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Abstract: Unmanned, autonomous air-to-sea vehicles, fully capable of transitioning between the two mediums, have only recently become technologically possible and have attracted great interest due to their numerous applications. However, current vehicles are unable to withstand the environmental conditions of the deep sea, especially with regards to their electronics. Previous methods for protecting electronics in the deep sea are not optimized for transitions to air. Here, a novel, lightweight, thermally-conductive, easily processed, mechanically robust, epoxy-based nanocomposite coating is presented. This material was developed with the intention of bringing the multi-domain air-water drone, known as the Naviator, to the deep ocean. In this work, the coating is thoroughly characterized and demonstrated to protect electronics submerged in water at high-pressure benchtop conditions as well as in an actual deep sea mission. The coating is also contrasted against unmodified epoxy, as well as commercial syntactic foam, and deemed superior for this application. Graphical Abstract:

One of the earliest mapped human deafness genes, DIAPH1, encodes the formin DIAPH1. To date, at least three distinct mutations in the C-terminal domains and two additional mutations in the N-terminal region are associated with autosomal dominant hearing loss. The underlying molecular mechanisms are not known, and the role of formins in the inner ear is not well understood. In this study, we use biochemical assays to test the hypotheses that autoinhibition and/or actin assembly activities are disrupted by DFNA1 mutations. Our results indicate that C-terminal mutant forms of DIAPH1 are functional in vitroand promote actin filament assembly. Similarly, N-terminal mutants are well-folded and have quaternary structures and thermal stabilities similar to those of the wild-type (WT) protein. The strength of the autoinhibitory interactions varies widely among mutants, with the ttaa, A265S, and I530S mutations having an affinity similar to that of WT and the 1213x and Δagmutations completely abolishing autoinhibition. These data indicate that, in some cases, hearing loss may be linked to weakened inhibition of actin assembly.

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome.

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLLtranslocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3AR882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.

Cisapride is contraindicated in patients with end-stage renal disease (ESRD) and gastrointestinal motility disorders. Ventricular arrhythmias have been associated with both cisapride and hemodialysis (HD). However, reports conflict regarding the safety of cisapride in HD patients. We undertook this study to characterize the effects of cisapride on QT intervals and QT dispersion (QTD) in HD patients. Baseline and steady-state electrocardiograms (ECGs) were retrospectively selected for calendar year 1999 for each patient administered cisapride if ECGs showed sinus rhythm, potassium level was 3.5 mEq/dL or greater, and there was no pharmacokinetic drug interaction. QT intervals were measured by two investigators, and QTDs were calculated (maximum [QTmax] - minimum QT interval [QTmin]). Averages between investigator measures (± SD), presented for each value, were evaluated using Wilcoxon's signed-rank test. Thirty-one HD patients were administered cisapride. Seventeen patients failed to meet entry criteria, and no patient had a pharmacokinetic drug interaction. In included patients (6 men, 8 women), heart rates were 86.71 ± 20.87 beats/min at baseline and 86.57 ± 14.23 beats/min during treatment (P= not significant). Serum potassium levels were 4.97 ± 1.2 mEq/dL at baseline and 4.94 ± 0.76 mEq/dL during treatment (P= not significant). Average baseline QTmaxand QTminwere 391.07 ± 42.43 and 330.71 ± 40.94 milliseconds, respectively. Treatment QTmaxand QTminwere 391.43 ± 38.2 and 343.93 ± 35.69 milliseconds, respectively (P= not significant for both). QTD was 60.36 ± 17.59 milliseconds at baseline and 47.5 ± 19.59 milliseconds during treatment (P= 0.074). Mean corrected QT (QTc) intervals increased from 426.57 ± 26.62 to 431.71 ± 29.98 milliseconds (P= 0.55) from baseline to treatment. No ventricular arrhythmia was observed during at least 160 days (range, 2 to 830 days) of cisapride exposure. Two patients died during this study, both of other causes 4 days after discontinuing cisapride therapy. Cisapride did not significantly increase mean QTc interval, QTmax, or QTD in patients with ESRD managed by HD when potassium levels were stable and pharmacokinetic drug interactions were avoided. © 2001 by the National Kidney Foundation, Inc.

