Journal articles on the topic 'Synode <589>'

Background and Objectives: Vasovagal syncope (VVS) is the most common cause of syncope and has multiple pathophysiological mechanisms. Asymmetric dimethylarginine (ADMA) is the major inhibitor of nitric oxide (NO). In this study, we aimed to investigate the relationship between plasma ADMA levels and syncope during the head-up tilt (HUT) test. Materials and Methods: Overall, 97 patients were included in this study. They were above 18 years of age and were admitted to our clinic with the complaint of at least one episode of syncope consistent with VVS. The HUT test was performed in all patients. Patients were divided into the following two groups based on the HUT test results: group 1 included 57 patients with a positive HUT test and group 2 included 35 patients with a negative HUT test. Blood samples were taken before and immediately after the HUT test to measure ADMA levels. Results: No significant intergroup differences were observed concerning gender and age (female gender 68% vs 60%; mean age 24.85 ± 4.01 vs 25.62 ± 3.54 years, respectively, for groups 1 and 2). ADMA values were similar between groups 1 and 2 before the HUT test [ADMA of 958 (544–1418) vs 951 (519–1269); p = 0.794]. In the negative HUT group, no significant differences were observed in ADMA levels before and after the HUT test [ADMA of 951 (519–1269) vs 951 (519–1566); p = 0.764]. However, in the positive HUT group, ADMA levels were significantly decreased following the HUT test [pretest ADMA of 958 (544–1418) vs post-test ADMA of 115 (67–198); p < 0.001]. Conclusion: ADMA levels significantly decreased after the HUT test in patients with VVS.

Introduction. Vasovagal syncope is the most common type of reflex syncope. Efficacy of cardiac pacing in this indication has not been the subject of many studies and pacemaker therapy in patients with vasovagal syncope is still controversial. Objective. This study aimed to assess the efficacy and safety of pacing therapy in treatment of patients with vasovagal syncope, to determine contribution of new therapeutic models in increasing its success, and to identify risk factors associated with a higher rate of symptoms after pacemaker implantation. Methods. A retrospective study included 30 patients with pacemaker implanted due to vasovagal syncope in the Pacemaker Center, Clinical Center of Serbia, between November 2003 and June 2014. Head-up tilt test was performed to diagnose vasovagal syncope. Patients with cardioinhibitory and mixed type of disease were enrolled in the study. Results. Mean age was 48.1 ? 11.1 years and 18 (60%) patients were men. Mean follow-up period was 5.9 ? 3.0 years. Primarily, implantable loop recorder was implanted in 10 (33.3%) patients. Twenty (66.7%) patients presented cardioinhibitory and 10 (33.3%) mixed type of vasovagal syncope. After pacemaker implantation, 11 (36.7%) patients had syncope. In multiple logistic regression analysis we showed that syncope is statistically more likely to occur after pacemaker implantation in patients with mixed type of vasovagal syncope (p = 0.018). There were two (6.7%) perioperative surgical complications. Conclusion. Pacemaker therapy is a safe treatment for patients with vasovagal syncope, whose efficacy can be improved by strict selection of patients. We showed that symptoms occur statistically more often in patients with mixed type of disease after pacemaker implantation.

In the final years of the sixth century, the Gothic chieftain, Reccared, wrote a letter to Pope Gregory the Great - a letter that offers a unique insight into that generation of Visigoths who abandoned their native tongue, embraced Catholicism, and established the kingdom of Spain. The letter demonstrates that Reccared was reasonably fluent in Latin, although commentators have, for some centuries now, felt compelled to point out just how many mistakes the warlord made and how egregious these mistakes were. These errors are particularly troubling given that, at the Third Synod of Toledo conducted in 589, Reccared had purportedly addressed the assembly in perfect, even slightly archaised, Latin. This article compares Reccared's letter with a selection of other early Germanic literature, especially those elements of the corpus that seek to translate Greek or Latin predecessors, in order to contextualise his errors and to offer some opinions as to why those mistakes might have been made.

Introduction: A recent cross-sectional study reported a 17.3% prevalence of pulmonary embolism (PE) among patients with syncope. However, the study had several flaws including spectrum and work-up bias with over-diagnosis due to excessive investigations. We sought to evaluate the prevalence of PE among Canadian emergency department (ED) patients presenting with syncope. Methods: We enrolled adults with syncope at 5 EDs and collected demographics, proportion of patients evaluated for suspected PE, their Wells PE score values and results of investigations [d-dimer, computed angiography (CT) of chest or ventilation-perfusion (VQ) scan]. 30-day adjudicated outcome included diagnosis of PE requiring treatment. We used descriptive statistics to report the results. Results: 4,739 patients [mean age 54.3 years, 54.4% females, and 587 (12.4%) hospitalized] were enrolled. 323 patients (6.8%) had further evaluation and investigations performed for suspected PE: 255 patients had D-dimer performed, 140 had CT chest and 17 had VQ performed. Of the 323 patients, 300 patients were low risk (Wells score ≤4) and 23 were high-risk (score &gt;4). A total of 16 patients (0.3%) in the study cohort were diagnosed with PE: 10 patients were diagnosed in the ED, 5 patients were diagnosed while hospitalized as inpatient, and 1 patient was diagnosed on a return ED visit. Overall the prevalence of PE was 0.3% among all ED patients with syncope; and a 0.9% among those hospitalized for syncope. Conclusion: Our study shows that the prevalence of PE is very low among all patients presenting to the ED with syncope. The prevalence is also very low among those hospitalized for syncope than previously reported. While PE should be suspected and further investigations performed among syncope patients if clinically appropriate, caution should also be taken against indiscriminate over-investigations for PE.

1. The aim of this study was to determine if there is impaired reflex venoconstriction in patients with hypertrophic cardiomyopathy and whether this is related to a history of syncope or exercise hypotension. 2. Thirty percent of patients with hypertrophic cardiomyopathy have exercise-induced hypotension associated with a failure of arteriolar constriction. Impaired venoconstriction could exacerbate this situation. 3. We evaluated 43 patients with hypertrophic cardiomyopathy and 24 controls. Nuclear venous plethysmography was used to measure forearm venous capacitance during lower body negative pressure, splenic venous volume changes during bicycle exercise and blood pressure responses to treadmill exercise. We assessed any association between abnormal reflex venous control and a history of syncope and exercise hypotension. 4. The percentage reduction in unstressed forearm venous volume during lower body negative pressure was similar in patients and controls (8.9 ± 7.1% versus 9.7 ± 5.9%, P not significant). Patients with a history of syncope demonstrated a less marked percentage reduction in volume than those without (−2.1 ± 6.9% versus −10.6 ± 6.0%, P = 0.001). In three patients with a history of syncope there was a paradoxical increase in forearm venous volume during lower body negative pressure. During exercise there was a substantially smaller decrease in splenic venous volume in patients compared with controls (−20.1 ± 14.0% and −42.6 ± 12.6% respectively, P = 0.0001). Furthermore, there was an association between attenuated splenic venoconstriction or venodilation and exercise hypotension in patients (P = 0.005). 5. Abnormal reflex control of venous capacitance beds in patients with hypertrophic cardiomyopathy was associated with both syncope and exercise hypotension.

Objective: The aim of the present study was to evaluate the time to syncope in Nitroglycerine potentiated short Head-up tilt test.Study Design, Settings & Duration: This was a descriptive cross sectional study conducted in Armed Forces Institute of cardiology from May2006 to May, 2007. Patients and methods: A total number of 90 patients with orthostatic intolerance both male and female were studied.Head-up tilt test protocol consisted of a Stabilization phase which lasted for five minutes Passive tilt phase: Patients were tilted at 70̊ fororthostatic stress for 15 minutes. In case of no symptoms the test continued with the drug provocation phase which lasted for 15 minutes. Thepatients were administered 400μg of nitroglycerine sublingually in aerosol preparation. Development of symptoms were noted at 5, 10 and 15minutes. Results: A total number of 90 patients were examined during the study period. The tilt table test was classified as positive in 58.9 % ofpatients and was negative in 41.1%. The test was positive in five patients without the drug provocation (9.4%). The responses were classifiedas positive vasodepressor in 35.8%, 15.09% as mixed and cardioinhibitory 15.09% in patients of neurally mediated syncope. The total time todisplay of symptoms to positivity in HUTT was 17.89± 6.99. The mean time to syncope after the administration of nitroglycerine was 5.61± 4.17minutes. Conclusions: Our study concludes that the drug administered phase can be reduced to 12±3 minutes.

Introduction: Syncope accounts for 1% of all annual emergency department (ED) visits in Canada with only 10.3% suffering serious adverse event (SAE) within 30-days. However, 66% are transported to ED by Emergency Medical Services (EMS). Our objectives were to assess 30 day SAE among syncope patients transported by Emergency medical services (EMS), assess the need to develop an EMS clinical decision aid, and estimate anticipated health care savings by diverting patients from the ED to alternative care pathways. Methods: We conducted a prospective cohort study at four tertiary care EDs from Feb 2012 to Feb 2013. We included patients ≥16 years of age with syncope and who arrived to the ED via EMS. We collected patient demographics, medical history, 30 day SAE, EMS time points (call received, EMS arrival on scene, EMS departure from scene, time of transfer of care in the ED), critical EMS interventions, and ED length of stay. We assessed for the occurrence of any SAE (death, arrhythmia, other cardiac and non-cardiac conditions) within 30 days of ED disposition. We used descriptive analysis, unpaired two-tailed t-test and chi-square test. Ethics approval was obtained at all study sites. Results: Of 1,475 ED patients with syncope during the study period, 992 (67.3%) arrived by EMS. Mean times (SD) for EMS arrival to the scene, patient assessment at the scene and transfer of patient from scene to the ED were 10.1 (6.4), 18.9 (8.3), and 14.6 (11.5) minutes respectively. Only two patients had critical interventions enroute (pacing and defibrillation). Overall 138 (13.9%) patients suffered a SAE; 32 (3.2%) detected by EMS, 58 (5.8%) detected during ED evaluation, 48 (4.8%) after ED disposition. The average ED length of stay was 5.9(4.2) hours. Based on average of cost from two sites, we estimated that total cost of transporting syncope patients from the scene to the ED to be $4 million in Canada. The total cost of ED care for syncope patients transported by EMS in Canada was calculated at $21.5 million. Conclusion: A substantial proportion of patients arriving to the ED via EMS suffer no SAE within 30 days. Correspondingly, our results suggest a need for an EMS clinical decision aid to divert low-risk syncope patients to alternative care pathways such as family physicians or rapid access clinics. If developed and implemented, this tool can potentially reduce EMS burden, ED crowding, and reduce healthcare costs.

Introduction: The majority of syncope patients transported to the emergency department (ED) by emergency medical services (EMS) are low-risk with very few suffering serious adverse events (SAE) within 30-days and over 50% are diagnosed with vasovagal syncope. These patients can potentially be diverted by EMS to alternate pathways of care (primary care or syncope clinic) if appropriately identified. We sought to identify high-risk factors associated with SAE within 30-days of ED disposition as a step towards developing an EMS clinical decision tool. Methods: We prospectively enrolled adult syncope patients who were transported to 5 academic EDs by EMS. We collected standardized variables at EMS presentation from history, clinical examination and investigations including ECG and ED disposition. We also collected concerning symptoms identified and EMS interventions. Adjudicated SAE included death, myocardial infarction, arrhythmia, structural heart disease, pulmonary embolism, hemorrhage and procedural interventions. Multivariable logistic regression was used for analysis. Results: 990 adult syncope patients (mean age 58.9 years, 54.9% females and 16.8% hospitalized) were enrolled with 137 (14.6%) patients suffering SAE within 30-days of ED disposition. Of 42 candidate predictors, we identified 5 predictors that were significantly associated with SAE on multivariable analysis: ECG abnormalities [OR=1.77; 95%CI 1.36-2.48] (non-sinus rhythm, high degree atrioventricular block, left bundle branch block, ST-T wave changes or Q waves), cardiac history [OR=2.87; 95%CI 1.86-4.41] (valvular or coronary heart disease, cardiomyopathy, congestive heart failure, arrhythmias or device insertions), EMS interventions or concerning symptoms [OR=4.88; 95%CI 3.13- 7.62], age &gt;50 years [OR=3.18; 95%CI 1.68-6.02], any abnormal vital signs [OR=1.58; 95%CI 1.03-2.42] (any EMS systolic blood pressure &gt;180 or &lt;100 mmHg, heart rate &lt;50 or &gt;100/minute, respiratory rate &gt;25/minute, oxygen saturation &lt;91%). [C-statistic: 0.81; Hosmer Lemeshow p=0.30]. Conclusion: We identified high-risk factors that are associated with 30-day SAE among syncope patients transported to the ED by EMS. This will aid in the development of a clinical decision tool to identify low-risk patients for diversion to alternate pathways of care.

The article attempts to analyze the regulation of situations in which, for the commission of the sacrament of baptism and other church demands, persons of Orthodox confession were forced to turn to the priests of the Armenian Apostolic Church, and persons of the Armenian confession to the Orthodox priests. However, it was not a question of a change in religion. It was established that such situations occurred due to forced circumstances and often entailed negative consequences of state-legal, church-canonical and domestic nature. For example, the fact that an Armenian priest baptized a child born to Orthodox spouses was regarded as "seduction from Orthodoxy", even if it was caused by a dangerous disease of a newborn. The baptism of an Armenian child in the Orthodox rank led to intra-family religious strife: the child was now considered a member of the Orthodox Church, while his parents continued to belong to the Armenian Church. It is concluded that, firstly, the entry of Eastern Armenia and the Armenian Apostolic Church into Russia played a significant role in the emergence of church-practical situations and the need for their regulation by Russian law and the governing bodies of both Churches. Secondly, the decree of the Echmiadzin Synod of 1854 granted the Armenian priests the right to perform all church sacraments in respect of children baptized in their infancy in the Orthodox rite, provided that the parents, being of Armenian religion, did not give a written obligation to raise their children in the Orthodox religion. Thirdly, the patronizing policy of the empire regarding Orthodoxy and the dominant position of the Russian Church led to a complication of relations between the Orthodox clergy and the clergy of the Armenian Church. In cases where representatives of both Churches had equal initial rights to perform public church actions (for example, the rite of blessing of water on the feast of the Epiphany within the same city), primacy, and in some cases (as, for example, in 1858 in Astrakhan) exclusive right granted to the Russian Church.

