INTRODUÇÃO: A HPN é uma patologia na qual a atividade do sistema complemento, sem oposição, leva a complicações sistêmicas. Ela é caracterizada por anemia hemolítica adquirida com hemoglobinúria intermitente, falência medular e fenômenos tromboembólicos (TE). A trombose venosa é a sua principal causa de mortalidade, entretanto o seu mecanismo fisiopatológico é apenas parcialmente elucidado. O grande número de pacientes com trombocitopenia dificulta o manejo da profilaxia antitrombótica secundária e primária. Optou-se por evidenciar o desequilíbrio hemostático associado ao clone HPN através de um teste de avaliação global da coagulação. MÉTODOS: Para a detecção do potencial hemostático de cada indivíduo foi utilizado um ensaio fluorogênico de geração de trombina, em amostra de plasma pobre em plaquetas na presença e na ausência de trombomodulina (TM). A eficiência na redução do potencial de trombina endógeno (ETP) e da concentração máxima de trombina (pico) pela TM foi utilizada para a identificação do estado de hipercoagulabilidade. O tempo para o início da geração de trombina (tempo de latência) e para a concentração máxima de trombina foram utilizados para a detecção do fenótipo hemorrágico. Os indivíduos foram categorizados em três grupos: HPN, se clone HPN >= 10%; anemia aplástica idiopática adquirida ou associada a clone < 10%, e normais. Os pacientes e controles foram submetidos a avaliação laboratorial que incluiu pesquisa de trombofilia (TB) e do clone HPN, hemograma, testes habituais de avaliação da hemostasia, e no grupo de pacientes análise bioquímica. Os participantes foram avaliados para a identificação da presença de fatores de risco para TE através de questionário. A análise dos resultados foi realizada em duas fases: a primeira incluiu apenas indivíduos com pesquisa de TB negativa e sem fatores de risco para TE; a segunda, realizada apenas no grupo de pacientes, também incluiu indivíduos em uso de contraceptivo hormonal, diagnóstico de infecção assintomática, evento de TE associado a fator de risco temporário, em período superior a 1 ano da inclusão no estudo, e com pesquisa de TB positiva. Esta última fase da análise teve como objetivo incluir um maior número de pacientes com o diagnóstico destas patologias, de baixa prevalência populacional. RESULTADOS: A presença do clone >= 10% foi associada à ineficiência da ação da TM em reduzir o ETP e o pico. O primeiro, de maior relevância científica e clínica, apresentou correlação positiva e negativa, respectivamente, com a atividade do fator von Willebrand (FvW:RCo) e com níveis plasmáticos de proteína C (PC). O grupo HPN apresentou menor tempo para atingir o pico. Na segunda fase, o tempo de latência apresentou correlação negativa com o número de plaquetas no grupo HPN, e houve correlação positiva do clone com a ineficiência da ação da TM na redução do ETP. CONCLUSÕES: o teste de geração de trombina é eficaz na detecção do fenótipo protrombótico associado ao clone HPN. As correlações encontradas com o FvW:RCo e a PC sugerem que a ativação endotelial e o sistema da PC, respectivamente, podem estar comprometidos. A inflamação secundária à ativação do sistema complemento pode levar à redução de expressão endotelial da TM e do receptor da PC. Entretanto os nossos achados, associados à descrição recente da redução de expressão e de atividade da TM, secundária à depleção de óxido nítrico (em estudos com estatinas), podem justificar a característica agressiva da trombofilia na HPN, e o desenvolvimento de TE mesmo nos pacientes em anticoagulação oral. Os parâmetros que avaliam o \'tempo\' no trombograma (tempo de latência e tempo para o pico) podem auxiliar na identificação do risco hemorrágico eventualmente associado à HPN / INTRODUCTION: PNH is a pathology in which the uncontrolled activity of the complement system leads to systemic complications. The pathology is characterized by an acquired hemolytic anemia with intermittent hemoglobinuria, bone marrow failure and thromboembolic event (TE). Venous thrombosis is the main cause of death, however, its physiopathological mechanism is only partially understood. The large number of patients with thrombocytopenia affects the management of primary and secondary antithrombotic prophylaxis. We chose to demonstrate the hemostatic unbalance associated with PNH clone through a global evaluation of the coagulation test. METHODS: To detect the hemostatic potential, we used a fluorogenic thrombin-generation assay, in platelet-poor plasma, with and without throbomodulin (TM). Analysis of the efficiency of TM in reducing the endogenous