Introduction:Transcatheter radiofrequency ablation of posteroseptal accessory pathways (AP) is challenging. A number of different interventional approaches have been suggested by different groups. The selection of the initial approach is crucial in order to reduce radiation exposure and the number of unsuccessful lesions applied. We present our ablation technique as guided by a simplified electrocardiographic analysis of the delta wave polarity and the electrophysiologic mapping results. Methods and Results:Out of 35 manifest APs encountered in the right (n=17) or the left posteroseptum (n=18) in 35 patients, 34 were successfully ablated. Despite their left sided location, 7 of the 18 “left” sided APs were ablated after switching from an initial arterial to a venous approach looking for an appropriate target site in the right posteroseptal space or within the coronary sinus network. The other 11 left sided APs were ablated in the mitral ring, on 2 occasions, on their atrial aspect through a retrograde transmitral approach. On the contrary, 16 of the 17 “right” sided APs were successfully ablated exclusively through a venous approach. Fourteen of these were ablated in the right posteroseptum, in 2 cases, only after reaching their ventricular aspect. Two right sided APs were interrupted in the coronary sinus os and the middle cardiac vein respectively. Conclusion:It appears that even though the electrocardiographic and electrophysiologic location of the AP in the posteroseptal space helps select the appropriate initial approach, it does not always guarantee a successful ablation procedure in the expected site of the corresponding atrioventricular ring. Not uncommonly, it will be necessary to look after intermediate target sites within the coronary sinus to improve the overall ablation success rate.

Introduction:Third-generation cardioverter-defibrillators have revolutionized management of ventricular tachyarrhythmias. Implantation can be performed in the electro-physiology laboratory, with minimal morbidity. Generator size has shrunk to the point that subcutaneous implantation is feasible and safe, even under local anesthesia. The prepectoral technique, however, is associated with increased mechanical stress to the subcutaneous tissue and can predispose to device erosion or infection. These complications may be avoided by submuscular placement. Among subpectoral techniques, the lateral approach offers unrestricted ability to deploy patches or array electrodes, should the need arise, and may represent the optimal implant technique under some circumstances. Methods:We studied 29 male patients, aged 29–78 years, who presented with syncope or sustained ventricular tachycardia, and underwent subpectoral defibrillator implantation under general anesthesia or conscious sedation. All devices were third-generation active can systems with biphasic shock capability. Six dual-chamber defibrillators were used. Results:Subpectoral implantation was successful in all cases, with an estimated blood loss of 28±17[emsp4 ]mL and no immediate complications. Except for one patient who developed twiddler's syndrome and ultimately required revision to a subcutaneous pocket, the implant site was tolerated well, and no limitation in the range of motion of the upper limb was observed during 20 months of follow-up. Conclusions:Subpectoral implantation using a lateral approach is technically straightforward and can be applied globally, with modest additional resource and equipment requirements. Familiarity with this approach can maximize the likelihood of successful defibrillator implantation in the electrophysiology laboratory.

Regulation of the mammalian branched-chain α-ketoacid dehydrogenase complex (BCKAD) occurs under a variety of stressful conditions associated with changes in circulating glucocorticoids. Multiple levels of regulation in hepatocytes, including alteration of the levels of the structural subunits available for assembly (E1, α-ketoacid decarboxylase; E2, dihydrolipoamide acyltransferase; and E3, dihydrolipoamide dehydrogenase), as well as BCKAD kinase, which serves to phosphorylate the E1α subunit and inactivate complex activity, have been proposed. The direct role of glucocorticoids in regulating the expression of the murine gene encoding the major BCKAD subunit E2, upon which the other BCKAD subunits assemble, was therefore examined. Deletion analysis of the 5ʹ proximal 7.0 kb of the murine E2 promoter sequence, using E2 promoter/luciferase expression minigene plasmids introduced into the hepatic H4IIEC3 cell line, suggested a promoter proximal region responsive to glucocorticoid regulation. Linker-scanning mutagenesis combined with deletion analysis established this functional glucocorticoid-responsive unit (GRU) to be located near the murine E2 proximal promoter site at -140 to -70 bp upstream from the transcription initiation site. The presence of this region in plasmid minigenes, containing varying amounts of the murine genomic sequence 5ʹ upstream from proximal E2 promoter sequences, conferred 2-10 fold increases in luciferase reporter gene expression in H4IIEC3 cells, whether introduced by transient transfection or following co-selection for stable transfectants. The GRU region itself appeared to contain multiple interacting elements that combine to regulate overall E2 promoter activity in response to changing physiological conditions associated with varying concentrations of glucocorticoids and likely other hormonal effectors.

