Suivi angiologique des patients artériopathes après geste de revascularisation [Vascular follow up in patients suffering peripheral arterial disease and undergoing revascularization].

The rapid evolution of revascularization techniques has allowed an improvement in quality of life of patients with peripheral artery disease. The angiological follow-up aims to insure durable results of revascularization, to diminish risk of amputation and to limit progression of atheroma plaques. The patient history and physical examination are essential in evaluating impact of peripheral artery disease upon quality of life and insuring the appropriate control of cardiovascular risk factors.

Rivascolarizzazione miocardica con arteria radiale: tecniche chirurgiche a confronto e risultati a breve termine [Myocardial revascularization and radial artery: different surgical strategies and short-term results]

BACKGROUND: The radial artery is routinely used as a graft for surgical arterial myocardial revascularization. The proximal radial artery anastomosis site remains unknown. In this study, we analyzed the short-term results and the operative risk determinants after having used four different common techniques for radial artery implantation. METHODS: From January 2000 to December 2004, 571 patients underwent coronary artery bypass grafting with radial arteries. Data were analyzed for the entire population and for subgroups following the proximal radial artery anastomosis site: 140 T-graft with the mammary artery (group A), 316 free-grafts with the proximal anastomosis to the ascending aorta (group B), 55 mammary arteries in situ elongated with the radial artery (group C) and 60 radial arteries elongated with a piece of mammary artery and anastomosed to the ascending aorta (group D). RESULTS: The mean age was 53.8 +/- 7.7 years; 55.5% of patients had a previous myocardial infarction and 73% presented with a satisfactory left ventricular function. A complete arterial myocardial revascularization was achieved in 532 cases (93.2%) and 90.2% of the procedures were performed under cardiopulmonary bypass and cardioplegic arrest. The operative mortality rate was 0.9%, a postoperative myocardial infarction was diagnosed in 19 patients (3.3%), an intra-aortic balloon pump was used in 10 patients (1.7%) and a mechanical circulatory device was implanted in 2 patients. The radial artery harvesting site remained always free from complications. The proximal radial artery anastomosis site was not a determinant of early hospital mortality. Group C showed a higher risk of postoperative myocardial infarction (p = 0.09), together with female gender (p = 0.003), hypertension (p = 0.059) and a longer cardiopulmonary bypass time. CONCLUSIONS: The radial artery and the mammary artery can guarantee multiple arterial revascularization also for patients with contraindications to double mammary artery use. The four most common techniques for proximal radial artery anastomosis are not related to a higher operative risk and they can be used alternatively to reach the best surgical results

Randomized comparison of biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for percutaneous coronary revascularization: Rationale and design of the BIOSCIENCE trial.

BACKGROUND: Biodegradable polymers for release of antiproliferative drugs from metallic drug-eluting stents aim to improve long-term vascular healing and efficacy. We designed a large scale clinical trial to compare a novel thin strut, cobalt-chromium drug-eluting stent with silicon carbide-coating releasing sirolimus from a biodegradable polymer (O-SES, Orsiro; Biotronik, Bülach, Switzerland) with the durable polymer-based Xience Prime/Xpedition everolimus-eluting stent (EES) (Xience Prime/Xpedition stent, Abbott Vascular, IL) in an all-comers patient population. DESIGN: The multicenter BIOSCIENCE trial (NCT01443104) randomly assigned 2,119 patients to treatment with biodegradable polymer sirolimus-eluting stents (SES) or durable polymer EES at 9 sites in Switzerland. Patients with chronic stable coronary artery disease or acute coronary syndromes, including non-ST-elevation and ST-elevation myocardial infarction, were eligible for the trial if they had at least 1 lesion with a diameter stenosis >50% appropriate for coronary stent implantation. The primary end point target lesion failure (TLF) is a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization within 12 months. Assuming a TLF rate of 8% at 12 months in both treatment arms and accepting 3.5% as a margin for noninferiority, inclusion of 2,060 patients would provide more than 80% power to detect noninferiority of the biodegradable polymer SES compared with the durable polymer EES at a 1-sided type I error of 0.05. Clinical follow-up will be continued through 5 years. CONCLUSION: The BIOSCIENCE trial will determine whether the biodegradable polymer SES is noninferior to the durable polymer EES with respect to TLF.

