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Patients with cardiogenic shock (CS) suffer high rates of in-hospital mortality, with little evidence guiding management. The impact of valvular heart disease in patients with CS remains unclear. We therefore conducted a post hoc analysis of the randomized Dobutamine Compared to Milrinone (DOREMI) trial to determine the impact of valvular disease on outcomes in patients with CS.We defined significant valvular disease as moderate to severe or greater valvular stenosis or regurgitation and divided participants into a group of those with significant valvular disease and those without. Our primary outcome was all-cause in-hospital mortality. Secondary endpoints included resuscitated cardiac arrest; cardiac transplantation or mechanical circulatory support; nonfatal myocardial infarction; stroke; initiation of renal replacement therapy; as well as changes in renal function, perfusion, and hemodynamics over time.One hundred eighty-nine (98.4%) participants from the DOREMI trial were included in our analysis, and 74 (39.2%) had significant valvular dysfunction. Thirty-six (48.7%) patients with valvular disease died in hospital, compared with 37 (32.2%) in the comparator group (relative risk, 1.5; 95% confidence interval 1.06-2.15; P = 0.02). Patients with aortic stenosis (2.42, 1.56-3.75; P0.01) and patients with mitral regurgitation (1.63, 1.1-2.43; P = 0.02) also had increased incidence of in-hospital mortality. There was no significant difference in any secondary outcomes among groups, apart from variances in mean arterial pressure observed in patients with valvular disease (P0.01).Significant valvular dysfunction is associated with increased in-hospital mortality in patients with CS. Randomized clinical trial data are needed to further elucidate the role of transcatheter valvular interventions as a therapeutic target in this population.

Ipsilateral approach in patients requiring cardiac implantable electronic device (CIED) revision or upgrade may not be feasible, primarily due to vascular occlusion. If a new CIED is implanted on the contralateral side, a common practice is to explant the old CIED to avoid device interaction.The purpose of this study was to assess a conservative approach of abandoning the old CIED after implanting a new contralateral device.We used an artificial intelligence algorithm to analyze postimplant chest radiographs to identify those with multiple CIEDs. Outcomes of interest included device interaction, abandoned CIED elective replacement indicator (ERI) behavior, subsequent programming changes, and explant of abandoned CIED. Theoretical risk of infection with removal of abandoned CIED was estimated using a validated scoring system.Among 12,045 patients, we identified 40 patients with multiple CIEDs. Occluded veins were the most common indication for contralateral implantation (n = 27 [67.5%]). Fifteen abandoned CIEDs reached ERI, with 4 reverting to VVI 65. One patient underwent explant due to device interaction, and 2 required device reprogramming. Of 32 patients with an implantable cardioverter-defibrillator, 8 (25%) had treated ventricular arrhythmia. There were no failed or inappropriate therapies due to interaction. Eighteen patients (45%) had hypothetical1% annual risk of hospitalization for device infection if the abandoned CIED had been explanted.In patients requiring new CIED implant on the contralateral side, abandoning the old device is feasible. This approach may reduce the risk of infection and concerns regarding abandoned leads and magnetic resonance imaging scans. Knowledge of ERI behavior is essential to avoid device interactions.

Background Cardiogenic shock is associated with substantial morbidity and mortality. Although inotropic support is a mainstay of medical therapy for cardiogenic shock, little evidence exis...

Background There are little data on the use of virtual care for patients with arrhythmia. We evaluated a virtual clinic platform, in conjunction with specialist care, for patients with symptomatic atrial fibrillation (AF). Methods This was a prospective, observational cohort study evaluating an online educational and treatment platform, with a randomized sub-study examining the use of an ambulatory single-lead electrocardiogram heart monitor (AHM). Follow-up was 6 months. The main outcome was patients’ platform use; success was defined as 90% of patients using the platform at least once, and 75% using it at least twice. The primary outcome in the AHM sub-study was Atrial Fibrillation Symptom Severity (AFSS) score. Other outcomes included patient satisfaction questionnaires, quality of life, emergency department visits, and hospitalizations for AF. Results We enrolled 94 patients between July 2018 and May 2019; 83% of patients logged in at least once and 54.3% more than once. Patients who were older, were male, or had new-onset AF were more likely to log in to the platform. Satisfaction scores were high; 70%–94% of patients responded favorably. Quality-of-life scores improved at 3 and 6 months. In the AHM sub-study (n = 71), those who received an AHM had lower AFSS scores (least square mean difference -2.52, 95% CI -4.48 to -0.25, P = .03). There was no difference in emergency department visits or hospitalizations. Conclusion The online platform did not reach our feasibility target but was well received. Allocation of an AHM was associated with improved quality of life. Virtual AF care shows promise and should be evaluated in further research.