Objectives. This study evaluates the hypothesis that in patients with syncope of unknown origin, inducible ventricular arrhythmias are specific arrhythmias and therefore should be appropriately treated.

The response of the murine genes encoding the subunits of branched‐chain α‐ketoacid dehydrogenase complex (BCKAD) to changes in dietary protein was determined. Steady‐state RNA levels for two of the subunits, E1βand E2, decreased by two‐ to fourfold in the livers of mice fed 0% protein isocaloric diets compared to the levels observed in mice fed standard (23%) or high (50%) protein isocaloric diets. In contrast, the levels of RNA encoding the E1αsubunit did not change significantly in response to these dietary protein changes. The hepatic decreases in E1βand E2 RNA associated with 0% protein isocaloric diets were reversible, with prompt return to baseline levels following 48 hours of 50% protein isocaloric diets ad libitum. In kidney, no significant changes in the RNAs encoding any of the three BCKAD subunits were observed in response to changes in dietary protein. Studies of RNA variations associated with growth and development in several murine tissues, including liver and kidney, demonstrated coordinated changes between all subunits. Similar coordinated changes were observed during 3T3‐L1 adipocyte differentiation. These studies suggest that the responses of the BCKAD subunit genes to alterations in dietary protein are noncoordinated and tissue‐specific, in contrast to the coordinated changes observed during growth and/or differentiation. The differences in BCKAD subunit RNA levels observed under varying nutritional and developmental conditions suggest that multiple regulatory mechanisms modulate BCKAD subunit expression.— Chinsky, J. M., Bohlen, L. M., Costeas, P. A. Noncoordinated responses of branched‐chain α‐ketoacid dehydrogenase subunit genes to dietary protein. FASEB J.8: 114‐120; 1994.

Arrhythmogenic right ventricular dysplasia is a clinical entitycharacterized by fatty infiltration of the right ventricle and left bundlemorphology ventricular tachycardia occurring in young patients. The mostcommon cause of death is tachyarrhythmic. Pharmacological andnonpharmacological therapies, including implantable cardioverterdefibrillators, have been used to treat the arrhythmias. However, rightventricular endocardial leads in this population may be associated with anincreased risk of perforation and suboptimal sensing and defibrillationefficacy due to the diseased right ventricle. We report on 12 patients witharrhythmogenic right ventricular dysplasia who were treated with implantablecardioverter defibrillators. The mean age was 31± 9 years (range15-48). Patients presented with presyncope (5), syncope (4), or cardiacarrest (3). All patients had electrocardiographic abnormalitiescharacteristic of the condition. Follow-up averaged 22 ± 13months (range 1-45). There was one sudden death at 1 month of follow-up. Ofthe 12 patients, 8 have had appropriate therapy delivered by the implantabledefibrillator. Six patients are currently on sotalol to reduce the frequencyof implantable defibrillator discharges. In conclusion, implantablecardioverter defibrillators with nonthoracotomy leads are feasible and safein patients with arrhythmogenic right ventricular dysplasia. The frequencyof appropriate therapy is high, supporting the use of implantablecardioverter defibrillators in this population. During programmedelectrical stimulation nine patients had sustained ventricular tachycardia,while three patients had no inducible arrhythmia. Transvenous leads wereplaced in nine patients. In these patients pacing thresholds weresignificantly higher, R-wave amplitudes were significantly lower, anddefibrillation thresholds were not significantly different than in a cohortof patients without right ventricular dysplasia. There were no acute orchronic complications of right ventricular lead placement.

