Lecanemab Clarity AD: Quality-of-Life Results from a Randomized, Double-Blind Phase 3 Trial in Early Alzheimer's Disease.

BACKGROUND: Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to amyloid-beta protein protofibrils. In phase 3 development, lecanemab has been shown to reduce markers of amyloid in early Alzheimer's disease and reduce decline on clinical endpoints of cognition and function at 18 months. OBJECTIVES: To describe the health-related quality-of-life (HRQoL) results from Clarity AD which were exploratory outcomes in this trial. DESIGN: Clarity AD was an 18-month, multi-center, double-blind, phase 3 trial. SETTING: Early Alzheimer's disease. PARTICIPANTS: Individuals 50-90 years of age with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer's disease and positron emission tomography or cerebrospinal fluid evidence of cerebral amyloid accumulation. INTERVENTION: Placebo or lecanemab 10-mg/kg IV biweekly. MEASUREMENTS: HRQoL was measured at baseline and every 6 months using the European Quality of Life-5 Dimensions (EQ-5D-5L; by subject) and Quality of Life in AD (QOL-AD; by subject and proxy). Study partner burden was measured using the Zarit Burden Interview (ZBI). RESULTS: A total of 1795 participants were enrolled (lecanemab:898; placebo:897). At month 18, adjusted mean change from baseline in EQ-5D-5L and QOL-AD by subject showed 49% and 56% less decline, respectively. QOL-AD rated by study partner as proxy resulted in 23% less decline. ZBI adjusted mean change from baseline at 18 months resulted in 38% less increase of care partner burden. Individual HRQoL test items and dimensions also showed lecanemab benefit. CONCLUSIONS: Lecanemab was associated with a relative preservation of HRQoL and less increase in caregiver burden, with consistent benefits seen across different quality of life scales and within scale subdomains. These benefits provide valuable patient reported outcomes which, together with previously reported benefits of lecanemab across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate that lecanemab treatment may offer meaningful benefits to patients, care partners, and society.

Correction of artefacts associated with large area EBSD.

There is an increasing requirement for the acquisition of large two (2D) or three (3D) dimensional electron back scattered diffraction (EBSD) maps. It is a well-known, but largely neglected fact, that EBSD maps may contain distortions. These include long-range distortions, which can be caused by the interaction of the electron beam with the sample geometry and it can also arise from sample or beam drift. In addition there are shorter range artefacts arising from topographical features, such as curtaining. The geometrical distortions can be minimised by careful SEM calibrations and sample alignment. However, the long-range distortions become increasingly prevalent when acquiring large area 2D EBSD maps which take a long time to acquire and thus are especially prone to drift. These distortions are especially evident in serial section tomography (SST) when 2D maps are stacked on top of one another to produce 3D maps. Here we quantify these distortions for large area EBSD data by referencing them to secondary electron (SE) images for 3D-EBSD data acquired on a WCCo hardmetal. Long-range distortions (due to drift) equating to around 10µm across a 200µm x 175 µm area map, and short-range distortions (due to topographical effects) as large as 3 µm over a distance of 40 µm were observed. Methods for correcting these distortions are then proposed. This study illustrates the benefits and necessity of such corrections if morphological features are to be properly interpreted when collecting large 3D EBSD datasets, for example by mechanical sectioning, serial block face SEM ultramicrotomy, laser sectioning, FIB-SEM tomography, PFIB spin milling, etc.

Propensity score matching confirms that primary surgery or neoadjuvant chemotherapy result in equivalent survival within a comprehensive cohort of patients with high-grade serous ovarian cancer.