Optimal sized balloon atrial septostomy improves hemodynamics in advanced pulmonary arterial hypertension. Occlutech Atrial Flow Regulator is designed to provide an atrial septal fenestration diameter titrated according to the age and right atrial pressures. This observational study analyzed symptoms, exercise distance, oxygen saturations, hemodynamics and echocardiographic parameters after Atrial Flow Regulator implantation in patients with syncope or right-heart failure. Patients with high-risk predictors of mortality during septostomy were scrutinized. Thirty-nine patients (9 children) with syncope (34/39) or right-heart failure (27/39) underwent Atrial Flow Regulator implantation without procedural complications. Six-minute walk distance increased from 310 ± 158.2 to 376.4 ± 182.6 m, none developed syncope. Oxygen saturations reduced from 96.4 ± 6.4% to 92 ± 4.9% at rest and further to 80.3 ± 5.9% on exercise. Right atrial pressures reduced from 9.4 ± 5 (2–27) mmHg to 6.9 ± 2.6 (1–12) mmHg, while cardiac index increased from 2.4 ± 0.8 (0.98–4.3) to 3 ± 1 (1.1–5.3) L/min/m2 and systemic oxygen transport increased from 546.1 ± 157.9 (256.2–910.5) to 637.2 ± 191.1 (301.3–1020.2) ml/min. Echocardiographic improvement included significant reduction of pericardial effusion and inferior caval congestion at a median follow-up of 37 months. Overall survival improved except two early and one late deaths in high-risk patients. Five of seven patients with advanced disease and key hemodynamic predictors of mortality survived. Acute hemodynamic benefits in pulmonary arterial hypertension after Atrial Flow Regulator were improved cardiac output, systemic oxygen transport, and reduced right atrial pressures. Improvement of symptoms especially syncope, exercise duration, and right ventricular systolic function as well as device patency were sustained on mid-term follow-up. Implantation was safe in all including young children without procedural complications. Mortality was noted only in patients who had high-risk predictors and patients at advanced stage of the disease.

Introduction: Emergency department (ED) syncope management is extremely variable. We developed practice recommendations based on the validated Canadian Syncope Risk Score (CSRS) and outpatient cardiac monitoring strategy with physician input. Methods: We used a 2-step approach. Step-1: We pooled data from the derivation and validation prospective cohort studies (with adequate sample size) conducted at 11 Canadian sites (Sep 2010 to Apr 2018). Adults with syncope were enrolled excluding those with serious outcome identified during index ED evaluation. 30-day adjudicated serious outcomes were arrhythmic (arrhythmias, unknown cause of death) and non-arrhythmic (MI, structural heart disease, pulmonary embolism, hemorrhage)]. We compared the serious outcome proportion among risk categories using Cochran-Armitage test. Step-2: We conducted semi-structured interviews using observed risk to develop and refine the recommendations. We used purposive sampling of physicians involved in syncope care at 8 sites from Jun-Dec 2019 until theme saturation was reached. Two independent raters coded interviews using an inductive approach to identify themes; discrepancies were resolved by consensus. Results: Of the 8176 patients (mean age 54, 55% female), 293 (3.6%; 95%CI 3.2-4.0%) experienced 30-day serious outcomes; 0.4% deaths, 2.5% arrhythmic, 1.1% non-arrhythmic outcomes. The serious outcome proportion significantly increased from low to high-risk categories (p < 0.001; overall 0.6% to 27.7%; arrhythmic 0.2% to 17.3%; non-arrhythmic 0.4% to 5.9% respectively). C-statistic was 0.88 (95%CI0.86–0.90). Non-arrhythmia risk per day for the first 2 days was 0.5% for medium-risk, 2% for high-risk and very low thereafter. We recruited 31 physicians (14 ED, 7 cardiologists, 10 hospitalists/internists). 80% of physicians agreed that low risk patients can be discharged without specific follow-up with inconsistencies around length of ED observation. For cardiac monitoring of medium and high-risk, 64% indicated that they don't have access; 56% currently admit high-risk patients and an additional 20% agreed to this recommendation. A deeper exploration led to following refinement: discharge without specific follow-up for low-risk, a shared decision approach for medium-risk and short course of hospitalization for high-risk patients. Conclusion: The recommendations were developed (with online calculator) based on in-depth feedback from key stakeholders to improve uptake during implementation.

OBJECTIVE: To report a syncopal episode associated with fluoxetine in a young, relatively healthy man. DESIGN: Single case report. SETTING: 585-bed private hospital. PATIENT: A 30-year-old man with hypertension, esophageal ulcers, and syncope of recent onset. RESULTS: Fluoxetine was started six weeks prior to the syncopal episode in this patient, and is the medication most temporally associated with the event. Because the patient had a normal neurologic examination and electroencephalogram, but an abnormal electrocardiogram on admission and one month after discharge, the syncopal episode was most likely caused by cardiovascular effects of fluoxetine. CONCLUSIONS: Fluoxetine has been reported to cause cardiac conduction abnormalities in otherwise normal individuals. Bradycardia secondary to a direct effect of fluoxetine, or to a drug interaction among fluoxetine, ranitidine, and enalapril is the most likely explanation for this patient's syncopal episode.

Hepatic Angiosarcoma is a rare malignancy of endothelial cell origin that is generally idiopathic and presents non-specific clinical manifestations. Hemoperitoneum can occur in 17-27% of cases and is a result of tumor rupture, which has a devastating prognosis. We present a 79-year-old female patient with history of diffuse right upper quadrant abdominal pain associated with syncope episodes and unintentional weight loss. Physical examination was unremarkable except for painful palpation of the right upper quadrant. Laboratory exams indicated chronic disease anemia, a 2.7 INR, decreased albumin, increased C-Reactive Protein and GGT, and normal AST, ALT, Alkaline Phosphatase and Bilirubin. Viral hepatitis serologies were negative. Abdominal ultrasonography revealed hepatomegaly and solid liver lesions of heterogeneous echogenicity and imprecise limits. Three-phase abdominal CT showed multiple liver masses of heterogeneous pattern of enhancement suggestive of atypical hemangioma associated with ascites. Chest CT revealed bilateral pulmonary nodules suggestive of metastasis. During hospital stay, the patient developed a massive hemoperitoneum that required emergency laparotomy. In this circumstance, liver and omentum biopsies were performed and the pathology reports ultimately indicated the possibility of hepatic angiosarcoma. The patient developed refractory hemoperitoneum and hemorrhagic shock and ultimately passed away, 48 days after hospital admission. Definitive diagnosis was only available posteriorly, with immunohistochemistry positivity for ERG, CD34 and Factor VIII-related antigen on both omentum and lung samples. This case study provides valuable clinical discussion and emphasizes how a transdisciplinary approach is essential to correctly diagnose and manage such complex cases.

A most important indicator of population health, its social and economic wellbeing is premature disability. 10.3 mln people had to retire from their jobs due to disability during the ten-year period from 2005 to 2014. The number of elderly subjects among them was twice that of the younger ones, with the leading cause of disability being blood circulation disorders (61,9%). At the same time, the fraction of old subjects in the group of invalids suffering from coronary heart disease and idiopathic hypertension accounted for only 58,9% and 40,9% respectively. The quantitative evaluation of persistent dysfunction of the cardiovascular system related to circulatory disturbances included in ICD class IX and to those referred to other classes is based mainly on an assessment of the following clinical andfunctional manifestations: pain syndrome (cardialgia or angina); hypertensive syndrome; pulmonary hypertension; arrhythmia; syncope. Other aspects of pathological process are taken into consideration, such as its form and severity, presence andfrequency of exacerbations, magnitude, involvement of target organs, complications. The gerontological slant of disabling cardiovascular pathology accounts for its social significance (idiopathic hypertension, coronary heart disease, chronic heart failure) which requires the adequate solution of the problem of healthcare provisions taking account of the current demographic situation and increased life expectancy within the older population suffering from a number of chronic diseases.

In modern practices of Russian Orthodoxy, the feast of the Virgin Mary Dormition is so­lemnized with great splendor. During these celebrations in large and small religious centers, a liturgical image, in the Russian Orthodox Church called “The Theotokos Holy Shroud”, becomes the central temple image. This article, for the first time, makes an attempt to track down a continuity in the Dormition Shroud images creation — from royal craftwork rooms of medieval Russia to modern workshops. Learning on previous masterpieces, present-day apprentices contribute to preservation and deve­lopment of the unique traditions of national culture. The article introduces into scientific circulation a number of rare artifacts that become a subject of research for the first time. The study provides facts refuting the nowadays-widespread opinions that, in the alleged absence of material evidence (preserved monuments) of an earlier time, the period in which these images originated dates back to the late 19th century. This determines the relevance of the study. The author comes to the conclusion that, however brief and undescriptive the data recorded in documentary sources are, they make it clear that these relics already existed in the late Middle Ages, though questions of authorship and artistic value of the works still remain to be answered. This analysis becomes possible through studying the Synodal era images discovered in vestiaries of churches in the Moscow region, as well as those reported in some historical descriptions. Modern masters recreate works of high artistic le­vel, applying a combination of the ancient heritage and the modern variety of materials and innovative technologies. The data presented in the article contribute to further studying of the issues embra­cing emergence and spread of the liturgical images of the Theotokos Shroud in the practices of Russian Orthodoxy. It is also important to trace back the historical background of those selected artifacts first mentioned in this paper.

AbstractIntroduction:Postural tachycardia syndrome is more frequently being recognised in adolescents and adults. However, its pathophysiology remains undefined. We evaluated our database for patterns in family history of clinical symptoms and associated disorders in these patients.Materials and methods:Patients with postural tachycardia syndrome diagnosed in our clinic between 2014 and 2018 and who were less than 19 years at diagnosis were included. The history was reviewed for family members with postural tachycardia syndrome, dizziness and/or syncope, joint hypermobility with or without hypermobile Ehlers–Danlos syndrome, and autoimmune disorders. Statistical analysis assessed the entire cohort plus differences in gender, presence or absence of joint hypermobility, and presence or absence of familial autoimmune disease.Results:A total of 579 patients met inclusion criteria. We found that 14.2% of patients had a family member with postural tachycardia syndrome, with male patients more likely to have an affected family member (20% versus 12.7%, p = 0.04). If the patient also had joint hypermobility, male patients were more likely to have a family member with postural tachycardia syndrome (25% versus 12.6%, p = 0.017), more than one affected family member (7.1% versus 0.74%, p = 0.001), and a family member with joint hypermobility (37.5% versus 23.7%, p = 0.032). Autoimmune disease was seen in 45.1% of family members, but more likely in female patients with concurrent hypermobility (21.1% versus 8.9%, p = 0.035).Discussion:This in-depth analysis of associated familial disorders in patients with postural tachycardia syndrome offers further insight into the pathophysiology of the disorder, and informs further screening of family members in these patients.

Abstract Background: Insulin autoimmune syndrome (IAS), also called Hirata syndrome, is a rare diagnosis which is characterized by hypoglycemia, normal or elevated fasting insulin level, and elevated anti-insulin antibody titers. Clinical Case: 45-year-old nondiabetic Caucasian female presented to the emergency department (ED) with chief complaint of near-syncope. She reported difficulty concentrating and feeling faint roughly 1 hour after consuming breakfast. Upon ED arrival, fingerstick glucose (FSG) was 47 mg/dL. Her symptoms resolved with ingestion of orange juice and repeat blood glucose (BG) 15 minutes later was 120 mg/dL. She reported similar symptoms in the last 5 years happening “every few months” without a predictable pattern; twice with witnessed loss of consciousness. Workup for syncope in the past included normal neurologic, cardiac, and tilt-table testing. She had no prior low FSG/BG recorded, no personal history of bariatric surgery or family history of diabetes mellitus and no access to antihyperglycemic medications. Past medical history included ulcerative colitis and medications included sulfasalazine and multivitamins. Pertinent review of systems was negative for weight loss, nausea, and diarrhea. Vital signs were within normal limits. Physical exam was unremarkable. Height was 165 cm, weight 67.8 kg and body mass index 24.9 kg/m2. Blood draw after overnight fast revealed BG of 78 mg/dL, C-peptide 0.7 ng/mL (ref range 0.8–3.5), insulin 10 µIU/mL (3–19), proinsulin &lt;1.6 pmol/L (&lt;8.0), insulin-like growth factor-2 (IGF-2) 339 ng/mL (180–580) and insulin antibody level 10.0 U/mL (0.0–0.4). She was managed conservatively with frequent small meals and patient has continued to do well without recurrence of symptoms. Conclusion: IAS is an exceedingly rare disease entity with about 460 cases described in literature, mostly in patients of Asian descent. Workup for hypoglycemia in non-diabetic patients should include insulin antibody titers to rule out IAS. There appears to be a genetic predisposition to developing IAS in patients with major histocompatibility complex (MHC) genes HLA-DQA1, HLA-DQB1 and HLA-DRB1. It is now being more frequently described in patients of non-Asian descent, particularly those with other autoimmune or plasma cell dyscrasias. It is also associated with drugs containing sulfhydryl groups and viral infections. Treatment should be tailored to severity of disease. Most drug induced IAS resolves after cessation of culprit drug. Conservative management is usually the first step with frequent, low carbohydrate meals with diazoxide or octreotide as adjunctive options. Immunosuppression (high-dose prednisolone or rituximab) and plasma exchanged are reserved severe or refractory cases.

