Le processus de sécurisation du transport maritime canadien : le cas de la voie maritime du Saint-Laurent

Le transport maritime canadien a subi divers bouleversements au cours des dernières années. Les événements du 11 septembre 2001 ont induit un processus de sécurisation qui a eu des conséquences sur le mode de gestion de la navigation et des infrastructures maritimes canadiennes. Le cadre en vertu duquel la sécurité de ces dernières est aujourd'hui conceptualisée s'est donc modifié radicalement.\ud L'hypothèse défendue dans ce mémoire est que le Canada a intégré sa nouvelle perception des choses en matière de sécurité à une politique plus vaste qui englobe des dimensions de toute première importance pour le pays, notamment dans les domaines économique, industriel et commercial. Dans cette perspective, le cas de la Voie maritime du Saint-Laurent s'avère intéressant pour comprendre l'ampleur des changements sécuritaires sur l'ensemble de la gestion maritime canadienne. Nous l'analyserons à l'aide des travaux d'Ole Waever sur les processus de sécurisation. Ce mémoire est divisé en quatre parties. Tout d'abord, il présente le cadre théorique utilisé pour exposer les principaux aspects du processus de sécurisation du transport maritime canadien. Ensuite, il explique les priorités établies par les acteurs industriels et commerciaux avant le 11 septembre, soient le partenariat, l'environnement et la sécurité, la gestion et les perspectives d'avenir. Puis, il esquisse le portrait du processus de sécurisation induit par les événements du 11 septembre. Finalement, il reprend les préoccupations telles qu'expliquées précédemment pour déterminer leur situation et leur importance pour les intervenants politiques, industriels et commerciaux post-11 septembre. Cela va permettre de comprendre le contexte dans lequel s'est développé l'actuel processus de sécurisation et de présenter les conséquences qu'un tel changement a actuellement sur la gestion de la Voie maritime du Saint-Laurent pour le Canada. Trois grandes conclusions sont tirées de ce mémoire. Tout d'abord, la question économique reste au coeur des priorités canadiennes. Ensuite, l'influence américaine prend de l'ampleur dans les choix d'Ottawa. Finalement, le Canada développe sa propre vision de la sécurité, tout en s'adaptant à la nouvelle donne nord-américaine et internationale, grâce au travail des acteurs industriels et commerciaux. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Saint-Laurent, Sécurité, Maritime, Canada, 11 septembre

MOLECULAR MECHANISMS REGULATING CHROMOSOME SIZE SCALING DURING C. ELEGANS EARLY EMBRYONIC DEVELOPMENT

During embryonic development in metazoans, cells decrease in volume by up to two orders of magnitude, a consequence of multiple rounds of cell divisions without growth of the embryo. Using C. elegans and X. laevis embryo as model, it has been shown that mitotic structures all scale with cell size, smaller cells have smaller organelles (reviewed in [1]). Due to technical limitations, scaling of mitotic chromosome has received less attention. It is expected that during anaphase, condensed mitotic chromosomes must be half the length of the mitotic spindle to be properly segregated to each daughter cell, a length that varies according to cell size. Using high-resolution time-lapse microscopy of dividing C. elegans embryos, we have precisely measured chromosome length in 3D and show that prometaphase condensed chromosomes are smaller in length as cell reduces in size. We hypothesize that this change in chromosome condensation could be: 1) an outcome of a cellular size control and/or 2) a programmed developmental change. To assess the first hypothesis of a cell autonomous regulated mechanism, we experimentally reduced cell and nuclei size. Surprisingly, we found that reduction of each resulted in a corresponding reduction of chromosome size. To test the second hypothesis, we used a C. elegans strain with one chromosome longer than any wild-type chromosome, resulting from a X/autosomeV end-to-end chromosome fusion. This worm strain should be sensitive to any defect in chromosome condensation or segregation. To identify new regulators of chromatin compaction, we depleted known chromatin modifying enzymes and identify genes that increased embryonic lethality in the fusion strain compared to a WT strain. This strategy allowed us to identify both CENP-A and Topoisomerase II as crucial chromosome size regulators during C. elegans early embryonic development. Thus we are using large-scale RNAi depletion and high resolution imaging to determine the mechanisms of mitotic chromosome size regulation. Mitotic chromosome assembly and the process of scaling organelles to cell size are often seen as cellular processes. Indeed, this project highlights an innovative idea since those problems are poorly understood in a developmental context.Doctor of Philosoph