thrombin potential (ETP) and of the upper limit of thrombin concentration (peak) was done to identify the hypercoagulable state. Times to initiate thrombin generation (latency time-LT) and for reaching the peak were used to identify hemorrhagic phenotypes. Subjects were divided in three groups: PNH patients (if PNH clone >= 10%), patients with acquired idiopathic aplastic anemia or clone-associated (clone < 10%), and controls. Patients and controls were investigated for thrombophilia (TB) and PNH clone, underwent blood test, and regular exams to evaluate hemostasis. Patients were evaluated for the presence of risk factors for TE through questionnaires. Results were analyzed in two steps: the first included only patients negative for TB and with no risk factors for TE; the second step, done only in patients, included individuals using hormonal contraceptive, diagnosis of any asymptomatic infection, TE associated to temporary risk factors, and which have occurred in a period longer than one year since inclusion in the study, and positive TB. The aim of the second step was to gather the largest possible number of patients in these low prevalence pathologies. RESULTS: The presence of the clone >= 10% was associated with TM inefficiency in reducing the ETP (ETP+TM) and peak. In the first analysis, which had greater clinical relevance, we observed a positive correlation between ETP+TM and the activity of the von Willebrand factor (FvW:RCo), whereas a negative correlation was observed with the levels of protein C (PC). The PNH group presented the shortest time to reach the peak. In the second step of the analysis, the LT showed negative correlation with platelet counts in the PNH group, whereas a positive correlation between the clone and ETP+TM was observed. CONCLUSION: The thrombin-generation assay effectively detects the prothrombotic phenotype associated to PNH. The correlation found with both FvW:RCo and PC suggests that endothelial activation, and the PC system as well, may be deficient in these patients. Secondary inflammation to activation of the complement system may lead to lower endothelial expression of TM and of the PC receptor. However, our findings, together with recent descriptions of a reduced expression of the TM activity secondary to nitric oxide depletion (observed in studies on statin) may explain the aggressive nature of thrombophilia in PNH and the development of TE in these patients, even in those taking oral anticoagulants. The parameters that measure the time of thrombin generation may help identify the hemorrhagic risk that might be associated with PNH

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Background: The Mountain Home Veterans Affairs (VA) Medical Center has been diagnosing and treating veterans with benign paroxysmal positional vertigo (BPPV) for almost 2 decades. The clinic protocol includes a 2-week follow-up visit to determine the treatment outcome of the canalith repositioning treatment (CRT). To date, the characteristics of BPPV and treatment efficacy have not been reported in a cohort of veterans with BPPV. Purpose: To determine the prevalence and characteristics of veterans diagnosed with BPPV in a Veterans Affairs Medical Center Audiology Clinic and to examine treatment outcomes. Research Design: Retrospective chart review. Study Sample: A total of 102 veterans who tested positive for BPPV in the Vestibular Clinic at the Mountain Home VA Medical Center from March 2010 to August 2011. Results: In 102 veterans who were diagnosed with BPPV, the posterior semicircular canal was most often involved (75%), motion-provoked vertigo was the most common symptom (84%), and the majority (43%) were diagnosed with BPPV in their sixth decade. The prevalence of BPPV in the Audiology Vestibular Clinic was 15.6%. Forty-one percent of veterans reported a symptom onset within 12 months of treatment for BPPV; however, 36% reported their symptoms began > 36 months prior to treatment. CRT was effective (negative Dix–Hallpike/roll test) in most veterans (86%) following 1 treatment appointment (M = 1.6), but more than half reported incomplete symptom resolution (residual dizziness) at the follow-up appointment. Eighteen percent of veterans experienced a recurrence (M = 1.8 years; SD = 1.7 years). Conclusions: The characteristics and treatment outcomes of BPPV in our veteran cohort was similar to what has been reported in the general population. Future work should focus on improving the timeliness of evaluation and treatment of BPPV and examining the time course and management of residual dizziness.