Objectives: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart-muscle disease, characterized by fibro-fatty replacement and ventricular arrhythmias, that primarily affects the right ventricle (RV). We aimed to look at the clinical presentation, cardiac magnetic resonance (CMR) imaging findings and prognosis of patients with ARVC in Pakistan. Material and Methods: It is a retrospective observational study, 17 consecutive patients with CMR and other findings consistent with ARVC, were enrolled from 2010 to 2019 at a single center. Results: Out of 17 patients, 12 (70.6%) were male with a mean age of 33.5 ± 17.5 years. Family history of sudden cardiac death was present in 3 (17.7%) patients while one (5.9%) patient had family history of ARVC. Syncope was the first presenting symptom in eight (47.1%) patients. On 12 leads ECG, T wave inversion in precordial leads was found in 6 (35.4%) patients, and epsilon wave was present in only 3 (17.7%) patients. On echocardiogram, 13 (76.5%) patients had dilated RV with reduced systolic function. On CMR, majority of patients (n = 14, 82.4%) were found to have RV dilatation with regional dyskinesia and fatty infiltration, 9 (52.9%) of them had left ventricular involvement also. Follow-up was available for 14 patients (82.4%) with a mean follow-up period of 35.5 ± 19.7 months. Three (21.4%) of them died and 10 (71.4%) got admissions for heart failure during follow-up period. Conclusion: Arrhythmia related events are the main presenting symptoms of ARVC in this region, and left ventricular involvement in ARVC is not rare in this population. The mortality is relatively high, probably due to advanced disease at the time of presentation and less medical facilities available.

Aim. To analyze hospitalizations due to drug-induced bradyarrhythmia (DIB) over a 5-year period (2014-2018), its clinical characteristics, causes and outcomes.Material and methods. The analysis included all hospitalizations due to DIB at the Ryazan Regional Vascular Center in 2017 and 2018 and retrospectively in 2014.Results. A total of 325 cases of DIB were included in the analysis (age 76,0 [68.0; 82.0] years; men — 26,1%). The proportion of DIB as a hospitalization cause in 2017 increased by 4,3 times compared to 2014 (p<0,001), in 2018 compared to 2014 — by 6,3 times (p<0,001) and compared to 2017 — by 46,2% (p=0,001). We recorded the following manifestations of DIB: bradycardia (<40 bpm — 51,4%), atrioventricular (31,7%) and sinoatrial (29,2%) block, syncope (36,0%), Frederick’s syndrome (8,6%), pauses >3 s (5,9%). Management in intensive care was required in 42,2% of patients, temporary cardiac pacing — in 7,7%, permanent pacemaker — in 6,2%. Mortality rate was 6,2%. Before hospitalization, patients took beta-blockers (65,1%), antiarrhythmic agents (39,6%), cardiac glycosides (23,0%), ^-imidazoline receptor agonist moxonidine (13,5%, its prescription rate increased 8,9 times over 5 years, p=0,004), nondihydropyridine calcium channel blockers (7,9%), and other drugs (15,4%). In 60,1% of patients, ≥2 drugs with bradycardic action were used, in 22,0% — ≥3, in 8,1% — ≥4, in 10,6% — with an excessive single/daily dose.Conclusion. The medical and social significance of DIB have been demonstrated. DIB due to exceeding the recommended dose was associated with independent try of patients to manage the deterioration. In other cases, DIB was due to the summation/ potentiation of several drugs’ action, the comorbidities contributing to the development of bradyarrhythmia and/or changes in pharmacokinetic properties of drugs.

Abstract. A sporadic phenomenon of internal tide resonance (ITR) in the western equatorial Pacific thermocline is shown to precede 11 of 12 major upturns in the Niño 3.4 index between 1992 and 2008. Observed ITR has up to 9 °C semidiurnal temperature excursions indicating thermocline heave, but is invisible in time resolution longer than one day. It is independent of westerly wind bursts (WWB). A hypothesis is advanced that (1) ITR dissipates vorticity, leading to Pacific countercurrent consolidation (PCC) by reducing the vortex stretching term in Sverdrup balance. The consequence of lost vorticity survives ephemeral ITR events; (2) The specific surface area of countercurrents is reduced by PCC, which reduces frictional opposition to zonal gradient pressure, which triggers eastward advection at El Niño onset; (3) PCC also accelerates transfer of potential energy to the "pycnostad" below the Equatorial Undercurrent. This shoals the equatorial thermocline, leading to a distinct mode of equatorially symmetric La Niña (ESLN) characterized by a winter monsoon cell above a "cold eye" that is separated from the South American continent, as in 1998; (4) Precessional southward intertropical convergence zone migration (ITCZ) is an alternate PCC trigger, but its effect is modulated by obliquity; and (5) ESLN causes global cooling in all timescales by (a) reduced Hadley cell water vapor production when its rising branch is above the cold eye, (b) equatorward shift in southern circumpolar westerlies due to Hadley cell constriction, (c) possible CO2 sequestration by increased EUC iron fertilized export production on the equator, and (d) possible adjacent cloud seeding by biogenic dimethyl sulphide. Surprising coincidences of WWB with perigean eclipses suggest a parallel atmospheric tide influence. Proposed PCC-ESLN forcing operates in multiple timescales, beginning where the annual cycle of strong equinoctial tides coincides with the minimum perigee cycle. This forcing corresponds with El Niño Southern Oscillation (ENSO) events in 1997, 2002, and 2006. Next, extreme central eclipses that perturb perigee-sysygy intervals also correspond with extreme ENSO events, notably in 1877, 1888, and 1982, and a 586 year cycle in the frequency of these eclipses corresponds with known stadial events in the past 4 thousand years. Contrast in the 586 year cycle increases with Earth eccentricity because it is the result of shorter synodic months at aphelion. Longer timescale forcing is by orbital control of the east-central Pacific ITCZ position, yielding a 10 thousand year fast ice sheet melt interval between March and September perihelion. But default ESLN is only interrupted when perihelion in March coincides with rising obliquity. A change in the phase relation between obliquity and precession from 1:2 to 3:5 or 2:5 may therefore explain skipped obliquity cycles after the mid-Pleistocene transition. A secular improvement in eclipse commensurability that parallels Cenozoic cooling is noted.

5114 Background: Angiogenesis plays a vital role in the progression of prostate cancer. Antiangiogenic agents thalidomide (T) and bevacizumab (Bv) may enhance docetaxel (Doc) activity in metastatic AIPC. However, T and Bv have different antiangiogenic mechanisms. Since tumor angiogenesis is a complex interplay of multiple angiogenic factors, we reasoned that combination of mechanistically different antiangiogenic agents T and Bv with Doc might be associated with an adequately high and durable PSA response to merit further study. Methods: Pts are required to have progressive metastatic AIPC and no prior chemotherapy for AIPC. Treatment consists of Doc 75 mg/m2 plus Bv 15 mg/kg day 1, q 21 days as a cycle (C), plus T 200 mg qhs and prednisone 10 mg qd. Enoxaparin is used for thrombosis prevention and pegfilgrastim initiated after detection of grade ≥3 neutropenia. PSA is assayed q C and staging studies are done at C 0, C 2, & then q 3 Cs. Results: 39 pts were enrolled, median age 66 [54–79], Gleason score 8 [74% Gs 10∼8, 26% Gs 7∼6], on-study PSA 92 ng/ml [5.9–4399] and pre-study PSA doubling time 1.6 months [0.3–18.2, 87 % <3 months]. Median treatment Cs is 14 [1- 28]. 34 pts (87%) had PSA declines of ≥50%, with median ≥50% PSA-duration 12 Cs [0∼28]. 3 pts have PSA declines around 40% and 2 stable. 26 pts (67%) had >80% PSA declines. 17 pts with measurable disease were evaluable: 1 CR, 9 PR, & 7 SD, with 59% ORR. Significant toxicities: febrile neutropenia (5/39), syncope (4/39), colon perforation or fistula (2/39), grade 3 bleeding (2/39), thrombosis (2/39). Conclusions: This trial is the first study to combine antiangiogenic agents of different mechanisms with Doc in metastatic AIPC. Most of the accrued patients have unfavorable characteristics as evidenced by a high Gleason score and a short PSA doubling time. However, the combination of T and Bv with Doc appears to result in both a high durable PSA decline rate (87%) and a high response in measurable disease (59%) with acceptable toxicities. No significant financial relationships to disclose.

6613 Background: The risk of venous thromboembolism is increased 4- to 7-fold in patients with malignancy, emphasizing the need to identify and treat these patients early to improve outcomes. We aimed to study the clinical presentation and outcomes of pulmonary embolism (PE) in patients with and without cancer. Methods: We performed a retrospective analysis of consecutive patients diagnosed with PE via CT scan from 2014-2016 at Jefferson Hospital. We compared patient characteristics, presentation, PE characteristics and mortality of patients with and without cancer. Cox proportional regression hazards model was used for survival-time analysis. Results: Our study included 581 patients, of which 187 (32.1%) had active cancer. Cancer patients were less likely to have chest pain (18.2% vs 37.4% p < 0.01), syncope (2.7% vs 6.6% p = 0.05), bilateral PEs (50% vs 60% p = 0.025), and right heart strain (RHS) (48% vs 58% p = 0.024). Indwelling catheters (IC) were present in 41.2% (n = 77) of cancer patients. However, presence of IC was not associated finding of incidental PEs (26% vs 18.2% p = 0.201). There was no difference in hospital length of stay (8.9 vs 9.4 days p = 0.61) or intensive care unit admission (31.9% vs 33.3% p = 0.75). There were fewer massive PE (3.2% vs 7.1% p = 0.06) in patients with cancer, but this difference was not statistically significant. Cancer patients elected comfort care at higher rates (15.2% vs 5.4% p = 0.01). Cancer patients had higher 1-year mortality as compared to non-cancer (adj HR 6.9, 95% CI 3.3- 14.7, p < 0.01). Among cancer patients, 52.7% had metastasis with a higher 1-year mortality (adj HR 2.5, 95% CI 1.8- 4.9, p < 0.1) and 35.8% were on active chemotherapy with no difference in 1-year survival (adj HR 1.1, 95% CI 0.6-1.8, p = 0.79). The most represented cancers were genitourinary, lung and head and neck (35.3%, 23.0%, 13.4%, respectively). Conclusions: Cancer patients presented with less severe pulmonary emboli which may be due to increased health care contact and pre-clinical suspicion. The presence of IC did not affect the size, location of PE or incidental PEs among cancer patients. Although cancer patients have higher 1-year mortality, PE may not be as large as a contributor as previously perceived.

Aim. To study the features of the use of thrombolytic therapy (TLT) in normotensive patients with pulmonary embolism (PE) in real clinical practice in Russian hospitals.Material and Methods. From 04/1 5/2018 to 04/15/2019 patients hospitalized with a diagnosis of PE consistently were included in the Russian multicenter observational prospective register "SIRENA” (RusSIan REgistry of pulmoNAry embolism).Results. For 12 months in the registry was included 609 patients with a lifetime confirmed diagnosis of PE. TLT was performed in 152 patients with PE (25.0%), of which only 51 (33.8%) were indicated as "high risk" (shock or hypotension). In 101 not high risk patients, the indications for TLT were: severe shortness of breath/respiratory failure - 19 (18.8%), massive venous thrombosis - 7 (6.9%), signs of massive/submassive PE - 10 (9.9%), intermediate-high risk - 14 (13.9%), suspicion of acute coronary syndrome with ST segment elevation - 3 (2.9%), high pulmonary hypertension -2 (2.0%). The other 46 (45.5%) non-high-risk patients had no clear indication of the reasons for TLT in their medical history. To study the features of management of patients with not high-risk PE who received TLT (group 1), a selection of pairs of patients from the "SIRENA” registry, comparable in gender and age, in a ratio of 1:1 of patients with not high-risk PE who did not perform TLT (group 2). Hospital mortality was 4 (4%) patients in the TLT group and 6 (5.9%) patients in group 2 (р=0,748). Logistic regression analysis showed that floating blood clot in the veins of the lower extremities, syncopes in the debut of PE, respiratory rate over 22 per minute were independent clinical factors that significantly influence the doctor's decision to perform thrombolysis, and probability of completion TLT decreased in the presence of a history of bleeding, chronic kidney disease, surgery in the previous 12 months, increase in the size of the right atrium on EchoCG (statistical significance of the model x2=51.574; p<0.001). The development of bleeding during hospitalization was recorded only in 10 (9.9%) patients of group 1, including severe (3 stage on the BARC scale) in 2 patients. Patients without TLT more often developed an acute heart failure (25.9% vs. 8.5%, p=0.043).Conclusion. In real clinical practice, there is a high frequency of TLT in patients with not high-risk PE. Floating blood clot in the veins of the lower extremities, syncope in the debut of PE, respiratory rate over 22 per minute were independent clinical factors that significantly influence the doctor's decision to perform thrombolysis.