OBJECTIVE: Our objective was to investigate whether trial evidence showing that neoadjuvant chemotherapy is non inferior to primary surgery for the primary treatment of advanced ovarian cancer could be extrapolated to groups of patients that were not included in the trials. METHODS: Using a detailed retrospective cohort of all patients managed through a single tertiary hospital we carried out a propensity score analysis, principal component analysis, and cox proportional hazard analysis to compare survival in matched cohorts. RESULTS: A propensity score analysis showed that for at least 41% of all patients with advanced high-grade serous cancer neoadjuvant chemotherapy is non inferior to primary surgery (median survival primary surgery: 38 months, neoadjuvant chemotherapy: 35 months. P = 0.39). However, principal component analysis, supported by cox modelling, suggests that for some subgroups, including patients with subdiaphragmatic nodal disease, primary surgery may be associated with improved survival (HR 0.11, CI 0.026-0.48). CONCLUSIONS: We have shown that the findings of previous trials can be extrapolated to a wider population and that statistical modelling can be used to identify groups or patients who benefit from specific modalities of treatment.

A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum.

Extracellular vesicles (EVs) are nano-sized vesicles containing nucleic acid and protein cargo that are released from a multitude of cell types and have gained significant interest as potential diagnostic biomarkers. Human serum is a rich source of readily accessible EVs; however, the separation of EVs from serum proteins and non-EV lipid particles represents a considerable challenge. In this study, we compared the most commonly used isolation techniques, either alone or in combination, for the isolation of EVs from 200 µl of human serum and their separation from non-EV protein and lipid particles present in serum. The size and yield of particles isolated by each method was determined by nanoparticle tracking analysis, with the variation in particle size distribution being used to determine the relative impact of lipoproteins and protein aggregates on the isolated EV population. Purification of EVs from soluble protein was determined by calculating the ratio of EV particle count to protein concentration. Finally, lipoprotein particles co-isolated with EVs was determined by Western blot analysis of lipoprotein markers APOB and APOE. Overall, this study reveals that the choice of EV isolation procedure significantly impacts EV yield from human serum, together with the presence of lipoprotein and protein contaminants.

Initial clinical experience with high-pitch dual-source CT as a rapid technique for thoraco-abdominal evaluation in awake infants and young children.

AIM: To evaluate dual-source high-pitch computed tomography (HPCT) imaging of the chest and abdomen as a rapid scanning technique to obtain diagnostic-quality imaging evaluation of infants and young children without sedation. MATERIALS AND METHODS: Fifty-three paediatric patients (age 24.1±2 months) who underwent chest or abdomen HPCT (≥1.5) and standard pitch CT (SPCT, <1.5) on a dual-source 128-row multidetector CT system were included in the study. Image quality assessment was performed by two paediatric radiologists for diagnostic confidence, image artefacts, and image noise. Objective image noise was measured. RESULTS: Most of the CT examinations were performed in children who were >1 year old (n=15 and n=20) followed by ≤1 year old (n=8 and n=10) in SPCT and HPCT, respectively. The mean radiation dose (SSDE) from HPCT was 1.96±1 mGy compared to 2.2±1 mGy for SPCT (p=0.3). No major artefacts were reported and overall image quality of all HPCT examinations was acceptable diagnostically. In addition, objective image noise values were not significantly different between HPCT compared with SPCT (11±3 versus 11±5, p=0.7). CONCLUSION: Ultra-fast, HPCT can be performed without the need for sedation as a potential alternative to anaesthetised magnetic resonance imaging in infants and young children.

Efficacy and safety of levetiracetam for migraine prophylaxis: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Migraine is a common and costly neurological disorder that affects approximately 1 of every 7 people annually. Pharmacological therapy for prevention of migraine is warranted when patients experience at least 6 headache days, 4 headache days with at least some impairment or 3 headache days with severe impairment or requiring bed rest in a month. Levetiracetam is an antiepileptic drug that has the potential to be beneficial for migraine prophylaxis. The objective of this review was to assess the safety and efficacy of levetiracetam for migraine prophylaxis. METHODS: A systematic search was conducted in MEDLINE (1946-August 2017), EMBASE (1947-August 2017) and CENTRAL using the terms: migraine disorders, migraine, or headache and etiracetam or levetiracetam. Animal studies, case reports, abstracts, letters to the editor and those not written in English were excluded. RESULTS AND DISCUSSION: Eleven articles were identified for inclusion. Of the studies included, 2 were retrospective chart reviews, 4 were randomized placebo- or active comparator-controlled trials, and the remaining 5 were prospective, open-label studies. All studies found a statistically significant decrease in headache frequency per month compared to baseline or placebo when used for treatment of episodic migraine (2.96-10.9 headache/mo decrease), and 57.9%-100% of patients had at least a 50% decrease in headache frequency from baseline. Significance was not consistently demonstrated in the prophylactic treatment of chronic migraine. The most common adverse effects noted included somnolence, dizziness and behavioural effects but generally did not require discontinuation. WHAT IS NEW AND CONCLUSION: The studies included in this review indicate that levetiracetam is well-tolerated and may be an alternative treatment option for episodic migraine prophylaxis. Additional clinical evidence is necessary to establish the efficacy of levetiracetam for the prophylactic treatment of chronic migraine.