Dizziness and balance problems are common symptoms at all ages. The aims were; to evaluate rehabilitation, static, dynamic balance and recovery in acute unilateral vestibular loss (AUVL), to evaluate the treatment of benign paroxysmal positional vertigo (BPPV) with assessment of static and dynamic balance and to evaluate the prevalence of dizziness and BPPV in a population of 75-year-olds. Study 1: Twenty-seven patients (51years) with AUVL were included and the recovery was followed regarding vestibular function, dizziness, and sick-leave. The recovery was rapid, with disappearance of spontaneous nystagmus and rapid return to work. Study II: Forty two patents (51 years) with AUVL were included and compared with a reference group. Static and dynamic balance were assessed after six months. Significant instability was found both in static and dynamic balance compared to a reference group. Study III: Seventeen patients (52 years) with severe BPPV (&gt; 3 months) were treated with Semonts´s manouver and/or Brandt-Daroff exercises. The recovery was evaluated by Dix-Hallpike test, subjective dizziness, unsteadiness and balance tests, after 1, 6 and 12 months. Semont´s maneouver resolved dizziness but the long term follow up showed impaired balance. Study IV: A large cohort (675) of elderly was assessed regarding dizziness and BPPV. Side lying test and balance tests were applied. A high prevalence of dizziness (36%) and BPPV (11%) was found. Conclusions: Patients with AUVL and BPPV have despite good symptomatic relief, still impaired static and dynamic balance at long term follow up. BPPV in elderly is common and should be examined since it can be treated.

Evidence-based practice, whose roots emanate from the mid-1960s, aims to provide fair, high-quality, and soundly researched health care with patients' best interests as a priority. Clinical practice guidelines are evidence-based and designed to assist clinicians with sound decision making. Despite the importance of evidence-based practice and the efforts invested into its development and dissemination, its uptake and implementation are poor. The disconnect between evidence-based practice and its translation into clinical practice was previously reported in low-to-middle income countries. This study investigated South African audiologists' and otorhinolaryngologists' (ear, nose and throat specialists') self-reported orientation to evidence-based practice. Second, adherence to evidence-based clinical practice guidelines was assessed with reference to the diagnosis and management of benign paroxysmal positional vertigo, a common vestibular condition for which a firm evidence base supporting treatment exists. A two-part quantitative approach was adopted. Part one surveyed South African audiologists and otorhinolaryngologists with the Evidence-Based Practice Profile Questionnaire and an additional researcher-developed questionnaire pertaining to the diagnosis and management of benign paroxysmal positional vertigo. A total of 130 survey responses were included in this study. Independent sample t-tests, one-way ANOVAs and Fisher's Exact tests were used to analyse the survey data. Part two used a retrospective record review at a tertiary academic hospital in the Western Cape of South Africa. Medical folders of patients diagnosed with benign paroxysmal positional vertigo, between 2010 – 2018 (n = 80), were analysed. The diagnosis and management strategies were recorded and compared against a gold standard evidence based guideline for congruence. Descriptive statistics were used to analyse and understand the data. Survey scores showed a positive association between increased years of experience and healthcare professionals' knowledge (p = .008) and confidence (p = .003) in evidence-based practice. Otorhinolaryngologists might be more knowledgeable than audiologists in evidence-based practice due to their increased training and exposure to evidence-based practice in their specialising years. Findings from the retrospective record review suggested adherence to the clinical practice guidelines in the diagnosis and management of posterior semi circular canal benign paroxysmal positional vertigo. The study outcomes propose that evidence-based clinical practice guidelines developed in the Global North may not be appropriate for the different health contexts that exist in low-to-middle income South Africa (e.g., rural settings). However, the benign paroxysmal positional vertigo clinical practice guidelines were adhered to at a tertiary, academic hospital in Cape Town. The results also support the notion that increased exposure to evidence-based practice reinforces its approach. Outcomes from this study raise implications for the development and dissemination of context-appropriate, evidence-based clinical practice guidelines.