Background:Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the treatment of signs and symptoms of osteoarthritis (OA).Objectives:To assess the safety and tolerability of subcutaneous (SC) tanezumab in patients with OA.Methods:Data were derived from 3 randomized placebo-controlled OA trials. SC treatment (every 8 weeks for 16–24 weeks with 8–24 week follow-up) included placebo, tanezumab 2.5 mg, tanezumab 2.5/5 mg (2.5 mg at day 1 and 5 mg at week 8), and tanezumab 5 mg. Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation were pooled from all 3 trials (placebo N = 586; tanezumab: 2.5 mg N = 602, 2.5/5 mg N = 219, 5 mg N = 347). Pre-specified TEAEs potentially associated with sympathetic neuropathy (anhidrosis, bradycardia, hypohidrosis, orthostatic hypotension, or syncope) and pre-specified joint events (primary osteonecrosis, rapidly progressive OA [RPOA] type 1 or type 2, subchondral insufficiency fracture, or pathological fracture; adjudicated by an independent committee of experts) were pooled from the 2 trials that included prospective evaluation of sympathetic and joint safety (placebo N = 514; tanezumab: 2.5 mg N = 528, 2.5/5 mg N = 219, 5 mg N = 284). TEAEs are presented for the treatment period; joint safety is presented for the full study (treatment plus follow up) period.Results:Patient demographics (80.7% white, 66.8% female, mean age ≈ 63 years) and clinical characteristics were similar across groups. TEAE rates were: placebo = 51.7%, tanezumab 2.5 mg = 52.3%, tanezumab 2.5/5 mg = 47.0%, and tanezumab 5 mg = 54.8%. Of TEAEs occurring in ≥2% of patients in any group, only oedema peripheral, joint stiffness, and paraesthesia had a higher incidence (95% confidence interval excluded 0) in any tanezumab group relative to placebo. Serious TEAE rates were: placebo = 1.5%, tanezumab 2.5 mg = 2.2%, tanezumab 2.5/5 mg = 1.4%, and tanezumab 5 mg = 2.6%. Rates of treatment and/or study discontinuation due to TEAEs were: placebo = 2.2%, tanezumab 2.5 mg = 1.8%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 1.4%. Only arthralgia and OA led to discontinuation in >1 patient in any group. TEAEs of abnormal peripheral sensation rates were: placebo = 2.2%, tanezumab 2.5 mg = 5.1%, tanezumab 2.5/5 mg = 3.2%, and tanezumab 5 mg = 6.1%. Paraesthesia and hypoaesthesia were the most common events. Potential sympathetic neuropathy TEAE rates were: placebo = 0.8%, tanezumab 2.5 mg = 1.5%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 2.8%; exposure-adjusted rates were not statistically different between any tanezumab group and placebo. Bradycardia and orthostatic hypotension were the most common events. No patient was considered to have a sympathetic neuropathy. TEAEs of abnormal peripheral sensation and potential sympathetic neuropathy were mostly mild and resolved. Joint safety event rates were statistically different for tanezumab 5mg (3.2%), but not 2.5mg (1.9%) or 2.5/5mg (0.5%), compared to placebo (0%). RPOA type-1 was the most common event. Total joint replacement rates were: placebo = 4.5%, tanezumab 2.5 mg = 5.9%, tanezumab 2.5/5 mg = 6.8%, and tanezumab 5 mg = 7.0%; rates were not statistically different between any tanezumab group and placebo.Conclusion:Tanezumab was generally safe and well tolerated in most patients, with rates of overall TEAEs and treatment/study discontinuations similar to placebo and no evidence of a sympathetic safety signal. TEAEs of abnormal peripheral sensation and joint safety events were infrequent but more common with tanezumab than placebo.Disclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Anne Hickman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Glenn Pixton Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Isabelle Davignon Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Abstract Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell-cycle and survival signaling pathways. In accord with this concept, we have shown that flavopiridol (F), a CDK inhibitor, interacts with bortezomib (B), a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene22:7108, 2003; Dai et al, Blood104:509, 2004). These actions were associated with inhibition of NF-kappaB DNA binding, increased expression of phospho-JNK, and downregulation of XIAP and Mcl-1. Based on these findings, a phase I trial has been initiated to identify appropriate doses of B+F for further investigation. Eligible patients (pts) include those with multiple myeloma or indolent B-cell neoplasms, and recurrent or refractory disease following at least 1 prior systemic therapy (excluding allogeneic stem cell transplantation). In the initial stage of the trial, pts received B (iv push) immediately followed by F bolus (1- hour infusion) on d1, 4, 8, and 11 out of a 21-day (d) cycle. Dose levels were, in mg/m2 (B/F): 1.0/15, 1.3/15, 1.3/22, 1.3/30, 1.3/40, 1.3/50, and 1.3/60. Subsequently, a “hybrid” F infusion schedule (30 minute load followed by a 4-hour infusion) was adopted based on evidence of activity of this schedule in chronic lymphocytic leukemia. With the hybrid schedule, all pts receive B (iv push) 1.3 mg/m2 on d1, 4, 8 and 11. Targeted F dose levels using the hybrid schedule are (Fload/Finfusion; mg/m2): 20/20 on d1 and 8; 30/30 on d1 and 8; 30/50 on d1 and 8; 30/30 on d1, 4, 8 and 11; 30/50 on d1, 4, 8 and 11. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelets for &gt; 1 week or grade ≥ 3 non-heme toxicity. 38 pts have been enrolled. 29 pts were treated at 7 dose levels with the bolus schedule, after which development of the hybrid schedule was begun. With the hybrid schedule, 11 pts have been treated at 3 dose levels. To date, one DLT (grade 3 lower back pain) was observed at level 5 of the bolus schedule and one DLT (grade 3 fatigue) was seen at the 1st hybrid dose level. The MTD of the hybrid schedule has not been reached. Non-DLT toxicities include herpes zoster (2 disseminated), peripheral neuropathy, fatigue, postural hypotension, syncope, diarrhea and ≤ grade 3 cytopenias. Of 35 pts evaluable for response, there have been 2 complete responses (1 lymphoma and 1 mantle cell lymphoma), 7 partial responses (5 myeloma and 2 lymphoma), 3 minor responses (2 myeloma and 1 extramedullary plasmacytoma), 15 patients with stable disease (5 myeloma, 7 lymphoma, 1 Waldenstrom’s and 2 mantle cell lymphomas). Of the 3 pts who had received prior bortezomib, 2 had minor responses and 1 had disease progression. To date, hyperacute tumor lysis has not occurred with the hybrid schedule, but aggressive prophylaxis and monitoring are integral to the treatment plan. Correlative laboratory studies involving bone marrow CD138+ cells from patients with myeloma revealed a reduction in post-treatment NF-kappaB nuclear localization in 4 of 5 evaluable patients. Variable effects on myeloma cell expression of phospho-JNK, Mcl-1, and XIAP have been observed. Collectively, these findings indicate that a regimen combining bortezomib and flavopiridol, including the use of a hybrid flavopiridol schedule, is well tolerated in patients with progressive B-cell malignancies, and has clear activity in some patients refractory to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), phase II evaluation of this therapeutic strategy should define its activity more definitively.

Background: Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been shown to improve outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for ibrutinib and acalabrutinib discontinuation (median time ≤6 mo; Mato et al, Haematologica 2018;103:874; Yazdy et al, Blood 2019; Supplement1: 4311). Off-target effects of ibrutinib have been implicated in BTKi-related AEs. Zanubrutinib, a BTKi approved for treatment of mantle cell lymphoma (MCL) and in development for other hematologic malignancies, was specifically engineered to optimize selectivity and maximize BTK occupancy. In the head-to-head ASPEN trial of zanubrutinib vs ibrutinib in patients with Waldenström macroglobulinemia (WM), zanubrutinib showed a lower rate of AEs leading to death, discontinuation, dose reduction, and dose holds (Dimopoulos et al, EHA 2020; Abstract S225). We conducted a prospective clinical trial of zanubrutinib in patients with relapsed/refractory B-cell malignancies who have become intolerant to prior BTKi (ibrutinib and/or acalabrutinib) therapy. Methods : In this ongoing phase 2, multicenter, US, single-arm, open-label study (NCT04116437; BGB-3111-215), the safety and efficacy of zanubrutinib monotherapy (160 mg twice daily or 320 mg once daily) is being evaluated in patients with B-cell malignancies who meet requirements for treatment and have become intolerant to prior BTKi therapy. An intolerant event was defined as an unacceptable toxicity where, in the opinion of the investigator (INV), treatment should be discontinued despite optimal supportive care as a result of 1 of the following: grade ≥2 nonhematologic toxicities for &gt;7 days (with or without treatment), grade ≥3 nonhematologic toxicity of any duration, grade 3 neutropenia with infection or fever, or grade 4 hematologic toxicity that persists to the point that the INV chose to stop therapy due to toxicity and not disease progression (PD). All enrolled patients must not have documented PD during prior BTKi therapy. Response assessment was evaluated by INV for CLL per modified International Workshop on CLL criteria (Hallek et al, Blood 2008;131:2745; Cheson et al, J Clin Oncol 2012;30:2820), for SLL, MCL, and marginal zone lymphoma per Lugano criteria (Cheson et al, J Clin Oncol 2014;32:3059), and for WM per modified 6th International Workshop on WM criteria (Owen et al, Br J Haemtol 2013;160:171). Disease parameters (imaging and laboratory parameters) performed at study entry were used as the baseline for response assessment. Results : As of 01 June 2020 (data cutoff), 17 patients with CLL/SLL were enrolled, received ≥1 dose of zanubrutinib, and were analyzed for safety. Median age was 70 years (range, 49-91) and median duration of treatment exposure was 3.02 mo (range, 0.56-7.59). The median number of prior regimens was 1 (range, 1-3). All patients had received ibrutinib. At data cut off, no patients had received acalabrutinib. At data cutoff, 16 patients remained on zanubrutinib treatment. One patient withdrew herself from the study following an AE (grade 3 syncope) unrelated, as per INV, to study treatment. Of the 31 BTKi-related AEs associated with intolerance (Table 1), 30 (96.8%) did not recur, and 1 event (3.2%; atrial fibrillation) recurred at a lower grade (grade 3 vs 2) and for a shorter duration (14 vs 3 days) vs the initial ibrutinib-intolerant event. Ten patients (58.8%) reported ≥1 AE. AEs reported in ≥10% of patients on zanubrutinib included dizziness (n=3; 17.6%) and cough (n=2; 11.8%). Grade ≥3 AEs were reported in 2 patients (11.8%): neutropenia and syncope (n=1 each; 5.9%). AEs of interest included hemorrhage and infections (n=3 each, 17.6%) and anemia, neutropenia, and atrial fibrillation (n=1 each; 5.9%). No AEs led to dose modification or treatment discontinuation. No serious AEs or deaths were reported. As of data cutoff, 10 patients were evaluable for efficacy with ≥1 response assessment. All 10 patients achieved at least stable disease, and 60% of these patients achieved a deepening of response since initiating zanubrutinib. Enrollment is ongoing and the presentation will include additional patients. Conclusions : Zanubrutinib demonstrated efficacy and tolerability in CLL/SLL patients who were intolerant to previous BTKi. These data suggest that zanubrutinib may provide a potential option after intolerance to other BTKi. Disclosures Shadman: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Ended employment in the past 24 months; Sunesis: Research Funding; Gilead: Research Funding. Sharman:Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Levy:Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Baylor University Med Center: Current Employment; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Misleh:Medical Oncology Hematology Consultants (MOHC): Current Employment; High Mark Blue Cross: Membership on an entity's Board of Directors or advisory committees. Zafar:Bristol Meyers Squibb: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AstraZeneca: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Honoraria; Sarah Canon Research Institute: Research Funding; Florida Cancer Specialists and Research Institute: Current Employment. Freeman:Summit Medical Group: Current Employment. Burke:Kura: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy; Roche: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Verastem: Consultancy; Epizyme: Consultancy; Seattle Genetics: Speakers Bureau; Adaptive Biotechnologies: Consultancy. Cultrera:Amgen: Speakers Bureau; Florida Cancer Specialists + Research Institute: Current Employment; Celgene: Speakers Bureau; AcroTech: Speakers Bureau; Verastem: Speakers Bureau. Yimer:BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TG Therapeutics: Consultancy; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chen:BeiGene: Current Employment, Current equity holder in publicly-traded company. Zhang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ro:BeiGene: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Flinn:Iksuda Therapeutics: Consultancy; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; AstraZeneca: Consultancy, Research Funding; ArQule: Research Funding; Agios: Research Funding; Takeda: Consultancy, Research Funding; Forty Seven: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Celgene: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Curio Science: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; AbbVie: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Gilead Sciences: Consultancy, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for R/R CLL/SLL, MZL, and WM in the US