On optimal dividend strategies with deficit or incomplete information

Rapport de synthèse Cette thèse consiste en trois essais sur les stratégies optimales de dividendes. Chaque essai correspond à un chapitre. Les deux premiers essais ont été écrits en collaboration avec les Professeurs Hans Ulrich Gerber et Elias S. W. Shiu et ils ont été publiés; voir Gerber et al. (2006b) ainsi que Gerber et al. (2008). Le troisième essai a été écrit en collaboration avec le Professeur Hans Ulrich Gerber. Le problème des stratégies optimales de dividendes remonte à de Finetti (1957). Il se pose comme suit: considérant le surplus d'une société, déterminer la stratégie optimale de distribution des dividendes. Le critère utilisé consiste à maximiser la somme des dividendes escomptés versés aux actionnaires jusqu'à la ruine2 de la société. Depuis de Finetti (1957), le problème a pris plusieurs formes et a été résolu pour différents modèles. Dans le modèle classique de théorie de la ruine, le problème a été résolu par Gerber (1969) et plus récemment, en utilisant une autre approche, par Azcue and Muler (2005) ou Schmidli (2008). Dans le modèle classique, il y a un flux continu et constant d'entrées d'argent. Quant aux sorties d'argent, elles sont aléatoires. Elles suivent un processus à sauts, à savoir un processus de Poisson composé. Un exemple qui correspond bien à un tel modèle est la valeur du surplus d'une compagnie d'assurance pour lequel les entrées et les sorties sont respectivement les primes et les sinistres. Le premier graphique de la Figure 1 en illustre un exemple. Dans cette thèse, seules les stratégies de barrière sont considérées, c'est-à-dire quand le surplus dépasse le niveau b de la barrière, l'excédent est distribué aux actionnaires comme dividendes. Le deuxième graphique de la Figure 1 montre le même exemple du surplus quand une barrière de niveau b est introduite, et le troisième graphique de cette figure montre, quand à lui, les dividendes cumulés. Chapitre l: "Maximizing dividends without bankruptcy" Dans ce premier essai, les barrières optimales sont calculées pour différentes distributions du montant des sinistres selon deux critères: I) La barrière optimale est calculée en utilisant le critère usuel qui consiste à maximiser l'espérance des dividendes escomptés jusqu'à la ruine. II) La barrière optimale est calculée en utilisant le second critère qui consiste, quant à lui, à maximiser l'espérance de la différence entre les dividendes escomptés jusqu'à la ruine et le déficit au moment de la ruine. Cet essai est inspiré par Dickson and Waters (2004), dont l'idée est de faire supporter aux actionnaires le déficit au moment de la ruine. Ceci est d'autant plus vrai dans le cas d'une compagnie d'assurance dont la ruine doit être évitée. Dans l'exemple de la Figure 1, le déficit au moment de la ruine est noté R. Des exemples numériques nous permettent de comparer le niveau des barrières optimales dans les situations I et II. Cette idée, d'ajouter une pénalité au moment de la ruine, a été généralisée dans Gerber et al. (2006a). Chapitre 2: "Methods for estimating the optimal dividend barrier and the probability of ruin" Dans ce second essai, du fait qu'en pratique on n'a jamais toute l'information nécessaire sur la distribution du montant des sinistres, on suppose que seuls les premiers moments de cette fonction sont connus. Cet essai développe et examine des méthodes qui permettent d'approximer, dans cette situation, le niveau de la barrière optimale, selon le critère usuel (cas I ci-dessus). Les approximations "de Vylder" et "diffusion" sont expliquées et examinées: Certaines de ces approximations utilisent deux, trois ou quatre des premiers moments. Des exemples numériques nous permettent de comparer les approximations du niveau de la barrière optimale, non seulement avec les valeurs exactes mais également entre elles. Chapitre 3: "Optimal dividends with incomplete information" Dans ce troisième et dernier essai, on s'intéresse à nouveau aux méthodes d'approximation du niveau de la barrière optimale quand seuls les premiers moments de la distribution du montant des sauts sont connus. Cette fois, on considère le modèle dual. Comme pour le modèle classique, dans un sens il y a un flux continu et dans l'autre un processus à sauts. A l'inverse du modèle classique, les gains suivent un processus de Poisson composé et les pertes sont constantes et continues; voir la Figure 2. Un tel modèle conviendrait pour une caisse de pension ou une société qui se spécialise dans les découvertes ou inventions. Ainsi, tant les approximations "de Vylder" et "diffusion" que les nouvelles approximations "gamma" et "gamma process" sont expliquées et analysées. Ces nouvelles approximations semblent donner de meilleurs résultats dans certains cas.