Cell Size: Chromosomes Get Slapped by a Midzone Ruler

SummarySpatial and temporal coordination of mitotic events has been generally attributed to the coincidental outcome of increasing cyclin-dependent kinase activity. A recent study reports that mitotic events and structures previously considered to be independently controlled are capable of trans-regulation to ensure genomic integrity

Mitotic chromosome length scales in response to both cell and nuclear size

Multicellular development requires that cells reduce in size as a result of consecutive cell divisions without increase in embryo volume. To maintain cellular integrity, organelle size adapts to cell size throughout development. During mitosis, the longest chromosome arm must be shorter than half of the mitotic spindle for proper chromosome segregation. Using high-resolution time-lapse microscopy of living Caenorhabditis elegans embryos, we have quantified the relation between cell size and chromosome length. In control embryos, chromosome length scaled to cell size. Artificial reduction of cell size resulted in a shortening of chromosome length, following a trend predicted by measurements from control embryos. Disturbing the RAN (Ras-related nuclear protein)-GTP gradient decoupled nuclear size from cell size and resulted in chromosome scaling to nuclear size rather than cell size; smaller nuclei contained shorter chromosomes independent of cell size. In sum, quantitative analysis relating cell, nuclear, and chromosome size predicts two levels of chromosome length regulation: one through cell size and a second in response to nuclear size

Bleeding and thrombotic risk in pregnant women with Fontan physiology

Background/objectives Pregnancy may potentiate the inherent hypercoagulability of the Fontan circulation, thereby amplifying adverse events. This study sought to evaluate thrombosis and bleeding risk in pregnant women with a Fontan.  Methods We performed a retrospective observational cohort study across 13 international centres and recorded data on thrombotic and bleeding events, antithrombotic therapies and pre-pregnancy thrombotic risk factors.  Results We analysed 84 women with Fontan physiology undergoing 108 pregnancies, average gestation 33 +/- 5 weeks. The most common antithrombotic therapy in pregnancy was aspirin (ASA, 47 pregnancies (43.5%)). Heparin (unfractionated (UFH) or low molecular weight (LMWH)) was prescribed in 32 pregnancies (30%) and vitamin K antagonist (VKA) in 10 pregnancies (9%). Three pregnancies were complicated by thrombotic events (2.8%). Thirty-eight pregnancies (35%) were complicated by bleeding, of which 5 (13%) were severe. Most bleeds were obstetric, occurring antepartum (45%) and postpartum (42%). The use of therapeutic heparin (OR 15.6, 95% CI 1.88 to 129, p=0.006), VKA (OR 11.7, 95% CI 1.06 to 130, p=0.032) or any combination of anticoagulation medication (OR 13.0, 95% CI 1.13 to 150, p=0.032) were significantly associated with bleeding events, while ASA (OR 5.41, 95% CI 0.73 to 40.4, p=0.067) and prophylactic heparin were not (OR 4.68, 95% CI 0.488 to 44.9, p=0.096). Conclusions Current antithrombotic strategies appear effective at attenuating thrombotic risk in pregnant women with a Fontan. However, this comes with high (>30%) bleeding risk, of which 13% are life threatening. Achieving haemostatic balance is challenging in pregnant women with a Fontan, necessitating individualised risk-adjusted counselling and therapeutic approaches that are monitored during the course of pregnancy

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society