Abstract Inhibitors of class I/II histone deacetylases (HDACi) possess anti-leukemic activity and have been reported to modulate the function of immune effector cells. Thus, they could provide specific clinical benefit in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. Panobinostat (PAN) is a potent, orally available pan-HDACi reported to either suppress or stimulate regulatory T cells (T reg), depending on the administered dose (Shen L & Pili R, OncoImmunology 1;7:948, 2012). The feasibility and efficacy of PAN treatment following HSCT for patients (pts) with high risk acute myeloid leukemia (AML) has not been established. We report clinical and translational results of the dose-escalation phase of the PANOBEST study with PAN as post-HSCT maintenance. Primary objectives were, based on dose-limiting toxicity (DLT), determining the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of PAN in patients with high risk AML or myelodysplastic syndromes (MDS) in complete remission (CR) after reduced-intensity conditioning HSCT. Secondary objectives were the evaluation of safety, tolerability and immunoregulatory properties of PAN, and overall (OS) and disease-free survival (DFS) of treated patients. PAN was started at 10 mg p.o. three times a week (TIW) and escalated to 20 and 30 mg TIW using a 3+3 design. Treatment was initiated 60-150 days after HSCT and continued for up to one year. Eligibility criteria included: recovery of peripheral blood counts, adequate organ function and no severe graft versus host disease (GvHD). All pts gave written informed consent. DLT was defined as prolonged grade 4 hematologic or grade 3/4 non-hematologic toxicity within 28 days of the first PAN dose. Immunophenoytyping of lymphocyte subsets was performed pre-treatment and on days 3, 8, 30, 90, 180 and 360. 12 pts (11 AML, 1 MDS), median age of 52 years (21-62) were enrolled. PAN was started within a median of 73 days (60-126) after HSCT, which was performed with active disease (n=11) or in CR2 (n=1). The RP2D was determined to be 20 mg TIW based on one DLT (fatigue grade 3) at 20 mg and two DLTs (nausea/emesis and colitis grade 3 each) at 30 mg. Grade 2-4 adverse events (AEs) were reported in 10 out of the 12 pts (83%). Grade 3/4 AEs included hematologic toxicity (50% of pts), laboratory alterations (33%), gastrointestinal symptoms (25%), fatigue, pulmonary infection (17% each), sepsis, herpes stomatitis, diabetes, syncope, deep vein thrombosis and pulmonary embolism (8% each). Toxicity was reversible and required at least one PAN dose reduction in 3 pts. Acute GvHD grade 2 (1 pt) and 3 (2 pts) was responsive to steroids in 2 pts or salvage therapy in 1 pt. Four pts developed mild (n=3) or moderate (n=1) chronic GvHD. To date, 5 pts have completed one year of PAN and 2 pts remain on treatment (days 238, 290). Five pts discontinued treatment prematurely after 10-217 days due to grade 3 toxicities (n=4) or AML relapse (n=1). With a median follow up of 579 days (129-911), 11/12 pts are alive and 10/12 in continuous CR after HSCT. Seven pts received prophylactic donor lymphocyte infusions (DLIs, 1-5 doses of 0.1-20x106 CD3+ cells/kg). Immunophenotyping revealed no impact of PAN on absolute T reg numbers (9 pts), but a significantly reduced proportion of CD4+CD25++CD127dim/- T reg to CD3+CD4+ T helper (Th) cells by day 8 after 3 doses of PAN (mean±SEM: 14.6±2.6 vs. 9.6±1.2%, p value of t test =0.03). While Treg/Th proportion continuously decreased in pts with ongoing CR, it again increased after PAN discontinuation or remained stable under PAN treatment in both relapsing patients. Outcome of the study population was compared with a historical cohort of 29 consecutive pts with active AML transplanted in Frankfurt in 2000-2009. Both cohorts were similar in age, gender, disease stage or BM blasts at time of HSCT, donor type and use of DLIs. In a landmark analysis including all pts who were in CR and without severe GvHD on day 73 after HSCT, probabilities for DFS and OS at 18 months after HSCT were 83±11% vs. 55±9% (p=0.145, log-rank test) and 92±8% vs.66±9% (p=0.085) in the PANOBEST vs. historical cohort (Fig 1). PAN is well tolerated after HSCT at a RP2D of 20 mg TIW. Comparison with a historical control cohort of pts transplanted with active AML shows a low relapse rate, which appears to be associated with a PAN-induced modulation of the T reg/Th proportion. Disclosures: Bug: Novartis: Honoraria, Travel grants, support for the clinical study Other. Ottmann:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Aim. To evaluate patients’ (pts.) compliance with Ventavis inhaled treatment. Secondary aim: to study pts. characteristics; reason for low compliance; changes in 6-minute walking distance (6MWD) test and dyspnea score; changes in the parameters of pulmonary hemodynamics; pulmonary function changes; quality of life (QOL) according to compliance with Ventavis use; to assess frequency, severity and other characteristics of AE. Materials and methods. Prospective, multicenter, single cohort non-interventional IV phase study IVENT (NCT01971450). The study lasted 12 month. Pts. evaluation was scheduled as follows: initial visit done at baseline (pts. inclusion) - iV, 6 (follow-up visit 1) - V1, and 12 (follow-up visit 2, final) month - V2 thereafter. Evaluation of basic demographic and functional characteristics using needed armamentarium was planned at these time points. Treatment compliance was analyzed at 1 (6 month) and 2 (12 month) follow-up visits (ITT population). Results. As many as 82 pts. averages (mean±SD) 47.6±14.2 years with mean PH syndrome duration 3.2±5.7 years were included. Substantial number of pts. presented with severe disorders in anamnesis, i.e. pulmonary embolism, heart defect, arterial hypertension, heart failure in 35.4; 14.6; 36.6 and 70.7% of pts., respectively. PH syndrome verification methods varied with right heart catheterization (RHC) being the most prevalent one in 45.1% of pts., following by echocardiography (EchoCG) in 30.5%. At the iV EchoCG was performed in all the pts; and at the final visit in 82.9%; RHC - in 62.2% and 7.3%, respectively. Study population mean 6MWD estimated to be 257.7±109.6 m at the time of inclusion with Borg index score 6.4±4.2. All 82 pts. were being treated with iloprost inhaled [average daily dose 8.0±7.9 (95% CI 6.2-9.7) mcg] at the iV. 53 and 29 pts. of ITT population formed ‘sufficient-compliant’ (SC) and ‘low-compliant’ (LC) subgroups (sbgr.), respectively. Patients’ compliance of inhaled treatment with Ventavis in the overall population was shown to be 82.3±27.7% at the V1 and 81.8±28.4% at the V2; in SC sbgr. - 96.9±5.4 and 96.6±5.8%, respectively; in LC sbgr. - 49.1±29.1 and 46.4±29.9%, respectively. AE, lack of the drug or drug ineffectiveness, patient preferences not to receive the drug were demonstrated to be the main reasons for treatment discontinuation in both sbgr. At 6 month mean daily dose of iloprost was 7.7±5.5 mcg; at 12 month 7.2±4.9 mcg. At the iV 63.4% of pts. was receiving inhalations 6 times in a days at month 6 and 12 - 58.5% and 48.8%, respectively. Mean number of inhalations per day was estimated to be 5.9±1.3 at the iV and 6.1±1.3 at V1 and V2. Ventavis treatment interruptions were registered in 37.8% of pts. at the end of observation period (22.6% SC sbgr.; 65.5% LC sbgr.). Premature discontinuation of the drug treatment was noted in 8.5% of pts. at V1 and 20.7% at the V2. Dose correction took place in 4.9% and 1.2% of pts. at V1 and final visit, accordingly. SC sbgr. of pts. at baseline was characterized by 6MWD of 266.9±114.23 vs. 240.5±100.2 m in LC one. At 12 month 6MWD had increased up to 307.1±115.4 vs. 263.5±107.4 m in SC and LC sbgr., respectively. Baseline Borg dyspnea score in SC sbgr. was 6.1±3.8 vs. 6.9±4.9 in LC pts. At the end of the study, Borg dyspnea score for SC and LC pts. estimated to be 6.3±3.6 and 7.7±5.7, respectively. Thus, in SC sbgr. was achieved positive changes in 6MWD with persistent dyspnea, but in LC sbgr. dyspnea severity had increased. In ITT population systolic PAP (SPAP) measured by EchoCG was slightly decreased from 83.2±27.9 to 76.6±29.7 mmHg at the final visit; in SC sbgr. - from 82.5±24.1 to 76.5±26.7 mmHg; in LC sbgr. - from 84.5±34.5 to 76.8±35.7 mmHg. Due to the fact RHC data is available only for several pts., it is impossible to analyze changes in hemodynamic variables. Patients’ QoL according to SF-12 questioner showed positive changes from mean score 30.8±7.7 to 35.1±9.3 in SC pts. at the end of observation. QoL in LC sbgr. did not change substantially. Same trend could be revealed when evaluating psychological component: 41.7±10.6 and 46.3±10.9 in SC sbgr.; 40.6±11.4 and 40.2±11.7 in LC sbgr. During the study 64 AE in 24.4% of pts. were registered, 37 AE in 17.1% of pts. judged to be drug-related. Iloprost dose was remaining unchanged in 13.4% of pts., whereas in 2.4% of pts. dose decreased; in 8.5% of pts. drug intake was discontinued. At the end of the study, 35 AE in 15.9% of pts. successfully resolved. The most frequent AE became cough (9.8%), dysphonia (3.7%), headache (6.1%), dizziness (4.9%), syncope (3.7%), asthenia (2.4%), edema (2.4%). Overall 24 serious AE (SAE) had occurred in 20.7 of pts. 17 (out of 24) SAE in 11 (37.9%) pts. emerged in LC sbgr. None of the SAE were considered to be drug-related. Iloprost dose remained unchanged in 6.1% of pts. (8 SAE cases), treatment paused in 1.2% of pts., and treatment was discontinued in a single case. 13 SAE in 11 (13.4%) pts. were fatal, 4 SAE in 4 (4.9%) pts. had resolved, 3 SAE in 2 (2.4%) pts. was resolving, 4 SAE in 2 (2.4%) pts. were continuing at the end of observation. In 8 cases in 6 (7.3%) pts. dose correction measures were not undertaken; in 6 SAE cases in 5 (6.1%) pts. there is no information available. Conclusion. In general population studied, it’s been demonstrated sufficient PH patients’ compliance of Ventavis inhaled treatment.

Abstract Background Cardiac syncope has been shown to carry the highest hazard for all-cause death compared to other causes of syncope including vasovagal and orthostatic syncope. However, little is known about the incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope. Purpose To evaluate the incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope. Methods We enrolled patients presenting to the emergency department (ED) with syncope in a large prospective international multicentre study. The cause of syncope (cardiac vs non-cardiac) including the detailed cardiac aetiology (if cardiac) was centrally adjudicated by two independent cardiologists based on detailed in-hospital as well as outpatient cardiac work-up during 360 days following presentation. Cardiac syncope was classified into four groups: bradyarrhythmia, tachyarrhythmia, structural disease and other (cardiopulmonary and great vessels), as recommended in the ESC Syncope Guidelines. All-cause death during 2-years follow-up was the primary outcome. Results Among 2025 patients presenting with syncope to the ED, cardiac syncope was the final adjudicated diagnoses in 318 (15.7%) patients. The incidence rate of all-cause death among cardiac syncope patients was 103 cases per 1000 person-years. Bradyarrhythmia was the most frequent primary cause of cardiac syncope (n=146, 45.9%) followed by tachyarrhythmia (n=75, 23.6%), structural disease (n=64, 20.1%) and other cardiac (n=26, 8.2%). Patients were 37% female with a median age of 77 years (IQR 67–83) showing no statistically significant difference between subgroups. Clinical characteristics differed significantly among the four subgroups. E.g. syncope occurred during exercise in 12 patients (8.2%) with bradyarrhythmia, 10 patients (13.3%) with tachyarrhythmia, 16 patients (25%) with structural disease, and 5 patients (19%) with other cardiac (p&lt;0.01). Likely of most importance, long-term mortality differed significantly among the four different cardiac subgroups. The multivariable-adjusted hazard ratios (HR) among patients with bradyarrhythmia, tachyarrhythmia, structural disease and other cardiac as compared to patients with vasovagal syncope, the HR were 1.3 (95% CI 0.7–2.5), 4.6 (95% CI 2.3–9.1), 3.1 (95% CI 1.5–6.4) and 5.9 (95% CI 2.3–15.2), respectively (Figure 1). Conclusions Bradyarrhythmia, tachyarrhythmia, and structural cardiac disease are the dominant causes of cardiac syncope. Interestingly, with the appropriate therapy initiated long-term mortality of bradyarrhythmia is comparable to that of vasovagal syncope, while long-term mortality of tachyarrhythmia and structural cardiac disease were substantially increased 3 to 5 fold. Figure 1. Kaplan-Meier curve Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Swiss National Science Foundation, the Swiss Heart Foundation, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel and the University Hospital Basel.

The intensity of the Semi-Pelagian controversy in the Gaulish Church of the fifth and sixth centuries The controversy over Augustine’s predestinarian views was transferred to Gaul after the Vandal conquest of Africa. The Pelagian controversy was characterised by the participation of several prominent figures and the convention of seven councils. The question, however, is why the Semi-Pelagian controversy was of such a different character. The answer is to be found in the context of the participants in the debate: the unique charac- ter of the Gaulish Church, the influence from the monasteries and the distinctive political setting of this region. John Cassian, founder of the monasteries of Marseilles, took the view that God’s grace comes as an answer to the beginning of a good will in the human person and the free will in man can either neg- lect or delight in the grace of God. The same sentiments were soon heard from the monastery on the island of Lerins. The reaction to this stance by Prosper of Aquitaine led to the literary involvement of Augustine. For several decades the bishops of Arles and Vienne attempted to raise their city’s ecclesiastical status above the other cities of Southern Gaul – a phenomenon typical of the public life of this region. In 529 Caesarius, former monk of Lerins, of aristocratic descent and bishop of Arles, held a synod at Orange. This synod affirmed a diluted form of the Augustinian position. All the elements of the character of this controversy can be found in the person of Caesarius who was also mainly responsible for the formulation of the canons of this synod.

Background: Syncope is a common reason for emergency department visits. Guidelines suggest minimal initial workup, including history, physical exam, and ECG testing. Additional cardiac testing is recommended in only high risk patients and neuroimaging is rarely indicated. Because of the low yield of neuroimaging, in 2012, the Choosing Wisely campaign recommended against its use for syncope. Our objective was to examine trends in cardiac testing and neuroimaging of patients presenting to the ED with syncope, before and after the Choosing Wisely recommendations and to describe hospital variation in testing rates. Methods: We linked State Inpatient and Emergency Department Databases to conduct a retrospective study of all ED visits in 2009 and 2013 for 8 states reporting procedure utilization. We calculated rates of ECG, advanced cardiac testing (echocardiogram, stress testing, diagnostic catheterization) and neuroimaging (head CT, brain MRI, carotid ultrasound) for all adults with a discharge diagnosis of syncope. Differences between years were estimated using mixed effect regression modeling adjusted for patient characteristics, comorbidities, and hospital random effects. Results: We identified 287,261 ED visits for syncope in 2009 and 315,221 ED visits in 2013 from 676 hospitals. Between 2009 and 2013, adjusted rates of ECG testing increased from 81.1% of discharges to 84.3% (p<.0001). Rates of advanced cardiac testing increased from 10.3% to 12.4% (p<.0001), driven primarily by a substantial increase in the use of echocardiograms (8.3% vs 11.3%, p<.0001). Rates of neuroimaging increased from 36.0% to 42.0% (p<.0001) with increased utilization of all tests. Rates of ECG, advanced cardiac testing and neuroimaging varied significantly between hospitals in both years (Figure). The median hospital-level change in testing between years was 1.6% (IQR -3.5 to 11.2) for ECG, 1.2% (IQR -1.8 to 5.9) for advanced cardiac imaging and 4.2% (IQR -5.3 to 18.4) for neuroimaging. Conclusions: Among patients presenting to the ED with syncope, rates of both high- and low-value diagnostic testing increased between 2009 and 2013, with substantial variation between hospitals. Thus, the 2012 Choosing Wisely recommendations do not appear to have had a significant effect on testing for patients presenting with syncope.