Three essays in incomplete contracts

General Introduction These three chapters, while fairly independent from each other, study economic situations in incomplete contract settings. They are the product of both the academic freedom my advisors granted me, and in this sense reflect my personal interests, and of their interested feedback. The content of each chapter can be summarized as follows: Chapter 1: Inefficient durable-goods monopolies In this chapter we study the efficiency of an infinite-horizon durable-goods monopoly model with a fmite number of buyers. We find that, while all pure-strategy Markov Perfect Equilibria (MPE) are efficient, there also exist previously unstudied inefficient MPE where high valuation buyers randomize their purchase decision while trying to benefit from low prices which are offered once a critical mass has purchased. Real time delay, an unusual monopoly distortion, is the result of this attrition behavior. We conclude that neither technological constraints nor concern for reputation are necessary to explain inefficiency in monopolized durable-goods markets. Chapter 2: Downstream mergers and producer's capacity choice: why bake a larger pie when getting a smaller slice? In this chapter we study the effect of downstream horizontal mergers on the upstream producer's capacity choice. Contrary to conventional wisdom, we find anon-monotonic relationship: horizontal mergers induce a higher upstream capacity if the cost of capacity is low, and a lower upstream capacity if this cost is high. We explain this result by decomposing the total effect into two competing effects: a change in hold-up and a change in bargaining erosion. Chapter 3: Contract bargaining with multiple agents In this chapter we study a bargaining game between a principal and N agents when the utility of each agent depends on all agents' trades with the principal. We show, using the Potential, that equilibria payoffs coincide with the Shapley value of the underlying coalitional game with an appropriately defined characteristic function, which under common assumptions coincides with the principal's equilibrium profit in the offer game. Since the problem accounts for differences in information and agents' conjectures, the outcome can be either efficient (e.g. public contracting) or inefficient (e.g. passive beliefs).

Casein Kinase 1γ Ensures Monopolar Growth Polarity under Incomplete DNA Replication Downstream of Cds1 and Calcineurin in Fission Yeast.

Cell polarity is essential for various cellular functions during both proliferative and developmental stages, and it displays dynamic alterations in response to intracellular and extracellular cues. However, the molecular mechanisms underlying spatiotemporal control of polarity transition are poorly understood. Here, we show that fission yeast Cki3 (a casein kinase 1γ homolog) is a critical regulator to ensure persistent monopolar growth during S phase. Unlike the wild type, cki3 mutant cells undergo bipolar growth when S phase is blocked, a condition known to delay transition from monopolar to bipolar growth (termed NETO [new end takeoff]). Consistent with this role, Cki3 kinase activity is substantially increased, and cells lose their viability in the absence of Cki3 upon an S-phase block. Cki3 acts downstream of the checkpoint kinase Cds1/Chk2 and calcineurin, and the latter physically interacts with Cki3. Autophosphorylation in the C terminus is inhibitory toward Cki3 kinase activity, and calcineurin is responsible for its dephosphorylation. Cki3 localizes to the plasma membrane, and this localization requires the palmitoyltransferase complex Erf2-Erf4. Membrane localization is needed not only for proper NETO timing but also for Cki3 kinase activity. We propose that Cki3 acts as a critical inhibitor of cell polarity transition under S-phase arrest.

