Utilisation de l'analyse des correspondances multiples et de la classification hiérarchique pour modéliser la valeur pronostique des marqueurs présents chez les patients avec polyarthrite d'installation récente

Ce projet de maîtrise a comme objectif d'évaluer, dans une cohorte de patients avec polyarthrite inflammatoire débutante, l'existence de différents sous-groupes de patients classifiables selon leurs caractéristiques cliniques lors de l'inclusion dans l'étude. Les patients sont recrutés au Centre hospitalier universitaire de Sherbrooke (CHUS). Ils doivent être âgés de plus de 18 ans, se présenter avec au moins 3 articulations atteintes d'inflammation articulaire, et ce depuis plus d'un mois et moins de 12 mois. Les patients exclus de l'étude sont ceux atteints d'arthrite microcristalline (ex: Goutte), de collagénose (maladie du tissu conjonctif), ou d'arthrite septique, ainsi que les patients inaptes à consentir. De plus, les patients sont suivis sur une période de 5 ans et réévalués tous les ans. Nous sommes donc en présence d'un dispositif d'observation avec cohorte prospective longitudinale. Chacun des patients est traité selon les traitements disponibles cliniquement et adaptés à sa situation clinique. Une classification hiérarchique a été effectuée chez les 211 premiers patients consécutifs pour lesquels l'information clinique à l'inclusion et à 30 mois était complète. Les variables de l'inclusion qui ont été incorporées dans l'analyse statistique sont: les données démographiques (âge, sexe), certains autoanticorps, le décompte d'articulations gonflées, les paramètres d'inflammation systémique, les paramètres sanguins, si les patients remplissent au moins 4 des 7 critères de classification de la polyarthrite rhumatoïde (PR) selon l'American College of Rheumatology (ACR), la présence de traitements lors de l'inclusion et les dommages articulaires (érosions osseuses et pincements articulaires) sur les radiographies des mains et des pieds. L'analyse statistique a permis l'identification de 5 sous-groupes de patients: 2 avec une meilleure issue clinique (Groupes 1 et 4), 2 avec une issue intermédiaire (Groupes 2 et 3) et 1 avec une très mauvaise issue radiologique et clinique (Groupe 5). Les patients des groupes 1 et 4 ont très peu d'anticorps ou d'érosions, peu d'inflammation systémique, et sont plus jeunes (63% et 47%, âge [< ou =] 50 ans respectivement). Aucun des patients du groupe 4 ne remplit les critères de la classification de la PR, contrairement au groupe 1 (0% vs 100% respectivement). Les patients des groupes 2 et 3 ont généralement des dommages radiographiques à l'inclusion et leur nombre d'érosions osseuses augmente à 30 mois. Les patients du groupe 2 se distinguent par un très faible taux d'anticorps (entre 0% et 17%), tout en présentant fréquemment une inflammation très importante et de l'anémie. Le groupe 3 quant à lui a modérément d'anticorps (entre 40 à 50%), un taux élevé de globules blancs circulants et les patients sont généralement traités très tôt dans le développement de la maladie. Finalement, le groupe 5 est le groupe avec un nombre très important d'anticorps, beaucoup de dommages radiographiques à l'inclusion et à 30 mois, les critères de l'ACR sont généralement remplis et il y a présence d'inflammation systémique. Comme les résultats le suggèrent, cette analyse semble compatible avec d'autres observations qui suggèrent que l'arthrite débutante représente plus d'une maladie. Le groupe 3 ressemble au groupe 5 pour les caractéristiques de l'inclusion. Ceci pourrait indiquer que de traiter très tôt peut, dans certains cas, modifier l'expression des anticorps et l'évolution de la maladie. D'autres analyses plus approfondies seront nécessaires pour améliorer la classification des divers sous-groupes. Éventuellement, un modèle de régression multivarié pourra être utilisé pour prédire l'évolution de la maladie chez de nouveaux patients à partir de leurs caractéristiques initiales. Un tel modèle pourrait alors être très utile en clinique pour établir le bon traitement à administrer aux patients en considérant leurs caractéristiques cliniques lors de leur première visite avec le rhumatologue

From Too Little to Too Much: Sorting Through the Online Resource Environment in Education

The Internet is considered to be one of the most important mechanisms for sharing research (Chavkin & Chavkin, 2008), raising questions about the scope and variety of research-based education resources available online. Whereas years ago, the challenge for educators was to find relevant research information for practice, this challenge has shifted to one of sorting through the “infoglut” (Edmunds & Morris, 2000), or the abundance of information claiming to be grounded in research, and being able to judge which resources are most valuable and reliable. Drawing on scholarship that seeks to mobilize evidence between researchers, practitioners, and policymakers (Levin, 2011), this study reports the results of a systematic search of online research-based resources for educators across seven subject areas. Our descriptive typology categorizes 333 products along various dimensions (e.g., producer organization, target audience, country of origin) and demonstrates a surprising variety claiming to be research–informed