Point-of-care ultrasound (POCUS) is an important tool for diagnosis and management across medical specialties. This scoping review consolidates POCUS education literature, examining how curricula are developed, implemented, and assessed. We identify literature gaps, explore directions for further research, and provide recommendations for curriculum development, implementation, and improvement. MethodsWe conducted a scoping review per the framework outlined by Arksey & O’Malley. A systematic search of the MEDLINE, EMBASE, Cochrane, ERIC, Web of Science, and Scopus databases was conducted to identify published, English language literature, on POCUS education in undergraduate or graduate medical training.ResultsOf 6,164 articles identified, 421 were analyzed in depth. Curricular content included diverse diagnostic and therapeutic applications, varying significantly by specialty. Teaching modalities included in-person didactics (74%), human models (58%), simulation (33%), and web-based didactics (18%). Several studies showed better outcomes for structured vs. apprenticeship curricula, hands-on teaching vs. didactic lectures, and human models vs. simulators. Web-based didactics were as effective as in-person didactics and conveyed benefits in reusability, cost, and instructor time. Dedicated electives and boot-camps were identified as effective. Few curricula assessed knowledge retention (5%), clinical decision making (3%), learner behavior (12%), or patient outcomes (6%). ConclusionScholarly POCUS education literature is expanding. Curricular content varies and should be tailored to specialty needs. Structured curricula utilizing hands-on learning, electives, and boot-camps can enhance educational outcomes. Higher-level outcomes such as knowledge retention, clinical decision making, learner behavior, and patient outcomes, are lacking and should be a focus of further researchResumeL’échographie au point de service (POCUS) est un outil important pour le diagnostic et la gestion dans toutes les spécialités médicales. Cette étude de portée consolide la littérature éducative POCUS, en examinant comment les programmes d’enseignement sont élaborés, mis en œuvre et évalués. Nous identifions les lacunes de la littérature, explorons les directions à prendre pour des recherches plus approfondies et fournissons des recommandations pour le développement, la mise en œuvre et l’amélioration des programmes d’enseignement. MéthodesNous avons procédé à un examen de portée conformément au cadre défini par Arksey & O’Malley. Une recherche systématique dans les bases de données MEDLINE, EMBASE, Cochrane, ERIC, Web of Science et Scopus a été effectuée afin d’identifier les publications en langue anglaise sur l’enseignement POCUS dans le cadre de la formation médicale de premier ou de deuxième cycle. RésultatsSur les 6 164 articles identifiés, 421 ont fait l’objet d’une analyse approfondie. Le contenu des programmes d’études comprenait diverses applications diagnostiques et thérapeutiques, variant considérablement selon les spécialités. Les modalités d’enseignement comprenaient la didactique en personne (74 %), les modèles humains (58 %), la simulation (33 %) et la didactique basée sur le web (18 %). Plusieurs études ont montré de meilleurs résultats pour les programmes structurés par rapport aux programmes d’apprentissage, l’enseignement pratique par rapport aux cours magistraux didactiques, et les modèles humains par rapport aux simulateurs. La didactique basée sur le web était aussi efficace que la didactique en personne et présentait des avantages en termes de réutilisation, de coût et de temps de l’instructeur. Les cours optionnels et les camps d’entraînement ont été jugés efficaces. Peu de programmes ont évalué la rétention des connaissances (5 %), la prise de décision clinique (3 %), le comportement des apprenants (12 %) ou les résultats pour les patients (6 %). ConclusionLa littérature éducative POCUS est en pleine expansion. Le contenu des programmes d’études varie et doit être adapté aux besoins spécifiques. Des programmes structurés utilisant un apprentissage pratique, des cours optionnels et des camps d’entraînement peuvent améliorer les résultats scolaires. Des résultats de plus haut niveau, tels que la rétention des connaissances, la prise de décision clinique, le comportement de l’apprenant et les résultats pour le patient, font défaut et devraient faire l’objet de recherches plus approfondies.