Cost evaluation and comparison of three decision strategies for cardiac revascularization : results of the suspected CAD protocol of the European CMR registry

Background: The public health burden of coronary artery disease (CAD) is important. Perfusion cardiac magnetic resonance (CMR) is generally accepted to detect and monitor CAD. Few studies have so far addressed its costs and costeffectiveness. Objectives: To compare in a large CMR registry the costs of a CMR-guided strategy vs two hypothetical invasive strategies for the diagnosis and the treatment of patients with suspected CAD. Methods: In 3'647 patients with suspected CAD included prospectively in the EuroCMR Registry (59 centers; 18 countries) costs were calculated for diagnostic examinations, revascularizations as well as for complication management over a 1-year follow-up. Patients with ischemia-positive CMR underwent an invasive X-ray coronary angiography (CXA) and revascularization at the discretion of the treating physician (=CMR+CXA strategy). Ischemia was found in 20.9% of patients and 17.4% of them were revascularized. In ischemia-negative patients by CMR, cardiac death and non-fatal myocardial infarctions occurred in 0.38%/y. In a hypothetical invasive arm the costs were calculated for an initial CXA followed by FFR testing in vessels with ≥50% diameter stenoses (=CXA+FFR strategy). To model this hypothetical arm, the same proportion of ischemic patients and outcome was assumed as for the CMR+CXA strategy. The coronary stenosis - FFR relationship reported in the literature was used to derive the proportion of patients with ≥50% diameter stenoses (Psten) in the study cohort. The costs of a CXA-only strategy were also calculated. Calculations were performed from a third payer perspective for the German, UK, Swiss, and US healthcare systems.

Cost-minimization analysis of three decision strategies for cardiac revascularization : results of the "suspected CAD"cohort of the european cardiovascular magnetic resonance registry.

BACKGROUND: Coronary artery disease (CAD) continues to be one of the top public health burden. Perfusion cardiovascular magnetic resonance (CMR) is generally accepted to detect CAD, while data on its cost effectiveness are scarce. Therefore, the goal of the study was to compare the costs of a CMR-guided strategy vs two invasive strategies in a large CMR registry. METHODS: In 3'647 patients with suspected CAD of the EuroCMR-registry (59 centers/18 countries) costs were calculated for diagnostic examinations (CMR, X-ray coronary angiography (CXA) with/without FFR), revascularizations, and complications during a 1-year follow-up. Patients with ischemia-positive CMR underwent an invasive CXA and revascularization at the discretion of the treating physician (=CMR + CXA-strategy). In the hypothetical invasive arm, costs were calculated for an initial CXA and a FFR in vessels with ≥50 % stenoses (=CXA + FFR-strategy) and the same proportion of revascularizations and complications were applied as in the CMR + CXA-strategy. In the CXA-only strategy, costs included those for CXA and for revascularizations of all ≥50 % stenoses. To calculate the proportion of patients with ≥50 % stenoses, the stenosis-FFR relationship from the literature was used. Costs of the three strategies were determined based on a third payer perspective in 4 healthcare systems. RESULTS: Revascularizations were performed in 6.2 %, 4.5 %, and 12.9 % of all patients, patients with atypical chest pain (n = 1'786), and typical angina (n = 582), respectively; whereas complications (=all-cause death and non-fatal infarction) occurred in 1.3 %, 1.1 %, and 1.5 %, respectively. The CMR + CXA-strategy reduced costs by 14 %, 34 %, 27 %, and 24 % in the German, UK, Swiss, and US context, respectively, when compared to the CXA + FFR-strategy; and by 59 %, 52 %, 61 % and 71 %, respectively, versus the CXA-only strategy. In patients with typical angina, cost savings by CMR + CXA vs CXA + FFR were minimal in the German (2.3 %), intermediate in the US and Swiss (11.6 % and 12.8 %, respectively), and remained substantial in the UK (18.9 %) systems. Sensitivity analyses proved the robustness of results. CONCLUSIONS: A CMR + CXA-strategy for patients with suspected CAD provides substantial cost reduction compared to a hypothetical CXA + FFR-strategy in patients with low to intermediate disease prevalence. However, in the subgroup of patients with typical angina, cost savings were only minimal to moderate.