A multiphysics approach for modeling early atherosclerosis.

This work is devoted to the development of a mathematical model of the early stages of atherosclerosis incorporating processes of all time scales of the disease and to show their interactions. The cardiovascular mechanics is modeled by a fluid-structure interaction approach coupling a non-Newtonian fluid to a hyperelastic solid undergoing anisotropic growth and a change of its constitutive equation. Additionally, the transport of low-density lipoproteins and its penetration through the endothelium is considered by a coupled set of advection-diffusion-reaction equations. Thereby, the permeability of the endothelium is wall-shear stress modulated resulting in a locally varying accumulation of foam cells triggering a novel growth and remodeling formulation. The model is calibrated and applied to an murine-specific case study, and a qualitative validation of the computational results is performed. The model is utilized to further investigate the influence of the pulsatile blood flow and the compliance of the artery wall to the atherosclerotic process. The computational results imply that the pulsatile blood flow is crucial, whereas the compliance of the aorta has only a minor influence on atherosclerosis. Further, it is shown that the novel model is capable to produce a narrowing of the vessel lumen inducing an adaption of the endothelial permeability pattern.

Practical application of direct electron detectors to EBSD mapping in 2D and 3D.

The use of a direct electron detector for the simple acquisition of 2D electron backscatter diffraction (EBSD) maps and 3D EBSD datasets with a static sample geometry has been demonstrated in a focused ion beam scanning electron microscope. The small size and flexible connection of the Medipix direct electron detector enabled the mounting of sample and detector on the same stage at the short working distance required for the FIB. Comparison of 3D EBSD datasets acquired by this means and with conventional phosphor based EBSD detectors requiring sample movement showed that the former method with a static sample gave improved slice registration. However, for this sample detector configuration, significant heating by the detector caused sample drift. This drift and ion beam reheating both necessitated the use of fiducial marks to maintain stability during data acquisition.

Broad ion beam serial section tomography.

Here we examine the potential of serial Broad Ion Beam (BIB) Ar+ ion polishing as an advanced serial section tomography (SST) technique for destructive 3D material characterisation for collecting data from volumes with lateral dimensions significantly greater than 100µm and potentially over millimetre sized areas. Further, the associated low level of damage introduced makes BIB milling very well suited to 3D EBSD acquisition with very high indexing rates. Block face serial sectioning data registration schemes usually assume that the data comprises a series of parallel, planar slices. We quantify the variations in slice thickness and parallelity which can arise when using BIB systems comparing Gatan PECS and Ilion BIB systems for large volume serial sectioning and 3D-EBSD data acquisition. As a test case we obtain 3D morphologies and grain orientations for both phases of a WC-11%wt. Co hardmetal. In our case we have carried out the data acquisition through the manual transfer of the sample between SEM and BIB which is a very slow process (1-2 slice per day), however forthcoming automated procedures will markedly speed up the process. We show that irrespective of the sectioning method raw large area 2D-EBSD maps are affected by distortions and artefacts which affect 3D-EBSD such that quantitative analyses and visualisation can give misleading and erroneous results. Addressing and correcting these issues will offer real benefits when large area (millimetre sized) automated serial section BIBS is developed.

The accuracy of breast volume measurement methods: A systematic review.