Alterations in dietary intake, especially of protein, may produce changes in the hepatic levels of the branched-chain α-keto acid dehydrogenase (BCKAD) complex. The possible role of insulin in the regulation of these observed changes in hepatic capacity for BCKAD expression was therefore examined. Steady-state RNA levels encoding three of the subunits, E1α, E1β and E2, increased by 2–4-fold in the livers of mice starved for 3 days, a known hypoinsulinaemic state. In contrast, the levels of E1β and E2, but not E1α, RNA were decreased when mice were fed 0% protein diets compared with the levels observed in mice fed standard (23%) or higher protein isocaloric diets. BCKAD subunit protein levels under these conditions changed co-ordinately even though the changes in RNA were not co-ordinate. The effects of hormonal changes that might be associated with these dietary changes were examined, using the rodent hepatoma cell line H4IIEC3. In these cells, the levels of E1α protein and mRNA were significantly depressed in the presence of insulin. In contrast, the levels of E1β and E2 RNAs were not decreased by insulin. The half-lives of the E1α and E2 RNAs were determined to be quite long, from 13 to 18 h, with insulin having no dramatic overall effect on the half-lives determined over 24 h. Therefore, it is likely that insulin directly affects the transcription of the E1α gene rather than RNA stability in exerting its negative regulatory effect. This effect is specific to the E1α subunit. The differences in BCKAD subunit RNA levels observed under various nutritional and developmental conditions may therefore be the result of the differential effects of insulin and other hormones on the multiple regulatory mechanisms modulating BCKAD subunit expression.

One of the earliest steps in the pathogenic cycle of the facultative intracellular pathogen Salmonella spp. is the invasion of the cells of the intestinal epithelium. We have previously identified a genetic locus, inv, that allows Salmonella spp. to enter cultured epithelial cells. invA is a member of this locus, and it is the first gene of an operon consisting of at least two additional invasion genes. We have constructed strains carrying nonpolar mutations in invA and examined the individual contribution of this gene to the invasion phenotype of Salmonella typhimurium. Nonpolar S. typhimurium invA mutants were deficient in invasion of cultured epithelial cells although they were fully capable of attaching to the same cells. In addition, unlike wild-type S. typhimurium, invA mutants did not alter the normal architecture of the microvilli of polarized epithelial cells nor did they cause any alterations in the distribution of actin microfilaments of infected cells. The invasion phenotype of invA mutants was readily rescued by wild-type S. typhimurium when cultured epithelial cells were simultaneously infected with both strains. On the contrary, in a similar experiment, the adherent Escherichia coli strain RDEC-1 was not internalized into cultured cells when coinfected with wild-type S. typhimurium. The invA locus was found to be located at about 59 min on the Salmonella chromosome, 7% linked to mutS. The nucleotide sequence of invA showed an open reading frame capable of encoding a polypeptide of 686 amino acids with eight possible membrane-spanning regions and a predicted molecular weight of 75,974. A protein of this size was visualized when invA was expressed in a bacteriophage T7 RNA polymerase-based expression system. The predicted sequence of InvA was found to be homologous to Caulobacter crescentus FlbF, Yersinia LcrD, Shigella flexneri VirH, and E. coli FlhA proteins. These proteins may form part of a family of proteins with a common function, quite possibly the translocation of specific proteins across the bacterial cell membrane.

Abstract: We present a method for the localized statistical discrimination of class populations based on the Karhunen-Love and Fukunaga-Koontz transforms. These transforms provide features that model the variance of a sample distribution. The spatial series of a 196 channel epicardial electrogram recording from an arrhythmogenic postinfarct canine were analyzed. For each type of rhythm studied, Karhunen-Love and Fukunaga-Koontz expansions were computed from five training sets of spatial data, corresponding to five locations across the surface of the heart. Nonparametric statistical tests were then used for discriminant analysis to compare properties representative of the distribution from each proposed class. In a comparison of properties from sinus rhythm to those of two ventricular tachycardias, several spatial regions exhibited statistically significantly different propagation characteristics. These areas were observed by visual inspection of electrogram activation maps to be characterized by conductive gradients, which differed in magnitude and direction from one rhythm to another. The regions in which the propagation characteristics are of greatest difference in each tachycardia were centered upon sites of conduction block, manifested by reentrant circuit rhythms. Therefore, the importance of the technique for the localization of specific electrophysiologic events is demonstrated. This study extends previous work of our group on biosignal pattern recognition to encompass localized spatial data.

