tests employing several methodologies although there are not studies that compare the bleeding time test by Ivy?s method with bleeding time accessed at the oral mucosa. We propose at this study the evaluation of a bleeding time method in the oral mucosa comparing the results with the conventional Ivy?s test in patients with bleeding disorders history in past oral minor surgical procedures. The patients were those selected in the Oral Surgery Clinic of the Dental School of University of São Paulo that underwent to oral minor surgery. The Ivy?s bleeding time test were previously obtained before bleeding time of the mucosa in 30 patients and it was concluded that the bleeding time of the mucosa did not present statistically difference significant comparing the Ivy?s test (p=0,755). The results evaluated by KOLMOGOROV-SMIRNOV?s method followed a normal distribution in both samples (p>0,15) and that the mean bleeding time at the skin and at the oral mucosa was 295 seconds and 291 seconds respectively showing similarity between the groups.

Simulating light is a very computationally expensive proposition. There are a wide variety of global illumination algorithms that are implemented and used by major motion picture companies to render interesting and believable scenes. Every algorithm strives to find a balance between speed and accuracy. The Point Based Approximate Color Bleeding algorithm is one of the most widely used algorithms in the field today. The Point Based Approximate Color Bleeding(PBACB) global illumination algorithm is based on the central idea that the geometry and direct illumination of the scene can be approximated by using a point cloud representation. This point cloud representation can then be used to generate the indirect illumination. The most basic unit of the point cloud is a surfel. A surfel is a two dimensional circle in space that contains the direct illumination for that section of space. The surfels are gathered in a tree structure and approximations are generated for the different levels of the tree. This tree is then used to calculate the appropriate color bleeding effect to apply to the surfaces in a rendered image. The main goal of this project was to explore the possibility of applying CUDA to the PBACB global illumination algorithm. CUDA is an extension of the C/C++ programing languages which allows for GPU parallel programming. In this paper, we present our GPU based implementation of the PBACB algorithm. The PBACB algorithm involves three central steps, creation of a surfel point cloud, generation of the spherical harmonics approximations for the point cloud, and using the surfel point cloud to generate an approximation for global illumi- nation. For this project, CUDA was applied to two of the steps of the PBACB algorithm, the generation of the spherical harmonic representations and the ap- plication of the surfel point cloud to generate indirect illumination. Our final GPU algorithm was able to obtain a 4.0 times speedup over our CPU version. We also discuss future work which could include the use of CUDA’s Dynamic Parallelism and a stack free implementation which could increase the speedups seen by our algorithm.

Trauma is a leading cause of death, and in potentially preventable trauma deaths insufficient bleeding control has often been noted. For bleeding-related injuries, providing aid quickly is crucial since people may die from haemorrhage within minutes. One group that has been identified as able to provide quick aid is bystanders and other people present at the scene of injury. In such settings, using bleeding control (b-con) equipment such as tourniquets is effective to help control bleeding. Thus, b-con kits including such equipment has been recommended to be placed in public areas. However, for publicly placed b-con kits to be effective people must be able to find the kits quickly. This leads to the aim of this thesis, which is to explore how b-con kits can be made easier to find for the public by using signage and b-con kit placement. Two studies were conducted to explore this topic. In the first study, signage for marking b-con kits was developed since no standardised or well-recognised signage for b-con kits existed. Three b-con kit signage designs were developed in accordance with existing standards and regulations for safety signage. Then, the three signage designs were evaluated by a survey. One design, depicting an injured arm, was found to be most effective for marking b-con kits. In the second study, the effect of signage use and b-con kit placement on time to find a b-con kit was examined by an experiment carried out in a virtual environment (VE) using virtual reality (VR). The study found that providing directional signage made people find the b-con kit faster. The study also found that placing the b-con kit at a reception (a central location) made people find the b-con kit quicker compared to when the b-con kit was placed between emergency exits (a more peripheral location). The study also examined if people would find the b-con kit faster when b-con signage was used for directional signage compared to when general first aid signage was used, but no significant difference was found. In addition, the VE was validated. The results of the validation showed that the findings in the study would likely transfer to real world settings. In conclusion, using signage and placing b-con kits strategically were found to be effective ways to aid the public in finding publicly placed b-con kits, which may help people provide possibly life-saving aid to haemorrhage victims.