Aim: To investigate the efficacy and safety of anti-tachycardia pacing (ATP) simultaneously delivered from right and left ventricles (BIV) vs conventional right ventricular (RV) delivery in heart failure (HF) patients treated with a biventricular ICD (CRT-D). Methods : Multicenter, prospective, randomized, controlled trial of pts implanted with a Medtronic CRT-D device. Anti-tachycardia detections were programmed: VF detection set at NID 18/24 for ≥250 bpm; FVT (via VF) with NID 18/24 between 188–250 bpm; VT detected when 20 consecutive RR intervals ≥143 bpm. Randomization was 1:1 to either BiV or RV ATP (single burst 8 pulse, 88% coupling interval ). Pts were followed for 12 months. Stored EGM, used to classify all spontaneous episodes, as well as all adverse events (including death) were adjudicated by an independent committee adjusting for pts with multiple episodes. The primary end-point (PEP) compared the efficacy of first BiV vs RV to terminate any ventricular tachyarrhythmias (VTs). The secondary composite end-point (SEP) compared adverse events (accelerations+ syncope/pre-syncope) to assess safety. Results : In total, 526 patients were enrolled and randomized (BiV = 260, RV = 266). There were no baseline differences between groups. In total, 1077 detections in 178 patients were recorded: 634 were true VTs in 119 patients (69 VF [11%] in 18 pts, 202 FVT [32%] in 49 pts, and 363 VT [57%] in 92 pts). PEP: Efficacy of first ATP was comparable between BiV (65%) and RV (68%) (p=0.58). In VT zone, RV was better (62% vs 71%., p=0.24), while in FVT zone BIV proved better (71% vs. 61%, p=0.33). RV ATP was significantly less effective in ischemic (I) pts (81% vs 59%, p=0.005). SEP: BIV ATP was ineffective 20 times and 3 accelerations occurred, whereas RV ATP failed 41 times and 14 accelerations occurred (p=0.12). Syncope/pre-syncope events never occurred for BiV ATP, while 4 times (3%) in RV ATP(p=0.3). No difference in mortality was observed. Conclusion : This trial demonstrated that ATP is also effective in CRT-D recipients. No significant differences in overall ATP efficacy were found between BIV and RV, but RV was significantly less effective in I patients; BIV was effective across different etiologies and showed a trend for superior safety profile.

Abstract Background Syncope and dementia have a high prevalence in elderly individuals. Atrial fibrillation (AF) frequently occurs at advanced age. The coexistence of these conditions can be indicative of a clinically relevant frail status. Purpose The aim of this study was to evaluate the characteristics and the long-term outcome of AF patients with dementia and a history of syncope. Methods We evaluated the Syncope and Dementia (SYD) Registry. Data were collected by 11 Geriatric Departments between 2012 and 2016. Follow-up was closed at the 12-month evaluation. Results During the study period, 522 patients (women – 324, 62.1%; MMSE: 17±6) were enrolled. Of these 138 (26.4%) have or presented a history of AF. Patients with AF were older (85±6 vs. 83±6 years, p=0.012), with a higher heart rate (78±17 vs. 73±14 bpm, p<0.001), had a more complex clinical picture with an increased number (3.9±2.0 vs. 3.0±1.8, p<0.001) and severity (1.8±0.3 vs. 1.6±0.4, p<0.001) of comorbidities, as assessed with the Cumulative Illness Rating Scale. In particular, the prevalence of diabetes (28.3 vs. 20.1%, p=0.047), heart failure (13.8 vs. 7.3%, p=0.023) and stroke/TIA (26.1 vs. 17.7%, p=0.035) was higher in patients with the arrhythmia. Cardiac syncope was more frequently diagnosed at the final evaluation (18.8 vs. 4.9%, p<0.001). Even if the use of antipsychotics (13.0 vs. 27.6%, p=0.001) and cholinesterase inhibitors (6.5 vs. 16.4%, p=0.004) were less used in AF subjects, the total number of prescribed drugs was higher (6.9±2.9 vs. 5.9±2.7, p<0.001). At multivariate analysis (overall predictivity: 75%), AF patients were characterized by advanced age (p=0.041), a higher severity of comorbidities (p<0.001), a greater number of drugs (p=0.020), an increased heart rate (p=0.004) and a more frequent presence of cardiac symptoms (p=0.049). At one-year follow-up (8 patients lost), the mortality rate in AF patients was 27.7% (N=36/130). Deceased patients presented a greater degree of disability (number of lost activities of daily living: 3.7±2.3 vs. 2.8±1.9, p=0.020) and a higher heart rate at baseline (85±17 vs. 76±15 bpm, p=0.006). Multivariate analysis (overall predictivity: 74%) confirmed the association of disability (p=0.039) and heart rate (p=0.045) with prognosis. Conclusions AF is frequently present in patients with dementia and a history of syncope. It is usually associated with a more complex clinical picture and high long-term mortality. Heart rate and a higher degree disability seem to be related to prognosis. Acknowledgement/Funding None

Abstract Introduction Besides the established class I indication for the evaluation of patients with recurrent syncope of uncertain origin, implantable loop recorders (ILRs) have been increasingly used for other diagnostic purposes (e.g. detection of atrial fibrillation (AF) following cryptogenic stroke). Purpose To describe the main indications to ILR and to investigate procedural parameters, outcomes and diagnostic yield of ILR in a single, high-volume tertiary care centre. Methods All patients undergoing ILR implantation between October 2010 and October 2019 were consecutively enrolled in this study. Clinical characteristics of patients, procedural data and outcomes were collected. The indications to ILR implantation were divided into four categories: 1) AF detection in patients with recent cryptogenic stroke or peripheral thromboembolism [CRYSP], 2) recurrent syncope of uncertain origin [RSUO], 3) monitoring of ventricular arrhythmic events [VAE] in patients with predisposing cardiomyopathy/channelopathy, 4) monitoring of AF burden [AFB]. The main endpoint of the study was the diagnostic yield (number of definitive diagnoses made) and the time to diagnosis following ILR implantation. The occurrence of acute or subacute complications was used as a secondary safety endpoint. Results Overall, 1008 patients underwent ILR implantation (mean age 64 years, 43% female). The two main indications to ILR were AF detection following CRYSP and RSUO (41% and 34% of all implantations respectively, table 1). The commonest site of implantation was the left parasternal position (570 patients, 57%), median procedural time was 20 minutes (IQR 15–25). During a median follow-up of 580 days (186–1179), a definitive diagnosis was achieved in 366 (36%) patients after a median time of 208 days (IQR 59–515) [table 1 shows details and action taken following diagnosis for each indication subgroup]. Infections requiring ILR extraction or pocket revision occurred in 12 patients (1.2%). Conclusions In this cohort of patients use of ILR was associated with a good diagnostic yield regardless of the initial indication, triggered timely therapeutic actions and was overall safe. Funding Acknowledgement Type of funding source: None

Abstract BACKGROUND: Thyrotoxic periodic paralysis (TPP) is an uncommon disorder characterized by acute flaccid paralysis due to hypokalemia. It is diagnosed primarily in Asian adult males and is rare in children and adolescents. Here we report an adolescent male patient of Vietnamese descent who presented to the emergency department with an episode of syncope, muscle weakness, and shortness of breath one day after the initiation of methimazole treatment for Graves’ disease. The laboratory revealed significant hypokalemia. In this report we also included and summarized the reported cases of TPP in adolescent patients since 1997. Clinical Case: A 17-year-old Vietnamese American male who was recently diagnosed with Graves’ disease presented to the emergency department after an episode of syncope, muscle weakness, and difficulty breathing. Two months previously, he began having episodes of tachycardia. He was diagnosed with hyperthyroidism with a TSH of 0.007 mIU/mL and free T 4 &gt; 7 ng/dL (0.8-1.9). He was subsequently evaluated by Cardiology and started on atenolol. He was then seen by Endocrinology 5 days after and started on methimazole 15 mg twice daily. On the next morning after starting methimazole, he reported feeling weak and passed out. His father had found him on the floor, weak and unable to move, approximately 30 minutes after his father “heard a thud upstairs”. The patient recalled that his legs gave out and he “hitting his face on a table”. In the emergency department, he was tachycardic at 116 bpm, widened pulse blood pressure of 131/50 mmHg with normal respiratory rate 24 BR/min. He had diffused and significant muscle weakness on his all extremities including grip strength. His potassium was 1.6 mmol/L (3.5 - 5.2) and magnesium 1.6 mmol/L (1.6-2.3). The rest of his chemistry panel was unremarkable. He had EKG changes consistent with hypokalemia with U waves, also revealing atrial rhythm with first degree AV block, intraventricular conduction delay, and QTc prolongation at 588 (&lt;450). His chest x-ray was normal. Normal saline was administered, and potassium replacement was given with 40 mEq of KCl followed by D5 NS with 40 meq/L KCl at maintenance. He continued taking atenolol and methimazole. He was also given an IV dose of magnesium. His muscle strength returned completely and potassium level returned to normal range at 4.6 mmol/L after 24 hours of treatment. Conclusion: TPP is a rare cause of acute paralysis and can lead to cardiac arrhythmia and death without accurate diagnosis and prompt treatment. Our case should raise awareness of this disorder among pediatricians, emergency department physicians and endocrinologists. Acute paralysis with hypokalemia should also prompt the physician to consider evaluating thyroid function as a differential diagnosis in young Asian men.

Abstract Background A spontaneous subarachnoid haemorrhage (SAH) is one of the most critical neurological emergencies a dispatcher can face in an emergency telephone call. No study has yet investigated which symptoms are presented in emergency telephone calls for these patients. We aimed to identify symptoms indicative of SAH and to determine the sensitivity of these and their association (odds ratio, OR) with SAH. Methods This was a nested case–control study based on all telephone calls to the medical dispatch center of Copenhagen Emergency Medical Services in a 4-year time period. Patients with SAH were identified in the Danish National Patient Register; diagnoses were verified by medical record review and their emergency telephone call audio files were extracted. Audio files were replayed, and symptoms extracted in a standardized manner. Audio files of a control group were replayed and assessed as well. Results We included 224 SAH patients and 609 controls. Cardiac arrest and persisting unconsciousness were reported in 5.8% and 14.7% of SAH patients, respectively. The highest sensitivity was found for headache (58.9%), nausea/vomiting (46.9%) and neck pain (32.6%). Among conscious SAH patients these symptoms were found to have the strongest association with SAH (OR 27.0, 8.41 and 34.0, respectively). Inability to stand up, speech difficulty, or sweating were reported in 24.6%, 24.2%, and 22.8%. The most frequent combination of symptoms was headache and nausea/vomiting, which was reported in 41.6% of SAH patients. More than 90% of headaches were severe, but headache was not reported in 29.7% of conscious SAH patients. In these, syncope was described by 49.1% and nausea/vomiting by 37.7%. Conclusion Headache, nausea/vomiting, and neck pain had the highest sensitivity and strongest association with SAH in emergency telephone calls. Unspecific symptoms such as inability to stand up, speech difficulty or sweating were reported in 1 out of 5 calls. Interestingly, 1 in 3 conscious SAH patients did not report headache. Trial registration NCT03980613 (www.clinicaltrials.gov).

Background: Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VA). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ring-like pattern of fibrosis. Methods: 686 patients with apparently idiopathic non-sustained VA underwent contrast enhanced CMR. A ring-like pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The endpoint of the study was time to the composite outcome of all cause death, resuscitated cardiac arrest due to ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) and appropriate implantable cardioverter defibrillator therapy. Results: A total of 28 (4%) patients had a ring-like pattern of scar (Group A), 78 (11%) a non ring-like pattern (Group B), and 580 (85%) had normal CMR with no LGE (Group C). Group A patients were younger compared to Group B and Group C (median age 40 vs. 52 vs. 45 years, p<0.01), more frequently males (96% vs. 82% vs. 55%, p<0.01) with a higher prevalence of family history of sudden cardiac death/cardiomyopathy (39% vs. 14% vs. 6%; p<0.01), and more frequent history of unexplained syncope (18% vs. 9% vs. 3%, p<0.01). All patients in Group A showed VA with a right bundle branch block morphology vs. 69% in Group B and 21% in Group C (p<0.01). Multifocal VA were observed in 46% of Group A patients compared to 26% of Group B and 4% of Group C (p<0.01). After a median follow-up of 61 (34-84) months, the composite outcome occurred in 14 patients (50%) in Group A vs. 15 (19%) in Group B and 2 (0.3%) in Group C (p<0.01). After multivariable adjustment, the presence of LGE with ring-like pattern remained independently associated with increased risk of the composite endpoint (HR 68.98, 95% CI 14.67-324.39, p<0.01). Conclusions: In patients with apparently idiopathic non-sustained VA, nonischemic LV scar with a ring-like pattern is associated with malignant arrhythmic events.