Deep Learning models are ubiquitous in machine learning. They offer state-of- the-art performance on tasks ranging from natural language processing to image classification. The drawback of these complex models is their black box nature. It is difficult for the end-user to understand how a model arrives at its prediction from the input. This is especially pertinent in domains such as medicine, where being able to trust a model is paramount. In this thesis, ways of explaining a model predicting paroxysmal atrial fibrillation from sinus electrocardiogram (ECG) data are explored. Building on the concept of feature attributions, the problem is approached from three distinct perspectives: time, scale, and frequency. Specifically, one method based on the Integrated Gradients framework and one method based on Shapley values are used. By perturbing the data, retraining the model, and evaluating the retrained model on the perturbed data, the degree of correspondence between the attributions and the meaningful information in the data is evaluated. Results indicate that the attributions in scale and frequency are somewhat consistent with the meaningful information in the data, while the attributions in time are not. The conclusion drawn from the results is that the task of predicting atrial fibrillation for the model in question becomes easier as the level of scale is increased slightly, and that high-frequency information is either not meaningful for the task of predicting atrial fibrillation, or that if it is, the model is unable to learn from it. / Djupinlärningsmodeller förekommer på många håll inom maskininlärning. De erbjuder bästa möjliga prestanda i olika domäner såsom datorlingvistik och bildklassificering. Nackdelen med dessa komplexa modeller är deras “svart låda”-egenskaper. Det är svårt för användaren att förstå hur en modell kommer fram till sin prediktion utifrån indatan. Detta är särskilt relevant i domäner såsom sjukvård, där tillit till modellen är avgörande. I denna uppsats utforskas sätt att förklara en modell som predikterar paroxysmalt förmaksflimmer från elektrokardiogram (EKG) som uppvisar normal sinusrytm. Med utgångspunkt i feature attribution (särdragsattribution) angrips problemet från tre olika perspektiv: tid, skala och frekvens. I synnerhet används en metod baserad på Integrated Gradients och en metod baserad på Shapley-värden. Genom att perturbera datan, träna om modellen, och utvärdera den omtränader modellen på den perturberade datan utvärderas graden av överensstämmelse mellan attributionerna och den meningsfulla informationen i datan. Resultaten visar att attributioner i skala- och frekvensdomänerna delvis stämmer överens med den meningsfulla informationen i datan, medan attributionerna i tidsdomänen inte gör det. Slutsatsen som dras utifrån resultaten är att uppgiften att prediktera förmaksflimmer blir enklare när skalnivån ökas något, samt att högre frekvenser antingen inte är betydelsefullt för att prediktera förmaksflimmer, eller att om det är det, så saknar modellen förmågan att lära sig detta.

Hematopoietic stem cells (HSCs) are critical to the development of the hematopoietic system during ontogeny and maintaining hematopoiesis under steady-state. Several genes implicated in asymmetric cell division (ACD) have been found to influence HSC self-renewal in normal hematopoiesis and various leukemias. From a separate survey of genes associated with ACD, I now present the results from dedicated functional studies on two genes – Arhgef2 and Staufen1 – in HSCs and identify their potential contributions to benign hematopoietic disorders. Specifically, I present evidence that demonstrates a conserved role of Arhgef2 in orienting HSC division, the loss of which leads to HSC exhaustion that may underlie and contribute to the pathogenesis of Shwachman-Diamond syndrome. I also identify Staufen1 as a critical RNA-binding protein (RBP) in HSC function, downregulation of which elicits expression signatures consistent with clinical anemias reminiscent of aplastic anemia and/or paroxysmal nocturnal hemoglobinuria. I end by reviewing how RBPs function in HSCs and discuss future research directions that could further elucidate how bone marrow failure syndromes arise at the stem cell level. / Thesis / Doctor of Philosophy (PhD)

Purpose: The purpose of this study was to evaluate the effectiveness of triaging patients with motion-provoked dizziness into a benign paroxysmal positional vertigo (BPPV) clinic. Method: A retrospective chart review was performed of veterans who were tested and treated for BPPV in a triaged BPPV clinic and veterans who were tested and treated for BPPV in a traditional vestibular clinic. Results: The BPPV triage clinic had a hit rate of 39%. On average, the triaged BPPV clinic reduced patient wait times by 23 days relative to the wait times for the traditional vestibular clinic while also reducing patient costs. Conclusion: Triaging patients with BPPV is one method to improve access to evaluation and treatment and a mechanism for the effective use of clinic time and resources.