Breast volume is a key metric in breast surgery and there are a number of different methods which measure it. However, a lack of knowledge regarding a method's accuracy and comparability has made it difficult to establish a clinical standard. We have performed a systematic review of the literature to examine the various techniques for measurement of breast volume and to assess their accuracy and usefulness in clinical practice. Each of the fifteen studies we identified had more than ten live participants and assessed volume measurement accuracy using a gold-standard based on the volume, or mass, of a mastectomy specimen. Many of the studies from this review report large (>200 ml) uncertainty in breast volume and many fail to assess measurement accuracy using appropriate statistical tools. Of the methods assessed, MRI scanning consistently demonstrated the highest accuracy with three studies reporting errors lower than 10% for small (250 ml), medium (500 ml) and large (1000 ml) breasts. However, as a high-cost, non-routine assessment other methods may be more appropriate.

Computational evaluation of aortic occlusion and the proposal of a novel, improved occluder: Constrained endo-aortic balloon occlusion.

Because aortic occlusion is arguably one of the most dangerous aortic manipulation maneuvers during cardiac surgery in terms of perioperative ischemic neurological injury, the purpose of this investigation is to assess the structural mechanical impact resulting from the use of existing and newly proposed occluders. Existing (clinically used) occluders considered include different cross-clamps (CCs) and endo-aortic balloon occlusion (EABO). A novel occluder is also introduced, namely, constrained EABO (CEABO), which consists of applying a constrainer externally around the aorta when performing EABO. Computational solid mechanics are employed to investigate each occluder according to a comprehensive list of functional requirements. The potential of a state of occlusion is also considered for the first time. Three different constrainer designs are evaluated for CEABO. Although the CCs were responsible for the highest strains, largest deformation, and most inefficient increase of the occlusion potential, it remains the most stable, simplest, and cheapest occluder. The different CC hinge geometries resulted in poorer performance of CC used for minimally invasive procedures than conventional ones. CEABO with a profiled constrainer successfully addresses the EABO shortcomings of safety, stability, and positioning accuracy, while maintaining its complexities of operation (disadvantage) and yielding additional functionalities (advantage). Moreover, CEABO is able to achieve the previously unattainable potential to provide a clinically determinable state of occlusion. CEABO offers an attractive alternative to the shortcomings of existing occluders, with its design rooted in achieving the highest patient safety. Copyright © 2016 John Wiley & Sons, Ltd.

Interaction of biomechanics with extracellular matrix components in abdominal aortic aneurysm wall.

OBJECTIVE: Little is known about the interactions between extracellular matrix (ECM) proteins and locally acting mechanical conditions and material macroscopic properties in abdominal aortic aneurysm (AAA). In this study, ECM components were investigated with correlation to corresponding biomechanical properties and loads in aneurysmal arterial wall tissue. METHODS: Fifty-four tissue samples from 31 AAA patients (30♂; max. diameter Dmax 5.98 ± 1.42 cm) were excised from the aneurysm sac. Samples were divided for corresponding immunohistological and mechanical analysis. Collagen I and III, total collagen, elastin, and proteoglycans were quantified by computational image analysis of histological staining. Pre-surgical CT data were used for 3D segmentation of the AAA and calculation of mechanical conditions by advanced finite element analysis. AAA wall stiffness and strength were assessed by repeated cyclical, sinusoidal and destructive tensile testing. RESULTS: Amounts of collagen I, III, and total collagen were increased with higher local wall stress (p = .002, .017, .030, respectively) and strain (p = .002, .012, .020, respectively). AAA wall failure tension exhibited a positive correlation with collagen I, total collagen, and proteoglycans (p = .037, .038, .022, respectively). α-Stiffness correlated with collagen I, III, and total collagen (p = .011, .038, and .008), while ß-stiffness correlated only with proteoglycans (p = .028). In contrast, increased thrombus thickness was associated with decreased collagen I, III, and total collagen (p = .003, .020, .015, respectively), and AAA diameter was negatively associated with elastin (p = .006). CONCLUSIONS: The present results indicate that in AAA, increased locally acting biomechanical conditions (stress and strain) involve increased synthesis of collagen and proteoglycans with increased failure tension. These findings confirm the presence of adaptive biological processes to maintain the mechanical stability of AAA wall.