International survey of acute stroke imaging used to make revascularization treatment decisions.

BACKGROUND: To assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging. METHODS: STroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies. RESULTS: We received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25,326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (i.v.) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) . CONCLUSION: There were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning.

Cardiac and vascular effects of diltiazem, dobutamine and amrinone, drugs used after myocardial revascularization

Hemodynamic care during postoperative management of myocardial revascularization should include vasorelaxing drugs to insure adequate graft and coronary flow, and stimulation of stroke volume to maintain vascular perfusion pressure. We tested the cardiac (inotropic and lusitropic) and vascular (relaxant) effects of diltiazem (0.1 nM to 0.1 mM), dobutamine (10 µM to 10 mM) and amrinone (10 µM to 1 mM) on isolated rat atria and thoracic aorta, and also on isolated human saphenous vein (HSV) and human mammary artery (HMA). Dobutamine produced a maximal positive inotropic effect (+dF/dt max = 29 ± 7%) at its ED50 for aortic relaxation (88 ± 7 µM). Conversely, at their ED50 for aortic relaxation diltiazem depressed myocardial contractility and amrinone did not exhibit myocardial effects. In HSV and HMA contracted with 80 mM potassium, diltiazem and dobutamine (but not amrinone) had a vasorelaxant activity similar to that in rat aorta. Norepinephrine-contracted human vessels were significantly more sensitive than potassium-contracted vessels to the relaxant effect of amrinone (ED50 HMA = 15 ± 5 µM, ED50 HSV = 72 ± 31 µM, P < 0.05). We conclude that at concentrations still devoid of myocardial effects dobutamine and amrinone are effective dilators in graft segment vessels and rat aorta contracted by membrane depolarization. If the difference between aortic and myocardial tissue still holds in human tissues, at the appropriate concentrations these drugs should be expected to improve cardiac performance while still contributing to the maintenance of graft patency.

Effect of lipoarabinomannan from Mycobacterium avium subsp avium in Freund’s incomplete adjuvant on the immune response of cattle

The aim of the present study was to determine whether lipoarabinomannan (LAM), in combination with Freund’s incomplete adjuvant (FIA), was able to improve cell-mediated and antibody-mediated immune responses against ovalbumin (OVA) in cattle. Twenty-three calves were assigned to four treatment groups, which were subcutaneously immunized with either OVA plus FIA, OVA plus FIA and LAM from Mycobacterium avium subsp avium, FIA plus LAM, or FIA alone. Lymphoproliferation, IFN-γ production and cell subpopulations on peripheral blood mononuclear cells before and 15 days after treatment were evaluated. Delayed hypersensitivity was evaluated on day 57. Specific humoral immune response was measured by ELISA. Inoculation with LAM induced higher levels of lymphoproliferation and IFN-γ production in response to ConA and OVA (P < 0.05). Specific antibody titers were similar in both OVA-immunized groups. Interestingly, our results showed that the use of LAM in vaccine preparations improved specific cell immune response evaluated by lymphoproliferation and IFN-γ production by at least 50 and 25%, respectively, in cattle without interfering with tuberculosis and paratuberculosis diagnosis.