Abstract Introduction Papillary fibroelastomas are rare benign primary cardiac tumors that more frequently involve cardiac valves. They are frequently incidentally discovered by echocardiography but may also cause symptoms. Purpose The aim of this study was to characterize several features of histologically confirmed fibroelastomas. Methods Retrospective analysis of patients with echocardiographic suspicion of fibroelastoma between 2009 and 2019 in a single tertiary center. Echocardiography was compared with histology, and echocardiographic, surgical and pathological information about confirmed fibroelastomas was collected. Results 37 patients (P) (54.1% men) with an echocardiographic suspicion and/or histologically confirmed fibroelastoma were included, with a mean age of 58 +- 3 years (min 22, max 82). Echocardiographic report was analyzed in 34P (91.9%), with 32P (94.1%) reporting a likely fibroelastoma and 2P (5.9%) reporting a non-specified mass. 21P (56.8%) had surgery, with 12P (57.1%) having a surgical suspicion of a fibroelastoma, 2P (9.5%) of a mixoma, 1P (4.8%) of a non-specified mass and 6P (28.6%) with undefined suspicion. Of the 21P who had surgery, 66.7% (14P) had a histologically confirmed fibroelastoma, 1P (4.8%) had a mixoma, and 6P (28.6%) had other diagnoses. From the 14P with histologically confirmed fibroelastoma 64.3% had this suspicion by echocardiography and 35.7% had an echocardiogram reporting a non-specified. There was a global concordance between echocardiography and histology in 52.9%. The mean age of confirmed fibroelastoma P was 54 +-5years, and 50% were men. 7P (50%) were asymptomatic, 2 (14.3%) had a stroke, 2 (14.3%) had syncope, 1 (7.1%) had fatigue, 1 (7.1%) had palpitations and 1P had consciousness alteration. In echocardiography most P (71.4%) had only one mass but 1P had 4 different masses. The tumors had a longer axis between 6 and 25mm, with the majority (57.1%) measuring more than 10mm. 12P (85.7%) had valvular fibroelastomas, 50% of these in the aortic valve (3 in non-coronary cusp, 1 in right coronary cusp and 2 non-specified) and 50% in the mitral valve (all in sub-valvular apparatus, involving anterior leaflet, tendinous chord or papillary muscle). 1P had a left ventricular fibroelastoma (apical) and 1P had four masses in the left atrium. Macroscopically 4 lesions had a gelatinous consistency, 2 of them were membranous, 2 were elastic, 2 were friable, 1 was villainous and in 3 of them consistency was not described. The majority (57%) was white, 14% was translucent and in the rest the color was not specified. There was no described recurrence after surgery and there were no deaths registered. Conclusion In this population there was a reasonable concordance between echocardiography and histology, but in some cases the diagnosis was undefined or wrong. 50% of the patients were asymptomatic and the majority had valvular fibroelastomas, but a few had a different location.

Abstract Background In pulmonary embolism (PE) suspicion, several strategies based on clinical criteria and D-dimer (Dd) measurement have been developed in order to reduce resource utilization. However, they used different clinical probability (CP) assessment methods limiting their combination. Purpose To develop and validate a unique probability score integrating most of previous proposals to allow safely reduction of imaging testing. Methods 4 CP levels were previously defined in order to obtain a false negative rate <1.9%: 1) without Dd test: very low CP (PE prevalence <1.9%), 2) with Dd <1000 μg/L: low CP (<15%), 3) with Dd <500 or age x10μg/L: moderate CP (<60%) and 4) precluding PE exclusion on Dd: high CP. We used individual data from 4 prospective cohorts of suspected PE patients in Europe and America (n=11 066) for derivation and internal validation. The variables significantly associated with PE in univariate analysis were included in a multivariate logistic regression model. Points were assigned according to the regression coefficients. The score was validated in two external independent cohorts (n=1554, n=1669). Results PEPS comprised 13 variables: age <50 years (−2), age 50–64 years (−1), heart rate <80 beats/min (−1), chronic lung disease (−1), chest pain and recent dyspnea (+1), syncope (+1), male sex (+1), previous venous thromboembolism (+2), medical or orthopaedic immobilization (+2), estrogenic treatment (+2), oxygen saturation <95% (+3), unilateral lower limb pain (+3) and PE is the most likely diagnosis (+ 5). The rates of false negative and avoidable imaging tests if the PEPS strategy would have been applied were 0.6% [95% CI: 0.3–1.1] and 22.7% [20.2–25.3] in the first external validation cohort, and 0.85 [0.5–1.45] and 26.6% [23.5–29.9] in the second one. Applied retrospectively, PEPS strategy compared favourably with other strategies and combinations. Derivation Int. validation Ext. validation 1 Ext. validation 2 nPE/N % [95% CI] nPE/N % [95% CI] nPE/N % [95% CI] nPE/N % [95% CI] TOTAL 615/5588: 11.0% [10.2–11.9] 432/3726: 11.6% [10.6–12.7] 327/1546: 21.2% [19.2–23.2] 196/1669: 11.7% [10.3–13.4] Very low CP PEPS<0 16/1445: 1.1% [0.7–1.8] 16/946: 1.7% [1.0–2.7] 3/118: 2.5% [0.7–6.8] 5/347: 1.4% [0.6–3.3] Low CP 0≤PEPS<5 127/2620: 4.9% [4.1–5.7] 106/1805: 5.9% [4.9–7.1] 49/611: 8.0% [6.1–10.4] 61/647: 7.2% [5.7–9.1] Moderate CP 5≤PEPS<12 347/1334: 26.0% [23.7–28.4] 243/867: 28.0% [25.1–31.1] 206/715: 28.8% [25.6–32.2] 107/430: 24.9% [21.0–29.2] High CP 12≤PEPS 125/179:69.8% [62.8–76.1] 67/108: 62.0% [52.6–70.6] 69/102: 67.7% [58.1–76.2] 23/45: 51.1% [37.0–65.0] AUC 0.84 [0.83–0.86] 0.82 [0.80–0.84] 0.79 [0.76–0.82] 0.77 [0.74–0.80] CP: Clinical probability; PEPS: Pulmonary Embolism Probability Score. Conclusions A strategy based on the proposed score may lead to a safely substantial reduction of imaging testing. It should now be tested in an outcome interventional study.

Abstract Funding Acknowledgements Type of funding sources: None. OnBehalf Portuguese Registry of Acute Coronary Syndromes Background Acute coronary syndromes (ACS) are frequent and are associated with high levels of comorbidities and complications. Ventricular tachycardia (VT) is one of the most danger and stressful situations in ACS. Objective Evaluate predictors of ventricular tachycardia in ACS. Methods Multicenter retrospective study, based on the Portuguese Registry of ACS between 1/10/2010-4/09/2019. Patients were divided in two groups: A – patients without VT, and B – patients that presented VT on the hospitalization. VT was defined as a register or more of the VT with at least 30 seconds. Logistic regression was performed to assess predictors of VT in ACS patients. Results 25361 in group A (98.6%) and 364 in group B (1.4%). Both groups were similar regarding gender, cardiovascular risk factors, except for dyslipidemia (61.7 vs 51.9%, p &lt; 0.001) and ST-segment elevation myocardial infarction (STEMI) location. Group B was elderly (67 ± 14 vs 70 ± 14, p &lt; 0.001), was admitted directly to the cat lab (10.6 vs 20.4%, p &lt; 0.001), had less time since the onset of symptoms until the admission (383 ± 157 vs 349 ± 121, p = 0.003), but presented higher previous history of heart failure (5.9 vs 10.6%, p &lt; 0.001), peripheral vascular disease (5.5 vs 8.4%, p = 0.015), chronic obstructive pulmonary disease (COPD) (4.4 vs 7.9%, p = 0.001) and dementia (1.7 vs 3.2%, p = 0.038). At admission presented higher levels of STEMI (42 vs 67%, p &lt; 0.001), dyspnea (29 vs 18.1%, p &lt; 0.001), syncope (1.3 vs 6.6%, p &lt; 0.001), cardiac arrest (0.4 vs 4.4%, p &lt; 0.001), Killip-Kimball classification &gt; I (14.8 vs 40.5%, p &lt; 0.001) and atrial fibrillation at admission (AF) (7.1 vs 15.3%, p &lt; 0.001). Ivabradine (3.7 vs 7.6%, p &lt; 0.001), aldosterone receptor antagonists (10.2 vs 24%, p &lt; 0.001), diuretic (28 vs 57.2%, p &lt; 0.001), amiodarone (5.6 vs 53.5%, p &lt; 0.001), digoxin (1.4 vs 4.7%, p &lt; 0.001) were more prevalent used in the admission. Group B exhibited higher multivessel disease (MVD) (51.5 vs 61.5%, p &lt; 0.001), culprit as common coronary trunk (CT) (1.7 vs 4.2%, p = 0.024), hybrid revascularization (0.8 vs 2%, p = 0.032) and left ventricular ejection fraction (LVEF)&lt;50% (38.7 vs 71%, p &lt; 0.001). On the other hand, the used of beta block (81.4 vs 62.3%, p &lt; 0.001), angiotensin-converting-enzyme inhibitor (85.5 vs 74.4%, p &lt; 0.001) and calcium channel blockers (10.1 vs 24%, p &lt; 0.001) since had a protect effect. Regarding reinfarction (0.9 vs 2.5%, p = 0.007), de novo heart failure (15.1 vs 50.3%, p &lt; 0.001), atrioventricular block (2.2 vs 17%, p &lt; 0.001), stroke (1.4 vs 4.9%, p &lt; 0.001) and death (3.4 vs 26.9%, p &lt; 0.001), all were higher in Group B. Logistic regression revealed COPD (odds ratio (OR) 1.9, p = 0.010, confidence interval (CI) 1.17-3.10), STEMI (OR 2.73, p &lt; 0.001, CI 2.00-3.73), AF (OR 2.30, p &lt; 0.001, CI 1.52-3.49), MVD (OR 1.44, p = 0.012, CI 1.08-1.92), CT (OR 2.87, p = 0.003, CI 1.45-5.69) and LVEF &lt; 50% (OR 3.44, p &lt; 0.001, CI 2.52-4.71) as predictors of VT in ACS. Conclusions COPD, STEMI, AF, MVD, CT and LVEF &lt; 50% were predictors of VT in ACS.