Chronic fatigue syndrome and fibromyalgia in Canada: prevalence and associations with six health status indicators.

INTRODUCTION: Few studies have considered the factors independently associated with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) or considered the impact of these conditions on health status using population-based data. METHODS: We used data from the nationally representative 2010 Canadian Community Health Survey (n = 59 101) to describe self-reported health professional-diagnosed CFS and/or FM, and their associations with 6 health status indicators. RESULTS: In 2010, diagnosed CFS and FM are reported by 1.4% (95% confidence interval [CI]: 1.3%-1.6%) and 1.5% (1.4%-1.7%), respectively, of the Canadian household population aged 12 years and over, with comorbid CFS and FM affecting 0.3% (0.3%-0.4%) of that population. Prevalent CFS and/or FM were more common among women, adults aged 40 years and over, those with lowest income, and those with certain risk factors for chronic disease (i.e. obesity, physical inactivity and smoking). After controlling for differences between the groups, people with CFS and/or FM reported poorer health status than those with neither condition on 5 indicators of health status, but not on the measure of fair/poor mental health. Having both CFS and FM and having multiple comorbid conditions was associated with poorer health status. CONCLUSION: Co-occurrence of CFS and FM and having other chronic conditions were strongly related to poorer health status and accounted for much of the differences in health status. Understanding factors contributing to improved quality of life in people with CFS and/or FM, particularly in those with both conditions and other comorbidities, may be an important area for future research.

TITRE: Le syndrome de fatigue chronique et la fibromyalgie au Canada : prévalence et associations avec six indicateurs de l'état de santé. INTRODUCTION: Peu d'études ont traité, à l'aide de données populationnelles, des facteurs associés de façon indépendante au syndrome de fatigue chronique (SFC) et à la fibromyalgie (FM) ou des répercussions de ces affections sur l'état de santé. MÉTHODOLOGIE: Nous avons utilisé les données de l'Enquête sur la santé dans les collectivités canadiennes de 2010 (n = 59 101), représentative de la population à l'échelle nationale, pour décrire les cas autodéclarés de SFC et de FM diagnostiqués par un professionnel de la santé et pour déterminer les associations de ces affections avec six indicateurs de l'état de santé. RÉSULTATS: En 2010, 1,4 % (intervalle de confiance [IC] à 95 % : 1,3 % à 1,6 %) des Canadiens de 12 ans ou plus vivant à domicile ont déclaré avoir reçu un diagnostic de SFC, 1,5 % (IC à 95 %: 1,4 % à 1,7 %) de FM, et 0,3 % (IC à 95 %: 0,3 % à 0,4 %) a déclaré être atteinte à la fois de SFC et de FM. Les cas de SFC comme ceux de FM étaient plus fréquents chez les femmes, les adultes de 40 ans ou plus, les personnes à faible revenu et les personnes présentant certains facteurs de risque de maladie chronique (obésité, sédentarité et tabagisme). Après ajustement en fonction des différences existant entre les groupes, les personnes ayant déclaré être atteintes du SFC ou de FM ou des deux avaient un moins bon état de santé que les personnes atteintes d'aucune de ces affections pour cinq indicateurs de l'état de santé, mais aucune différence n'a été trouvée entre ces groupes par rapport à l'indicateur de santé mentale. Le fait d'être atteint à la fois du SFC et de FM et de présenter de multiples affections comorbides était associé à un moins bon état de santé. CONCLUSION: La présence concomitante du SFC, de la FM et d'autres affections chroniques était étroitement associée au fait d'avoir un moins bon état de santé, et les différences relatives à l'état de santé étaient dues en bonne partie à la présence concomitante de ces affections. La compréhension des facteurs qui contribuent à l'amélioration de la qualité de vie des personnes atteintes du SFC ou de FM, et en particulier des personnes qui présentent ces deux affections ainsi que diverses affections comorbides, serait un champ important à explorer dans le cadre de travaux de recherche ultérieurs.

Metrological challenges for reconstruction of 3-D microstructures by focused ion beam tomography methods.