Inotropic support is widely used in the management of cardiogenic shock (CS). Existing data on the incidence and significance of arrhythmic events in patients with CS on inotropic support is at high risk of bias.The Dobutamine Compared to Milrinone (DOREMI) trial randomized patients to receive dobutamine or milrinone in a double-blind fashion. Patients with and without arrhythmic events (defined as arrhythmias requiring intervention or sustained ventricular arrhythmias) were compared to identify factors associated with their occurrence, and to examine their association with in-hospital mortality and secondary outcomes.Ninety-two patients (47.9%) had arrhythmic events, occurring equally with dobutamine and milrinone (P = 0.563). The need for vasopressor support at initiation of the inotrope and a history of atrial fibrillation were positively associated with arrhythmic events, whereas predominant right ventricular dysfunction, previous myocardial infarction, and increasing left ventricular ejection fraction were negatively associated with them. Supraventricular arrhythmic events were not associated with mortality (relative risk [RR], 0.97; 95% confidence interval [CI], 0.68-1.40; P = 0.879) but were positively associated with resuscitated cardiac arrests and hospital length of stay. Ventricular arrhythmic events were positively associated with mortality (RR, 1.66; 95% CI, 1.13-2.43; P = 0.026) and resuscitated cardiac arrests. Arrhythmic events were most often treated with amiodarone (97%) and electrical cardioversion (27%), which were not associated with mortality.Clinically relevant arrhythmic events occur in approximately one-half of patients with CS treated with dobutamine or milrinone and are associated with adverse clinical outcomes. Five factors may help to identify patients most at risk of arrhythmic events.

Atrial fibrillation (AF) recurs post-ablation in 30-40% of patients. The approach to a repeat ablation, beyond isolation of reconnected pulmonary veins (PVs), is not well established. We sought to prospectively assess outcomes and predictors of recurrence among consecutive patients who underwent repeat AF ablation with a standardized approach.This was a single-center prospective study of consecutive patients who underwent repeat AF ablation. Our protocol consisted of six steps: PV re-isolation, ablation of left atrial low-voltage areas (LVAs), ablation of isoproterenol-induced non-PV triggers, electrophysiology study (EPS) and ablation of induced AVNRT/AVRT, ablation of induced clinical atrial flutters, and lastly empiric ablation as per operator discretion if no other ablation was performed.Among 725 AF ablations performed during the study period, 74 were repeat ablations. Of those undergoing repeat ablation, 53 (72%) had PV reconnection, 30 (41%) had LVAs, seven (10%) had non-PV triggers, five (7%) had AVNRT, and 15 (20%) had typical atrial flutter. Following repeat ablation, arrhythmia-free survival was 65% at 1 year. The absence of PV reconnection was the only factor independently associated with recurrence after repeat ablation (recurrence rate 71%, adjusted OR 7.91, 95% CI 2.31-27.16, p = 0.001).A comprehensive approach to repeat AF ablation including PV re-isolation, LVA ablation, non-PV trigger ablation, EPS, and flutter ablation was associated with a 65% 1-year arrhythmia-free survival. The absence of PV reconnection was the only independent predictor of arrhythmia recurrence. Further research is needed to identify therapies beyond PV isolation for patients undergoing repeat ablation.

Introduction: Cardiogenic shock (CS) is associated with significant morbidity and mortality. Although inotropic support is a mainstay of medical therapy for CS, little evidence exists to guide the selection of inotropic agents in clinical practice. Methods: In this double blind randomized controlled trial, we assigned patients with SCAI class B to E shock to either milrinone or dobutamine for inotropic support. Therapy was titrated based on clinical, biochemical and hemodynamic response as evaluated by the treating physician. The primary outcome was a combined endpoint of in hospital mortality, non-fatal MI, stroke, new initiation of renal replacement therapy (RRT), need for MCS or cardiac transplant, or cardiac arrest with successful resuscitation. Secondary outcomes included individual components of the primary outcome. Results: Among 192 participants, there was no significant difference in the primary outcome, occurring in 49% (47 of 96) of patients in the milrinone arm and 54% (52 of 96) patients in the dobutamine group (RR 0.90, 95% CI of 0.69-1.19, p-value = 0.47). There were also no differences in important secondary outcomes between milrinone and dobutamine, including in-hospital mortality 37% (35 of 96) vs 43% (41 of 96) (RR 0.85, 95% CI 0.60-1.21, p-value = 0.38) or need for RRT 22% (21 of 96) vs 17% (16 of 96) (RR 1.31, 95% CI 0.73-2.36, p-value = 0.36). Conclusions: In this randomized clinical trial of milrinone and dobutamine in CS, there was no difference in the primary composite outcome or in important secondary outcomes. The selection of inotropic agent could reasonably be based on physician comfort, cost and individual response to therapy.