The past two decades have seen the publication of at least half a dozen books that consider the part that fairs, circuses, sideshows and freakshows play in the continuing cultural labour to define, categorise and control the human body, including Robert Bogdan’s Freakshow, Rosemarie Garland-Thomson’s Extraordinary Bodies, and her edited collection Freakery, and Rachel Adams’s Sideshow USA. These writers cast the freakshow as a theatre of culture, worthy of critical attention precisely because of the ways in which it has provided a popular forum for staging, solidifying and transforming ideas about the body and bodily difference, and because of its prominence in the project of modernity (Garland-Thomson “From Wonder to Error” 2-13). They point to the theatrical mechanisms by which the freakshow maps cultural anxieties about corporeal difference across ‘suitable’ bodies. For, as Bogdan (3) says, being a freak is far more than a fact of biology. The freak personae that populate the Western cultural imaginary—the fat lady, the bearded lady, the hermaphrodite and the geek—can only be produced by a performative isolation, manipulation and exaggeration of the peculiar characteristics of particular human bodies. These peculiarities have to be made explicit, in Rebecca Schneider’s (1) terms; the horror-inducing tropes of the savage, the bestial and the monstrous have to be cast across supposedly suitable and compliant flesh. The scopic mechanisms of the freakshow as a theatre, as a cabinet of corporeal curiosities in which spectators are excited, amazed and edified by the spectacle of the extraordinary body, thus support the specific forms of seeing and looking by which freak bodies are produced. It would, however, be a mistake to suggest that the titillating threat of this face-to-face encounter with the Levinasian other fully destabilises the space between signifier and signified, between the specific body and the symbolic framework in which it sits. In a somewhat paradoxical cultural manoeuvre, the ableist, sexist and racist symbolic frameworks of the freakshow unfold according to what Deleuze and Guattari (178) would call a logic of sameness. The roles, relationships and representational mechanisms of the freakshow—including the ‘talkers’ that frame the spectator’s engagement with the extraordinary body of the freak—in fact function to delineate “degrees of deviance” (178) or difference from an illusory bodily norm. So configured, the monstrous corporeality of the freak is also monstrously familiar, and is made more so by the freak spectacle’s frequent emphasis on the ways in which non-normative bodies accommodate basic functions such as grooming and eating. In such incarnations, the scenography and iconography of the freakshow in fact draws spectators into performative (mis)recognitions that manage the difference of other bodies by positioning them along a continuum that confirms the stability of the symbolic order, and the centrality of the able, white, male self in this symbolic order. Singular, specific, extraordinary bodies are subject to what might, in a Levinasian paradigm, be called the violence of categorisation and comprehension (“Is Ontology Fundamental?” 9). The circumstances of the encounter reduce the radical, unreadable difference of the other, transporting them “into the horizon of knowledge” (“Transcendence and Height” 12), and transforming them into something that serves the dominant cultural logic. In this sense, Petra Kuppers suggests, “the psychic effects of the freak spectacle have destabilizing effects, assaulting the boundaries of firm knowledge about self, but only to strengthen them again in cathartic effect” (45). By casting traits they abhor across the freak body (Garland-Thomson Extraordinary Bodies 55-56), spectators become complicit in this abhorrence; comforted, cajoled and strangely pleasured by a sense of distance from what they desire not to be. The subversive potential of the prodigious body evaporates (Garland-Thomson “From Wonder to Error” 3; Extraordinary Bodies 78). An evaporation more fully effected, writers on the freakshow explain, as the discursive construct of the freak was drawn into the sphere of medical spectacle in the late nineteenth century. As the symbolic framework for understanding disabled bodies ‘advances’ from the freak, the monster and the mutant to the medical specimen (Garland-Thomson “From Wonder to Error” 13; Extraordinary Bodies 70, 78-80; Synder and Mitchell 370-373; Stephens 492), the cultural trajectory away from extraordinary bodies with the capacity to expand the classes and categories of the human is complete. The medical profession finally fulfils the cultural compulsion to abstract peculiar bodily characteristics into symptoms, and, as Foucault says in The Birth of the Clinic, these symptoms become surveillable, and controllable, within an objective schema of human biology. Physical differences and idiosyncrasies are “enclosed within the singularity of the patient, in that region of ‘subjective symptoms’ that—for the doctor—defines not only the mode of knowledge, but the world of objects to be known” (xi). The freak body becomes no more than an example of human misfortune, to be examined, categorised and cared for by medical experts behind closed doors, and the freakshow fades from the stage of popular culture (Garland-Thomson Extraordinary Bodies 70). There can, of course, be no denying the need to protect people with disabilities from exploitation at the service of a cultural fetish that enacts a compulsion to define and control bodily difference. However, recent debates in disability, cultural and performance studies have been characterised by the desire to reconsider the freakshow as a site for contesting some of the cultural logics it enacts. Theorists like Synder and Mitchell argue that medical discourse “disarms the [disabled] body of its volatile potency” (378), in the process denying people with disabilities a potentially interesting site to contest the cultural logics by which their bodies are defined. The debate begins with Bogdan’s discussion of the ways in which well-meaning disability activists may, in their desire to protect people with disabilities from exploitative practices and producers, have overlooked the fact that freakshows provided people with disabilities a degree of independence and freedom otherwise impossible (280-81). After all, as disabled performer Mat Fraser says in his documentary Born Freak, The Victorian marvels found fame and some fortune, and this actually raised the visibility, even the acceptability, of disabled people in general during a time when you could be attacked on the streets just for looking different. These disabled performers found independence and commanded respect.… If I had been born a hundred years ago, given the alternatives of—what? living the life of a village monster or idiot or being poked or prodded for cataloguing by medical types—there’s no doubt about it, I would have wanted to be in show business. (Born Freak) This question of agency extends to discussion of whether disabled performers like Fraser can, by consciously appropriating the figures, symbols and scenography of the freakshow, start to deconstruct the mechanisms by which this contested sphere of cultural practice has historically defined them, confronting spectators with their own complicity in the construction of the freak. In her analysis of Coney Island’s Sideshows by the Seashore, Elizabeth Stephens reflects on this contemporary sideshow’s capacity to reclaim the political currency of the freak. For Stephens, sideshows are sites in which norms about the body, its limits and capabilities, are theatricalized and transformed into spectacle, but, in which, for this very reason, they can also be contested. Non-normative bodies are not simply exhibited or put on display on the sideshow stage, but are rather performed as the unstable—indeed, destabilising—product of the dynamic interrelationship between performer, audience and theatrical space. (486) Theorists like Stephens (487) point to disabled performers who manipulate the scopic and discursive mechanisms of the sideshow, street performance and circus, setting them against more or less personal accounts of the way their bodies have historically been seen, to disrupt the modes of subjection the freak spectacle makes possible and precipitate a crisis in prescribed categories of meaning. Stephens (485-498) writes of Mat Fraser, who reperformed the historical personal of the short-armed Sealo the Sealboy, and Jennifer Miller, who reperformed the persona of Zenobia the bearded lady, at Sideshows by the Seashore. Sharon Mazer (257-276) writes of Katy Dierlam, who donned a Dolly Dimples babydoll dress to reperform the clichéd fat lady figure Helon Melon, again at Sideshows by the Seashore, counterposing Melon’s monstrous obesity with comments affirming her body’s potent humanity, and quotes from feminist scholars and artists such as Suzy Orbach, Karen Finley and Annie Sprinkle. Sharon Synder and David Mitchell (383) write of Mary Duffy, who reperforms the armless figure of the Venus de Milo. These practices constitute performative interventions into the cultural sphere, aligned with a broader set of contemporary performance practices which contest the symbolic frameworks by which racial and gender characteristics are displayed on the popular stage in similar ways. Their confrontational performance strategies recall, for instance, the work of American performance artist Guillermo Gómez-Peña, who reappropriates colonial and pop cultural figurations of the racialised body in works like Two Undiscovered Amerindians Visit…, in which he and Coco Fusco cast themselves as two caged savages. In such works, Gómez-Peña and his collaborators use parallel performance strategies to engage the “spectacle of the Other-as-freak” (297). “The idea is to exaggerate the features of fear and desire in the Anglo imagination and ‘spectacularize’ our ‘extreme identities’, so to speak, with the clear understanding that these identities have been invented by the surgery of the global media” (297) Gómez-Peña says. These remobilisations of the monstrous operate within the paradigm of the explicit, a term Schneider coined a decade ago to describe the performance art practices of women who write the animalised, sexualised characteristics with which they are symbolically aligned across their own corporeally ‘suitable’ bodies, replaying their culturally assigned identities “with a voluble, ‘in your face’ vengeance” (100), “a literal vengeance” (109). Such practices reclaim the destablising potential of the freak spectacle, collapsing, complicating or exploding the space between signifier and signified to show that the freak is a discursive construct (22-23), and thus for Schneider, following Benjamin, threatening the whole symbolic system with collapse (2, 6). By positioning their bodies as a ground that manifestly fails to ground the reality they represent, these performers play with the idea that the reality of the freak is really just part of the order of representation. There is nothing behind it, nothing beyond it, nothing up the magician’s sleeve—identity is but a sideshow hall of mirrors in which the ‘blow off’ is always a big disappointment. Bodies marked by disability are not commodified, or even clearly visible, in the Western capitalist scopic economy in the same way as Schneider’s women performers. Nevertheless, disabled performers still use related strategies to reclaim a space for what Schneider calls a postmodern politics of transgression (4), exposing “the sedimented layers of signification themselves” (21), rather than establishing “an originary, true or redemptive body” (21) beneath. The contestational logic of these modes of practice notwithstanding, Stephens (486) notes that performers still typically cite a certain ambivalence about their potential. There are, after all, specific risks for people with disabilities working in this paradigm that are not fully drawn out in the broader debate about critical reappropriation of racist and sexist imagery in performance art. Mobilisations of the freak persona are complicated by the performer’s own corporeal ‘suitability’ to that persona, by the familiar theatrical mechanisms of recognition and reception (which can remain undertheorised in meta-level considerations of the political currency of the freakshow in disability and cultural—rather than performance—studies), and by a dominant cultural discourse that insists on configuring disability as an individual problem detached from the broader sphere of identity politics (Sandahl 598-99). In other words, the territory that still needs to be addressed in this emergent field of practice is the ethics of reception, and the risk of spectatorial (mis)recognitions that reduce the political potency of the freak spectacle. The main risk, of course, is that mobilisations of the freak persona may still be read by spectators as part of the phenomenon they are trying to challenge, the critical counterpositions failing to register, or failing to disrupt fully the familiar scopic and discursive framework. More problematically, the counterpositions themselves may be reduced by spectators to a rhetorical device that distances them from the corporeal reality of the encounter with the other, enabling them to interpret or explain the experience of disability as a personal experience by which an individual comes to accommodate their problems. Whilst the human desire to construct narrative and psychological contexts for traumatic experience cannot be denied, Carrie Sandahl (583) notes that there is a risk that the encounter with the disabled body will be interpreted as part of the broader phenomenon Synder and Mitchell describe in Narrative Prosthesis, in which disability is little more than a metaphor for the problems people have to get past in life. In this interpretative paradigm, disability enters a discursive and theoretical terrain that fails to engage fully the lived experience of the other. Perhaps most problematically, mobilisations of the freak persona may be read as one more manifestation of the distinctively postmodern desire to break free from the constraints of culturally condoned identity categories. This desire finds expression in the increasingly prevalent cultural phenomenon of voluntary enfreakment, in which people voluntarily differentiate, or queer their own experience of self. As Fraser says when he finds out that a company of able-bodied freaks is competing with him for audiences at the Edinburgh Fringe Festival, “[t]he irony is, these days, everyone is trying to get in on our act” (Born Freak). In a brave new world where everybody wants to be a freak, activist artists “must be watchful”, Gómez-Peña warns, “for we can easily get lost in the funhouse of virtual mirrors, epistemological inversions, and distorted perceptions” (288). The reclamation of disability as a positive metaphor for a more dispersed set of human differences in the spectacle of daily life (287-98), and in theoretical figurations of feminist philosophy that favour the grotesque, the monstrous and the mechanical (Haraway Simians, Cyborgs and Women; Braidotti Nomadic Subjects), raises questions for Garland-Thomson (“Integrating Disability, Transforming Feminist Theory” 9) and Sandahl (581-83). If “disability serves as a master trope for difference,” Sandahl says, then anybody can adopt it “…to serve as a metaphor expressing their own outsider status, alienation and alterity, not necessarily the social, economic and political concerns of actual disabled people” (583). The work of disabled performers can disappear into a wider sphere of self-differentiated identities, which threatens to withdraw ‘disability’ as a politically useful category around which a distinctive group of people can generate an activist politics. To negotiate these risks, disabled performers need to work somewhere between a specific, minoritarian politics and a universal, majoritarian politics, as Sedgwick describes in Epistemology of the Closet (91; cf. Garland-Thompson “Integrating Disability, Transforming Feminist Theory” 5; cf. Stephens 493). Performers need to make their experience of otherness explicit, so that their corporeal specificity is not abstracted into a symbolic system that serves the dominant cultural logic. Performers need to contextualise this experience in social terms, so that it is not isolated from the sphere of identity politics. But performers cannot always afford to allow the freak persona to become one more manifestation of the myriad idiosyncratic identities that circulate in the postmodern popular imaginary. It is by negotiating these risks that performers encourage spectators to experience—if only fleetingly, and provisionally—a relationship to the other that is characterised not by generalisation, domestication and containment (Levinas “Substitution” 80, 88), but by respect for the other’s radical alterity, by vulnerability, and, in Derrida’s reformation of Levinasian ethics, by a singular, reciprocal and undecidable responsibility towards the other (Derrida 60-70). This is what Levinas would call an ethical relationship, in which the other exists, but as an excess, a class of being that can be recognised but never seized by comprehension (“Is Ontology Fundamental?” 7, “Transcendence and Height” 17), or sublimated as a category of, or complement to, the same (13, “Meaning and Sense” 51). Mat Fraser’s mobilisation of Sealo the Sealboy is one of the most engaging examples of the way disabled performers negotiate the complexities of this terrain. On his website, Fraser says he has always been aware of the power of confrontational presentations of his own body, and has found live forms that blur the boundaries between freakshow, sideshow and conventional theatre the best forums for “the more brutal and confrontational aspect of my investigation into disability’s difficult interface with mainstream cultural concerns” (MatFraser.co.uk). Fraser’s appropriation of Sealo was born of a fascination with the historical figure of Stanley Berent. “Stanley Berent was an American freakshow entertainer from the 1940s who looked like me,” Fraser says. “He had phocomelia. That’s the medical term for my condition. It literally means seal-like limbs. Berent’s stage name was Sealo the Sealboy” (Born Freak). Fraser first restaged Sealo after a challenge from Dick Zigun, founder of the modern Sideshows by the Seashore. He restaged Berant’s act, focused on Berant’s ability to do basic things like shaving and sawing wood with his deformed hands, for the sideshow’s audiences. While Fraser had fun playing the character on stage, he says he felt a particular discomfort playing the character on the bally platform used to pull punters into the sideshow from the street outside. “There is no powerful dynamic there,” Fraser laments. “It’s just ‘come look at the freak’” (Born Freak). Accordingly, after a season at Sideshows by the Seashore, Fraser readapted the experience as a stage play, Sealboy: Freak, in which Sealo is counterposed with the character Tam, “a modern disabled actor struggling to be seen as more than a freak” (Born Freak). This shift in the theatrical mechanisms by which he stages the freak gives Fraser the power to draw contemporary, politically correct spectators at the Edinburgh Fringe Festival into the position of sideshow gawkers, confronting them with their own fascination with his body. A potent example is a post-audition scene, in which Tam says I read this book once that said that the mainstream will only see a disabled performer in the same way they view a performing seal. Very clever, but just mimicry. No. No it can’t be like that anymore. We’ve all moved on. People are no longer more fascinated by how I do things, rather than what I say. I am an actor, not a fucking freak. (Born Freak) But, as Tam says this, he rolls a joint, and spectators are indeed wrapped up in how he does it, hardly attending to what he says. What is interesting about Fraser’s engagement with Sealo in Sealboy: Freak is the way he works with a complicated—even contradictory—range of presentational strategies. Fraser’s performance becomes explicit, expositional and estranging by turns. At times, he collapses his own identity into that of the freak, the figure so stark, so recognisable, so much more harshly drawn than its real-life referent, that it becomes a simulacrum (cf. Baudrillard 253-282), exceeding and escaping the complications of the human corporeality beneath it. Fraser allows spectators to inhabit the horror, and the humour, his disabled identity has historically provoked, reengaging the reactions they hide in everyday life. And, perhaps, if they are an educated audience at the Fringe, applauding themselves for their own ability to comprehend the freak, and the crudity of sideshow display. However, self-congratulatory comprehension of the freak persona is interrupted by the discomforting encounter with Tam, suspending—if only provisionally—spectators’ ability to reconcile this reaction with their credentials as a politically correct audience. What a closer look at mobilisations of the freak in performances such as Fraser’s demonstrates is that manipulating the theatrical mechanisms of the stage, and their potential to rapidly restructure engagement with the extraordinary body, enables performers to negotiate the risk of (mis)recognition embedded in the face-to-face encounter between self and spectator. So configured, the stage can become a site for contesting the cultural logic by which the disabled body has historically been defined. It can challenge spectators to experience—if fleetingly—the uncertainties of the face-to-face encounter with the extraordinary body, acknowledging this body’s specificity, without immediately being able to abstract, domesticate or abdicate responsibility for it—or abdicate responsibility for their own reaction to it. Whilst spectators’ willingness to reflect further on their complicity in the construction of the other remains an open and individual question, these theatrical manipulations can at least increase the chance that the cathartic effect of the encounter with the so-called freak will be disrupted or deferred. References Adams, Rachel. Sideshow USA: Freaks and the American Cultural Imagination. Chicago, IL: University of Chigaco Press, 2001. Baudrillard, Jean. “The Precision of Simulacra”. Art After Modernism: Rethinking Representation. Ed. Brian Wallis. Boston, MA: David R. Godine, 1984, 253-282. Born Freak. Dir. Paul Sapin. Written Paul Sapin and Mat Fraser. 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Acknowledgements An earlier version of this paper was presented at “Extreme States: Issues of Scale—Political, Performative, Emotional”, the Australasian Association for Drama Theatre and Performance Studies Annual Conference 2007.