The development of combined focused ion beam and scanning electron microscopes has enabled significant advances in the characterization of the 3-D structure of materials. The repeated removal of thin layers or slices with an ion beam and imaging or mapping the chemical or crystallographic structure of each slice enables a 3-D reconstruction from the images or maps. The accuracy of the reconstruction thus depends on the accuracy with which the slice thickness is measured and maintained throughout the process, and the alignment accuracy of the slices achieved during acquisition or by postacquisition corrections. A survey of papers published in this field suggests that the reconstruction accuracy is not often considered or reported. Using examples from examination of the 3-D structure of hardmetals, issues affecting the accuracy of slice thicknesses and image realignments are examined and illustrated and potential errors quantified by the use of fiducial markers and the expected isotropy of the hardmetal structure itself.

Methodology of the 2009 Survey on Living with Chronic Diseases in Canada--hypertension component.

INTRODUCTION: The Survey on Living with Chronic Diseases in Canada--hypertension component (SLCDC-H) is a 20-minute cross-sectional telephone survey on hypertension diagnosis and management. Sampled from the 2008 Canadian Community Health Survey (CCHS), the SLCDC-H includes Canadians (aged ≥ 20 years) with self-reported hypertension from the ten provinces. METHODS: The questionnaire was developed by Delphi technique, externally reviewed and qualitatively tested. Statistics Canada performed sampling strategies, recruitment, data collection and processing. Proportions were weighted to represent the Canadian population, and 95% confidence intervals (CIs) were derived by bootstrap method. RESULTS: Compared with the CCHS population reporting hypertension, the SLCDC-H sample (n = 6142) is slightly younger (SLCDC-H mean age: 61.2 years, 95% CI: 60.8-61.6; CCHS mean age: 62.2 years, 95% CI: 61.8-62.5), has more post-secondary school graduates (SLCDC-H: 52.0%, 95% CI: 49.7%-54.2%; CCHS: 47.5%, 95% CI: 46.1%-48.9%) and has fewer respondents on hypertension medication (SLCDC-H: 82.5%, 95% CI: 80.9%-84.1%; CCHS: 88.6%, 95% CI: 87.7%-89.6%). CONCLUSION: Overall, the 2009 SLCDC-H represents its source population and provides novel, comprehensive data on the diagnosis and management of hypertension. The survey has been adapted to other chronic conditions--diabetes, asthma/chronic obstructive pulmonary disease and neurological conditions. The questionnaire is available on the Statistics Canada website; descriptive results have been disseminated by the Public Health Agency of Canada.

TITRE: Méthodologie de l'Enquête sur les personnes ayant une maladie chronique au Canada ­ composante de l'hypertension de 2009. INTRODUCTION: L'Enquête sur les personnes ayant une maladie chronique au Canada ­ composante de l'hypertension (EPMCC-H) est une enquête téléphonique transversale de 20 minutes sur le diagnostic et la prise en charge de l'hypertension. L'échantillon de l'EPMCC-H, sélectionné à partir des répondants à l'Enquête sur la santé dans les collectivités canadiennes (ESCC) de 2008, était composé de Canadiens (de 20 ans et plus) des dix provinces ayant déclaré avoir reçu un diagnostic d'hypertension. MÉTHODOLOGIE: Le questionnaire a été élaboré au moyen de la technique Delphi et a fait l'objet d'un examen externe ainsi que de tests qualitatifs. Statistique Canada s'est chargé des stratégies d'échantillonnage, du recrutement, de la collecte et du traitement des données. Les proportions ont été pondérées afin de représenter la population canadienne et les intervalles de confiance (IC) à 95 % ont été calculés au moyen de la méthode de rééchantillonnage bootstrap. RÉSULTATS: Si on le compare à la population de l'ESCC ayant déclaré souffrir d'hypertension, l'échantillon de l'EPMCC-H (n = 6 142) est légèrement plus jeune (âge moyen des répondants à l'EPMCC-H : 61,2 ans, IC à 95 % : 60,8 à 61,6; âge moyen des répondants à l'ESCC : 62,2 ans, IC à 95 % : 61,8 à 62,5), comporte plus de détenteurs d'un diplôme d'études postsecondaires (EPMCC-H : 52,0 %, IC à 95 %: 49,7 % à 54,2 %; ESCC : 47,5 %, IC à 95 % : 46,1 % à 48,9 %) et moins de répondants prenant un médicament pour l'hypertension (EPMCC-H : 82,5 %, IC à 95 % : 80,9 % à 84,1 %; ESCC : 88,6 %, IC à 95 % : 87,7 % à 89,6 %). CONCLUSION: Dans l'ensemble, l'EPMCC-H de 2009 est représentatif de sa population source et fournit des données nouvelles et exhaustives sur le diagnostic et la prise en charge de l'hypertension. L'enquête a été adaptée à d'autres maladies chroniques ­ diabète, asthme/maladie pulmonaire obstructive chronique et troubles neurologiques. Le questionnaire est accessible à partir du site Web de Statistique Canada; des résultats descriptifs ont été publiés par l'Agence de la santé publique du Canada.