Background Recent data have suggested a substantial incidence of atrial arrhythmias (AAs) in cardiac sarcoidosis (CS). Our study aims were to first assess how often AAs are the presenting feature of previously undiagnosed CS. Second, we used prospective follow‐up data from implanted devices to investigate AA incidence, burden, predictors, and response to immunosuppression. Methods and Results This project is a substudy of the CHASM‐CS (Cardiac Sarcoidosis Multicenter Prospective Cohort Study; NCT01477359). Inclusion criteria were presentation with clinically manifest cardiac sarcoidosis, treatment‐naive status, and implanted with a device that reported accurate AA burden. Data were collected at each device interrogation visit for all patients and all potential episodes of AA were adjudicated. For each intervisit period, the total AA burden was obtained. A total of 33 patients met the inclusion criteria (aged 56.1±7.7 years, 45.5% women). Only 1 patient had important AAs as a part of the initial CS presentation. During a median follow‐up of 49.1 months, 11 of 33 patients (33.3%) had device‐detected AAs, and only 2 (6.1%) had a clinically significant AA burden. Both patients had reduced burden after CS was successfully treated and there was no residual fluorodeoxyglucose uptake on positron emission tomography scan. Conclusions First, we found that AAs are a rare presenting feature of clinically manifest cardiac sarcoidosis. Second, AAs occurred in a minority of patients at follow‐up; the burden was very low in most patients. Only 2 patients had clinically significant AA burden, and both had a reduction after CS was treated. Registration URL: https://www.clini​caltr​ials.gov ; unique identifier NCT01477359.

BACKGROUND Recurrence of atrial fibrillation (AF) post-ablation occurs in 30-50% of patients. The approach to a repeat ablation, beyond isolation of reconnected pulmonary veins (PVs), is not well established. We sought to prospectively assess outcomes and determine predictors of recurrence among consecutive patients who underwent repeat AF ablation with a standardized approach. METHODS AND RESULTS This was a single-center prospective study of consecutive patients who underwent repeat AF ablation. Our ablation protocol consisted of six steps: PV re-isolation, ablation of left atrial low-voltage areas (LVAs), ablation of isoprenaline induced non-PV triggers, electrophysiology study (EPS), and ablation of all clinical and induced atrial flutters. Between February 2017 and January 2020, 725 AF ablations were performed at our center. Of these, 74 were repeat AF ablation using the new protocol. The average age was 62.5 ± 9.2 years; 18% were female; 51% had paroxysmal AF at time of initial ablation. The indication for repeat ablation was paroxysmal AF in 39 (53%) patients, persistent AF in 24 (32%) patients. Among the study cohort of 74 patients undergoing repeat AF ablation, 53 (72%) had PV reconnection; 30 (41%) had LVA; 7 (10%) had non-PV triggers; five (7%) had AVNRT, and five (7%) had typical atrial flutter. Arrhythmia-free survival was 65% at one year. The absence of PV reconnection was the only factor independently associated with recurrence (overall rate 71%, adjusted OR 7.91, 95% CI 2.31-27.16, p=0.001). The arrhythmia-free survival was 29% in those without PV reconnection; meanwhile it was 88% in those with all PVs reconnected. Those with absence of reconnection had more LVA (67% vs 30%, p=0.004) and hypertension (67% vs 30%, p=0.004), suggesting more atrial myopathy. CONCLUSION We describe a comprehensive approach to repeat AF ablation using a standardized protocol that included isolation of reconnected PVs, targeting all areas of low-voltage, ablating all non-PV triggers, inducible SVT, and atrial flutters. Finding reconnected PVs at repeat procedure was a strong predictor of arrhythmia-free survival. Recurrence rates were high among those with absence of PV reconnection, potentially suggesting advanced atrial substrate as the underlying etiology. Our findings demonstrate that PV re-isolation remains the most important treatable cause of atrial arrhythmia recurrence after AF ablation; however further research is needed to investigate therapies beyond PV re-isolation.