Vorhofflimmern ist die häufigste behandlungsbedürftige Herzrhythmusstörung. Die Erhöhung des Schlaganfallrisikos, die Einschränkung der Herzleistung und nicht zuletzt ein Verlust an Lebensqualität sind bedeutsame Folgen dieser Erkrankung. Bisherige pharmakologische Therapieansätze sind insbesondere beim paroxysmalem Vorhofflimmern nur von unzureichender Wirkung, so dass in letzter Zeit nicht-pharmakologische Therapieoptionen untersucht werden. Elektrophysiologische und klinische Untersuchungen legen nahe, dass bifokale rechtsatriale Schrittmacherstimulation die Rezidivhäufigkeit von paroxysmalem Vorhofflimmern senken kann. In der DUSTI-Studie (DUal-site STImulation for prevention of paroxysmal atrial fibrillation) wurde untersucht, ob bifokale atriale Überstimulation die Rezidivhäufigkeit gegenüber unifokaler Überstimulation und lediglich antibradykarder Stimulation senken kann. Hierzu wurden 19 Patienten (61 ± 12 Jahre, 13 männlich) mit paroxysmalem Vorhofflimmern und einer Indikation zur Schrittmacherimplantation in eine prospektive, einfach-blinde, randomisierte Cross-over-Studie eingeschlossen. Ein herkömmlicher Zwei-Kammer-Schrittmacher, eine ventrikuläre Sonde und zwei über einen Y-Konnektor verbundene rechtsatriale Sonden, eine septal, die andere lateral wurden implantiert. Alle Patienten wurden zunächst 12 Wochen durch Programmierung einer Interventionsfrequenz von 50/min möglichst wenig atrial stimuliert. Danach wurden alle Patienten möglichst immer atrial stimuliert (Überstimulation mit 10/min über der Eigenfrequenz), in zufälliger Reihenfolge 12 Wochen bifokal (septal und lateral) und 12 Wochen unifokal (septal oder lateral). Unter bifokaler Stimulation war die Vorhofflimmerlast ebenso groß wie unter unifokaler Stimulation (6,20% ± 9,91% vs. 6,15% ± 11,09%, Intention-to-treat-Analyse) In den Überstimulationsphasen zeigte sich ein Trend zur Abnahme der Vorhofflimmerlast gegenüber der Phase mit geringen atrialen Stimulationsraten (6,15% ± 10,32% vs. 8,84% ± 11,34%, p=0,09, Intention-to-treat-Analyse). Hinsichtlich der Anzahl der Vorhofflimmerepisoden, der Zeit bis zum Vorhofflimmerrezidiv und der Symptomatik fanden sich signifikante Unterschiede weder zwischen uni- und bifokaler Stimulation, noch zwischen Überstimulation und geringer atrialer Stimulation. Die verwendeten Methoden waren gut durchführbar und sicher. Die schrittmacherbasierte Vorhofflimmerdiagnostik erwies sich, vor allem durch die zusätzliche atriale Elektrode, als technisch kompliziert und teilweise fehlerbehaftet. In einem nicht selektierten Patientenkollektiv ist die bifokale rechtsatriale Schrittmacherstimulation zur Rezidivprophylaxe des paroxysmalen Vorhofflimmerns nicht besser geeignet als unifokale Stimulation. Der höhere Aufwand der Implantation einer zweiten atrialen Sonde scheint nicht gerechtfertigt. Andere Studien müssen zeigen, ob bestimmte Patienten-Subgruppen von der bifokalen rechtsatrialen Stimulation profitieren / Atrial fibrillation is the most common sustained cardiac arrhythmia. It substantially increases the risk of stroke, impairs cardiac output and may lower the quality of life. Because pharmacotherapeutic approaches often yield unsatisfactory results - especially with paroxysmal atrial fibrillation, various non-pharmacological therapies have been studied. Electrophysiological and clinical research suggests, that dual-site atrial stimulation may suppress paroxysms of atrial fibrillation. The DUSTI trial was designed to test the hypothesis that dual-site stimulation prevents atrial fibrillation better than single-site stimulation or support pacing. Nineteen patients (61 ± 12 years, 13 male) with paroxysmal atrial fibrillation and a standard indication for pacemaker implantation were included in a prospective, single-blinded, randomized cross-over-trial. A conventional dual-chamber pacemaker with one ventricular and two atrial leads was implanted. Atrial leads were placed at the atrial septum and at the right atrial wall, and connected via a Y-connector to the atrial port. For the first twelve weeks patients only received support pacing (at 50 bpm). Afterwards patients received continuous atrial pacing (at 10 bpm above the intrinsic heart rate), 12 weeks dual-site pacing (septal and lateral) and 12 weeks single-site pacing (septal or lateral) in random order. Atrial fibrillation burden was the same between dual-site pacing and single-site pacing (6.20% ± 9.91% vs. 6.15% ± 11.09%, intention-to-treat-analysis). A trend towards less atrial fibrillation with continuous pacing compared to support pacing was observed (6.15% ± 10.32% vs. 8.84% ± 11.34%, p=0.09, intention-to-treat-analysis). There was no significant difference in number of atrial fibrillation episodes, time to recurrence and symptoms, neither between dual- and single-site pacing, nor between continuous and support pacing. Dual-site pacing proved to be feasible and safe. The detection of atrial fibrillation by the pacemaker''s diagnostic algorithms was, however, troubled by the additional atrial lead. Dual-site pacing offers no further advantage to single-site pacing for prevention of atrial fibrillation recurrences in unselected patients. The implantation of an additional atrial lead in patients with paroxysmal atrial fibrillation, requiring a pacemaker, seems to be not justified. Future trials will investigate whether certain subgroups of patients will benefit from dual-site atrial pacing.