Sequential Cdk1 and Plk1 phosphorylation of protein tyrosine phosphatase 1B promotes mitotic cell death.

Mitotic cell death following prolonged arrest is an important death mechanism that is not completely understood. This study shows that Protein Tyrosine Phosphatase 1B (PTP1B) undergoes phosphorylation during mitotic arrest induced by microtubule-targeting agents (MTAs) in chronic myeloid leukaemia cells. Inhibition of cyclin-dependent kinase 1 (Cdk1) or polo-like kinase 1 (Plk1) during mitosis prevents PTP1B phosphorylation, implicating these kinases in PTP1B phosphorylation. In support of this, Cdk1 and Plk1 co-immunoprecipitate with endogenous PTP1B from mitotic cells. In addition, active recombinant Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B. Furthermore, overexpression of wild-type PTP1B induced mitotic cell death, which is potentiated by MTAs. Moreover, mutation of serine 286 abrogates the cell death induced by PTP1B, whereas mutation of serine 393 does not, highlighting the importance of serine 286 phosphorylation in the execution of mitotic cell death. Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. Collectively, these data reveal that PTP1B activity promotes mitotic cell death and is regulated by the co-operative action of Cdk1 and Plk1 during mitotic arrest.

Measuring and modeling patient-specific distributions of material properties in abdominal aortic aneurysm wall.

Both the clinically established diameter criterion and novel approaches of computational finite element (FE) analyses for rupture risk stratification of abdominal aortic aneurysms (AAA) are based on assumptions of population-averaged, uniform material properties for the AAA wall. The presence of inter-patient and intra-patient variations in material properties is known, but has so far not been addressed sufficiently. In order to enable the preoperative estimation of patient-specific AAA wall properties in the future, we investigated the relationship between non-invasively assessable clinical parameters and experimentally measured AAA wall properties. We harvested n = 163 AAA wall specimens (n = 50 patients) during open surgery and recorded the exact excision sites. Specimens were tested for their thickness, elastic properties, and failure loads using uniaxial tensile tests. In addition, 43 non-invasively assessable patient-specific or specimen-specific parameters were obtained from recordings made during surgery and patient charts. Experimental results were correlated with the non-invasively assessable parameters and simple regression models were created to mathematically describe the relationships. Wall thickness was most significantly correlated with the metabolic activity at the excision site assessed by PET/CT (ρ = 0.499, P = 4 × 10(-7)) and to thrombocyte counts from laboratory blood analyses (ρ = 0.445, P = 3 × 10(-9)). Wall thickness was increased in patients suffering from diabetes mellitus, while it was significantly thinner in patients suffering from chronic kidney disease (CKD). Elastic AAA wall properties had significant correlations with the metabolic activity at the excision site (PET/CT), with existent calcifications, and with the diameter of the non-dilated aorta proximal to the AAA. Failure properties (wall strength and failure tension) had correlations with the patient's medical history and with results from laboratory blood analyses. Interestingly, AAA wall failure tension was significantly reduced for patients with CKD and elevated blood levels of potassium and urea, respectively, both of which are associated with kidney disease. This study is a first step to a future preoperative estimation of AAA wall properties. Results can be conveyed to both the diameter criterion and FE analyses to refine rupture risk prediction. The fact that AAA wall from patients suffering from CKD featured reduced failure tension implies an increased AAA rupture risk for this patient group at comparably smaller AAA diameters.