Objectives This study investigated the benefit of an implantable cardioverter-defibrillator (ICD) generator replacement in patients who did not have an ongoing theoretical indication for ICD therapy at time of replacement. Background Primary prevention ICD therapy is known to reduce mortality in patients with cardiomyopathy and reduced left ventricular systolic function. The data describing outcomes after generator replacement are limited. Methods This was a retrospective cohort study following patients implanted with primary prevention ICD therapy from 2002 until 2015 who subsequently received a generator replacement. Patients with an ongoing theoretical indication for ICD therapy were defined as either left ventricular ejection fraction ≤35% or having had prior appropriate ICD therapy. Outcomes were mortality, appropriate ICD therapy and shock, inappropriate shock, and device and lead complications. Results A total of 614 patients were identified; 173 (28.2%) underwent a generator replacement and were followed for a mean of 2.9 years after replacement; 144 (83.2%) had an ongoing theoretical indication. Patients with no ongoing theoretical indication (n = 29, 16.7%) had lower mortality (hazard ratio [HR]: 0.39, 95% confidence interval [CI]: 0.15-1.00, p = 0.0495), appropriate shock rate (HR: 0.29, 95% CI: 0.09 to 0.96, p = 0.04), and appropriate ICD therapy rate (HR: 0.30, 95% CI: 0.12 to 0.77, p = 0.012) when compared with patients with ongoing theoretical indication. In the entire cohort, there were low rates of inappropriate shock (4.0%), device complication (5.1%), and lead complication (2.3%). Conclusions In patients with primary prevention ICD therapy who underwent generator replacement, improved left ventricular ejection fraction and lack of prior appropriate ICD therapy at time of replacement were associated with a lower risk of mortality and incident ventricular arrhythmia.

Background—The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition.Methods and Results—We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 27% by other methods [collagen and ADP-induced light transmittance aggregation, platelet function analyzer (PFA-100)]. Platelet response to aspirin as measured by collagen-induced light transmittance aggregation, ADP-induced light transmittance aggregation, PFA-100 (81 mg versus 162 mg,P≤0.05), and urinary 11-dehydrothromboxane B2was dose-related (81 mg versus 325 mg,P=0.003). No carryover effects were observed.Conclusions—The assessment of aspirin resistance is highly assay-dependent; aspirin is an effective blocker of AA-induced platelet function at all doses, whereas higher estimates of resistance were observed with methods that do not use AA as the stimulus. The observation of dose-dependent effects despite nearly complete inhibition of AA-induced aggregation suggests that aspirin may exert antiplatelet properties through non–cyclooxygenase-1 pathways and deserves further investigation.

A large landslide occurred November 21, 2000 at Paatuut, facing the Vaigat Strait onthe west coast of Greenland. 90 million m3 (260 million tons) of mainly basalticmaterial slid very rapidly (average velocity 140 km/h) down from 1,000–1,400 maltitude. Approximately 30 million m3 (87 million tons) entered the sea, creatinga tsunami with an run-up height of 50 m close to the landslide and 28 m at Qullissat,an abandoned mining town opposite Paatuut across the 20 km wide Vaigat strait. Theevent was recorded seismically, allowing the duration of the slide to be estimated tocirca 80 s and also allowing an estimate of the surface-wave magnitude of the slideof 2.3. Terrain models based on stereographic photographs before and after the slidemade it possible to determine the amount of material removed, and the manner ofre-deposition. Simple calculations of the tsunami travel times are in good correspondencewith the reports from the closest populated village, Saqqaq, 40 km from Paatuut, whererefracted energy from the tsunami destroyed a number of boats. Landslides are notuncommon in the area, due to the geology with dense basaltic rocks overlying poorlyconsolidated sedimentary rocks, but the size of the Paatuut slide is unusual. Based onthe observations it is likely at least 500 years since an event with a tsunami of similarproportions occurred. The triggering of the Paatuut slide is interpreted to be caused byweather conditions in the days prior to the slide, where re-freezing melt water inpre-existing cracks could have caused failure of the steep mountain side.