Development of effective surgical means in the management of cerebral vascular insufficiency has recently become one of the most gratifying advances in the field of arterial reconstructive surgery. For, whereas from time immemorial the "stroke victim" has been in most instances considered doomed, operative procedures now in clinical use can prevent more severe attacks in the majority of the cases. Follow-up studies confirmed the low incidence of recurrence following carotid endarterectomy and emphasis has been placed in the group of "transient" ischemia which is actually most benefited from reconstructive surgery. Follow-up studies were undertaken in a group of 21 patients who underwent surgical reconstitution of different types of cerebrovascular insufficiency. In 17 cases carotid arteries were primarily involved, unilaterally in 15, and bilaterally in 2. In the remaining group of four, one case of vertebral artery disease was noted, while in the other three, "subclavian steal syndrome" was documented. Low incidence of recurrence following arterial reconstruction presents evidence of the value of such a procedure in cases amenable to surgery.

Introduction:Left atrial appendage (LAA) closure is a standard therapy to reduce thromboembolic risk in atrial fibrillation patients intolerant to anticoagulation. Intraoperative TEE is performed for device sizing. It has been demonstrated that the 135? view provides adequate information for sizing of the closure device. In the RAO/Caudal projection, cineradiography (Cine) approximates the 135? TEE view.Hypothesis:LAA landing site measurements obtained using Cine correlate well with those obtained by 2D-TEE.Methods:We retrospectively compared echocardiography and Cine data for 126 patients who underwent LAA closure using the Watchman (Boston Scientific) device between 01/2017 and 12/2018. Experienced operators measured landing site diameters at 0?, 45?, 90?, and 135? on TEE, as well as on Cine in RAO 20?/caudal 20? projection.Results:There was no significant difference in measurements obtained from Cine and those obtained from the 135? TEE view (average diameter 18.7 ? 3.5 vs 18.8 ? 4.0 mm ). Similarly, no difference was found between Cine and the largest Echo measurement (18.7 ? 3.5 vs 19.2 ? 3.9 mm). The mean difference between measurements of the landing zone made in Cine RAO-Caudal and Echo in the 135? plane was -0.1 ? 2.4 mm while that between Cine and the largest Echo measurement was -0.47? 2.4.mm. There was no interaction from appendage morphology. We found a strong correlation between the 135? measurement and the Cine measurement with r = 0.81 (p - value < 0.01). Similarly, the Pearson correlation coefficient between Cine derived measurements and the largest echo measurement was r= 0.79 (p-value < 0.01).Conclusion:LAA landing site measurements obtained using the Cine RAO/Caudal projection show acceptable correlation with those obtained by 2D-TEE and are adequate for device sizing at implant.Figure 1:Scatter plot demonstrating the relationship between landing zone measurements obtained in Cine and Echo 135

Hoffmann: Novartis Oncology Europe: Research Funding. Baccarani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hasford:Novartis: Research Funding. Lindoerfer:Novartis Oncology Europe: Research Funding. Burgstaller:Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Mayer:Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding; BMS: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding. Koskenvesa:GSK: Consultancy; Pfizer: Consultancy; Ariad: Other: funding of travel, accomodations or expenses; BMS: Consultancy, Other: funding of travel, accomodations or expenses; Novartis: Consultancy, Research Funding. Castagnetti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Griskevicius:Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Sacha:Angelini: Consultancy; Adamed: Consultancy; Novartis: Consultancy; BMS: Consultancy. Hellmann:Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau. Turkina:Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis Pharma: Consultancy. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy. Sninska:Novartis: Consultancy. Simonsson:Novartis Pharma: Research Funding. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; Pfizer: Honoraria, Other: Travel grant; BMS: Honoraria, Other: Travel grant, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

Introduction

THE retrograde conduction of automatic ventricular beats in a complete auriculoventricular (A-V) block was considered for a long time to be impossible.1 New data accumulated in the recent years concerning this phenomenon have changed this view, and today retrograde conduction is considered not at all uncommon.The form of the abnormal P waves (P') is identical. They are peaked, of short duration, inverted in leads II, III and aVF and positive in lead aVR. They indicate an activation of the atria in a reversed direction, i.e., from the area of the A-V node towards the sinus node.Certain features are common to all tracings displaying these retrograde P waves: (1) Retrograde P waves appear only after automatic ventricular beats and not after conducted beats from atria to ventricles, or as isolated blocked P waves. (2) The abnormal P waves are seen very late in the atrial diastole, only shortly

Hasford: Novartis Pharma: Research Funding.

Abstract 4272