Perampanel Study 207: long-term open-label evaluation in patients with epilepsy.

OBJECTIVES: Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel α-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures. MATERIALS AND METHODS: Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70 years) who completed one of two randomized, placebo-controlled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2 mg increments of perampanel every 2 weeks to 12 mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424 weeks (~8 years). Interim analysis data cut-off date was 1 December, 2010. RESULTS: Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4 years after study start), over a third (n = 53, 38.4%) remained on perampanel; 41.3% (n = 57) of patients had >3 years of exposure; and 13.0% (n = 18) had at least 4 years' exposure. Mean ± standard deviation (SD) duration of exposure was 116 ± 75 weeks and mean ± SD dose during the OLE Maintenance Period was 7.3 ± 3.3 mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28 days during open-label treatment was -31.5% (-99.2 to 512.2). CONCLUSIONS: Long-term - up to 4 years - adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

Stabilization of ribozyme-like cis-noncoding rRNAs induces apoptotic and nonapoptotic death in lung cells.

Bidirectional non-protein-coding RNAs are ubiquitously transcribed from the genome. Convergent sense and antisense transcripts may regulate each other. Here, we examined the convergent cis-noncoding rRNAs (nc-rRNAs) in A5 and E9 lung cancer models. Sense nc-rRNAs extending from rDNA intergenic region to internal transcribed spacer of around 10 kb in length were identified. nc-rRNAs in sense direction exhibited in vitro characteristics of ribozymes, namely, degradation upon incubation with MgCl(2) and stabilization by complementary oligonucleotides. Detection of endogenous cleavage-ligation products carrying internal deletion of hundreds to thousands nucleotides by massively parallel sequencing confirmed the catalytic properties. Transfection of oligonucleotides pairing with antisense nc-rRNAs stabilized both target and complementary transcripts, perturbed rRNA biogenesis, and induced massive cell death via apoptotic and/or nonapoptotic mechanisms depending on cell type and treatment. Oligonucleotides targeting cellular sense transcripts are less responsive. Spontaneously detached cells, though rare, also showed accumulation of nc-rRNAs and perturbation of rRNA biogenesis. Direct participation of nc-rRNAs in apoptotic and nonapoptotic death was demonstrated by transfection of synthetic nc-rRNAs encompassing the rDNA promoter. In sum, convergent cis-nc-rRNAs follow a feed-forward mechanism to regulate each other and rRNA biogenesis. This opens an opportunity to disrupt rRNA biogenesis, commonly upregulated in cancers, via inhibition of ribozyme-like activities in nc-rRNAs.

Diffusion tensor imaging of white matter tract evolution over the lifespan.

Diffusion tensor imaging (DTI) has been used widely to show structural brain changes during both development and aging. Lifespan studies are valuable because they connect these two processes, yet few DTI studies have been conducted that include both children and elderly subjects. This study used DTI tractography to investigate 12 major white matter connections in 403 healthy subjects aged 5-83 years. Poisson fits were used to model changes of fractional anisotropy (FA) and mean diffusivity (MD) across the age span, and were highly significant for all tracts. FA increased during childhood and adolescence, reached a peak between 20 and 42 years of age, and then decreased. MD showed an opposite trend, decreasing first, reaching a minimum at 18-41 years, and then increasing later in life. These trajectories demonstrate rates and timing of development and degradation that vary regionally in the brain. The corpus callosum and fornix showed early reversals of development trends, while frontal-temporal connections (cingulum, uncinate, superior longitudinal) showed more prolonged maturation and delayed declines. FA changes were driven by perpendicular diffusivity, suggesting changes of myelination and/or axonal density. Tract volume changed significantly with age for most tracts, but did not greatly influence the FA and MD trajectories. This study demonstrates clear age-related microstructural changes throughout the brain white matter, and provides normative data that will be useful for studying white matter development in a variety of diseases and abnormal conditions.