During the afternoon of 21 November 2000 the village of Saqqaq in central West Greenland was hit by a series of giant waves. Ten small boats were destroyed, but luckily neither humans nor dogs were killed. The following day a police inspection by helicopter revealed that the giant waves were caused by a major landslide at Paatuut, c. 40 km north-west of Saqqaq on the south coast of Nuussuaq (Figs 1, 2). The landslide deposits were dark grey-brown in colour, in marked contrast to the snow-covered slopes, and protruded as a lobe into the Vaigat strait. Along the adjacent coastlines the snow had been washed off up to altitudes about 50 m a.s.l. and severe damage had been caused at the abandoned coal-mining town Qullissat on the opposite side of Vaigat.

Background: Secreted PCSK9 regulates LDL levels in plasma by mediating degradation of hepatic LDL receptors. Results: LDL binds to PCSK9 in human plasma and in vitro and inhibits PCSK9 binding to cell surface LDL receptors. Conclusion: A large proportion of circulating PCSK9 is bound to LDL in humans. Significance: Regulatory mechanisms that affect activity of secreted PCSK9 represent novel targets for cholesterol-lowering therapies., Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that binds to the epidermal growth factor-like-A domain of the low density lipoprotein receptor (LDLR) and mediates LDLR degradation in liver. Gain-of-function mutations in PCSK9 are associated with autosomal dominant hypercholesterolemia in humans. Size-exclusion chromatography of human plasma has shown PCSK9 to be partly associated with undefined high molecular weight complexes within the LDL size range. We used density gradient centrifugation to isolate LDL in plasma pooled from 5 normolipidemic subjects and report that >40% of total PCSK9 was associated with LDL. Binding of fluorophore-labeled recombinant PCSK9 to isolated LDL in vitro was saturable with a KD ∼ 325 nm. This interaction was competed >95% by excess unlabeled PCSK9, and competition binding curves were consistent with a one-site binding model. An N-terminal region of the PCSK9 prodomain (amino acids 31–52) was required for binding to LDL in vitro. LDL dose-dependently inhibited binding and degradation of cell surface LDLRs by exogenous PCSK9 in HuH7 cells. LDL also inhibited PCSK9 binding to mutant LDLRs defective at binding LDL. These data suggest that association of PCSK9 with LDL particles in plasma lowers the ability of PCSK9 to bind to cell surface LDLRs, thereby blunting PCSK9-mediated LDLR degradation.

Dr Klein appears concerned about the uniform inhibition of arachidonic acid–induced aggregation observed in the Aspirin-Induced Platelet Effect (ASPECT) trial. We would like to reassure Dr Klein that the compliance of the patients in ASPECT was meticulously recorded and, as reported in the manuscript, was overall 98%. Dr Klein should also be aware of the significance of results determined by double crossover studies such as the ASPECT study and the robust statistical analyses performed.1 Why were we not surprised by the results of the ASPECT study? In a previous study of 223 patients undergoing stenting who were treated with long-term aspirin therapy, only 1 compliant patient was …

Introduction Among FVIII-treated hemophilia A (HA) patients, 25-30% develop FVIII antibodies that inhibit its pro-coagulant function. However, the etiology of FVIII inhibitor formation remains poorly understood, particularly the role played by myeloid innate immune cells. Myeloid-derived suppressor cells (MDSC – CD11b/Gr1 co-expressing, immunosuppressive myeloid cells found in peripheral blood, lymphoid tissue and bone marrow) are expanded in cancer and inhibit adaptive immune responses against tumors. MDSC also mediate organ transplant tolerance. Therefore, we investigated MDSC dynamics during the course of FVIII exposure in HA mice and the potential to harness MDSC as a novel means of mediating FVIII tolerance. Methods 6 to 12 week-old F8-knockout Balb/c hemophilia A mice (HA mice) were used in accordance with Queen's University Animal Care Committee protocols. Over 3 independent experiments, HA mice were either untreated (Week 0; n = 4-6) or tail vein infused weekly for 2 or 4 weeks with 2 IU rhFVIII (Kogenate-FS for 2 experiments or Advate for one; n = 6 and 7, at 2 and 4 weeks) or 200 μl HBSS vehicle alone (n = 4 and 5). Alternatively HA mice were infused weekly with 2 pdFVIII (Wilate) for 2 (n = 2) or 4 weeks (n = 2) or subjected to a 4-day G-CSF preconditioning regimen during Week minus-1 (10 μg/day, SC, in 200 μl HBSS; n = 4) or HBSS alone (n = 4), followed by 2 or 4 weekly rFVIII infusions. Red cell-lysed blood, spleen and bone marrow suspensions were subjected to MDSC flow cytometry using anti-CD11b(Mac1)-APC and anti-Gr1-PE (Miltenyi Biotec). Week 2 and 4 plasma was subjected to anti-FVIII antibody ELISA and Bethesda assays. Means were compared using student's t-test. Results HA mice contained CD11b+Gr1+ MDSC in expected proportions in the blood, bone marrow and spleen. Peripheral blood MDSC proportions declined significantly from baseline following 4 weeks of rFVIII infusions (baseline mean 12.6%, versus 5.9% at 4 weeks, p = 0.041) (Figure 1A). More striking, however, was the observation of diminishing CD11b expression within all three MDSC compartments during the course of rFVIII exposure (magnitude of reduction: 46-65%; at 4 weeks in blood, p = 0.0011; at 2 and 4 weeks in bone marrow, p = 0.0014 and 0.0002; spleen, p = 0.057 and Conclusions For the first time, to our knowledge, we assessed the dynamics of endogenous MDSC in FVIII-treated HA mice, revealing decreased circulating MDSC after 4 weeks of rFVIII exposure, and diminished CD11b expression in all examined MDSC compartments. We hypothesize this phenomenon leads to impaired MDSC function, necessary to mount an optimal adaptive immune response to FVIII, although this awaits further confirmation. Finally, our studies suggest it is feasible to expand MDSC ex vivo from na•ve HA bone marrow for future adoptive transfer experiments, and to expand endogenous HA MDSC using growth factors such as G-CSF, as novel investigative approaches to mediating FVIII tolerance. If warranted by murine studies, G-CSF may be an attractive novel immune tolerance strategy, given extensive clinical experience with human G-CSF administration. Disclosures: No relevant conflicts of interest to declare.

The East Greenland margin consists of a number of sedimentary basins, platforms and structural highs (Figs 1, 2). Due to the challenges imposed by the Arctic climate, the region is in an early stage of exploration, and knowledge of the geology and petroleum potential of the margin is limited. However, the significant prospectivity of the conjugated European North Atlantic margin and the nature of the North-East Greenland onshore geology prompt for future offshore exploration. The US Geological Survey thus highlighted the North-East Greenland margin in their latest assessment of the Arctic region (Gautier et al. 2011). With a mean estimate of undiscovered recoverable oil, gas, and natural gas liquids of approximately 31 billion barrels of oil equivalents, the US Geological Survey ranked the North-East Greenland margin fourth in the entire Arctic region, only superseded by known producing petroleum provinces. In preparation for the initial East Greenland licence rounds in 2012 and 2013 the Geological Survey of Denmark and Greenland gathers geological information on the margin necessary for the decision process of the Greenland authorities regarding exploration. Geophysical analyses complemented by well-data, onshore geology and information from the conjugated Atlantic margin form the backbone of the study. The East Greenland margin is covered by an open seismic grid supplemented by gravimetric and magnetic data. All existing 2D seismic, gravimetric and magnetic data are included in the current study. Most of the data are confi-dential. Restricted by the general confidential nature of the project, this paper aims to summarise the geology of the East Greenland margin based on the current and previous studies and to briefly assess some of the implications for the regional petroleum prospectivity.

This paper summarises the status of the Continental Shelf Project of the Kingdom of Denmark after the recent submission for an extended continental shelf in the area to the north of Greenland. We discuss some of the similarities between the submission areas north of the Faroe Islands and north of Greenland including the morphological continuation of ridges extending seaward of the geomorphical continental shelf. Documentation of the sediment thickness in the adjoining basins and sediment continuity with the continental slope plays a vital role in the delineation of the outer limits of the extended continental shelf. Here, we compare how these issues were addressed around the well-studied Faroe Islands and in the sparsely surveyed Arctic Ocean.