G-quadruplex located in the 5’UTR of the BAG-1 mRNA affects both its cap-dependent and cap-independent translation through global secondary structure maintenance

Abstract: The anti-apoptotic BAG-1 protein isoforms are known to be overexpressed in colorectal tumors and are considered to be potential therapeutic targets. The isoforms are derived fromalternative translation initiations occuring at four in-frame start codons of a single mRNA transcript. Its 5'UTR also contains an internal ribosome entry site (IRES) regulating the capindependent translation of the transcript. An RNA Gquadruplex (rG4) is located at the 5'end of the BAG- 1 5'UTR, upstream of the known cis-regulatory elements. Herein, we observed that the expression of BAG-1 isoforms is post-transcriptionally regulated in colorectal cancer cells and tumors, and that stabilisation of the rG4 by small molecules ligands reduces the expression of endogenous BAG-1 isoforms. We demonstrated a critical role for the rG4 in the control of both cap-dependent and independent translation of the BAG-1 mRNA in colorectal cancer cells. Additionally, we found an upstream ORF that also represses BAG-1 mRNA translation. The structural probing of the complete 5'UTR showed that the rG4 acts as a steric block which controls the initiation of translation at each start codon of the transcript and also maintains the global 5'UTR secondary structure required for IRES-dependent translation

The serine protease inhibitor serpinE2 is a novel target of ERK signaling involved in human colorectal tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Among the most harmful of all genetic abnormalities that appear in colorectal cancer (CRC) development are mutations of KRAS and its downstream effector BRAF as they result in abnormal extracellular signal-related kinase (ERK) signaling. In a previous report, we had shown that expression of a constitutive active mutant of MEK1 (caMEK) in normal rat intestinal epithelial cells (IECs) induced morphological transformation associated with epithelial to mesenchymal transition, growth in soft agar, invasion and metastases in nude mice. Results from microarrays comparing control to caMEK-expressing IECs identified the gene encoding for serpinE2, a serine protease inhibitor, as a potential target of activated MEK1.</p> <p>Results</p> <p>1- RT-PCR and western blot analyses confirmed the strong up-regulation of serpinE2 expression and secretion by IECs expressing oncogenic MEK, Ras or BRAF. 2- Interestingly, serpinE2 mRNA and protein were also markedly enhanced in human CRC cells exhibiting mutation in <it>KRAS </it>and <it>BRAF</it>. 3- RNAi directed against serpinE2 in caMEK-transformed rat IECs or in human CRC cell lines HCT116 and LoVo markedly decreased foci formation, anchorage-independent growth in soft agarose, cell migration and tumor formation in nude mice. 4- Treatment of CRC cell lines with U0126 markedly reduced <it>serpinE2 </it>mRNA levels, indicating that expression of <it>serpinE2 </it>is likely dependent of ERK activity. 5- Finally, Q-PCR analyses demonstrated that mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues and in colorectal tumors, regardless of tumor stage and grade.</p> <p>Conclusions</p> <p>Our data indicate that serpinE2 is up-regulated by oncogenic activation of Ras, BRAF and MEK1 and contributes to pro-neoplastic actions of ERK signaling in intestinal epithelial cells. Hence, serpinE2 may be a potential therapeutic target for colorectal cancer treatment.</p

Anti-Sa antibodies and antibodies against cyclic citrullinated peptide are not equivalent as predictors of severe outcomes in patients with recent-onset polyarthritis

The prognostic value of two antibodies targeting citrullinated antigens, anti-Sa and anti-cyclic citrullinated peptide (CCP), present at inclusion, was evaluated prospectively in a cohort of 165 consecutive patients with recent-onset or early polyarthritis (EPA) followed for up to 30 months. Patients were treated according to current Good Clinical Practice standards. Predefined outcomes were severe arthritis and persistent arthritis. At inclusion, a median of 3 months after disease onset, 133 (81%) patients fulfilled at least four American College of Rheumatology criteria for rheumatoid arthritis and 30 (18%) had erosive changes on radiographs of hands and feet. Disease-modifying anti-rheumatic drugs were used in close to 80% of the patients at 30 months. Joint damage increased linearly over time, whereas disease activity declined markedly and remained low at each follow-up. Autoantibodies were identified in 76 (46%) patients: rheumatoid factor (RF) in 68 (41%), anti-CCP in 53 (33%), and anti-Sa in 46 (28%). All three antibodies were correlated, but anti-Sa antibodies best predicted severity at 18 and 30 months. RF and anti-CCP performed less well. For both outcomes, anti-Sa alone performed better than any combination of antibodies. The presence of any autoantibody identified about 50 to 60% of the patients with poor outcomes. In multivariate analysis, anti-Sa (odds ratio (OR) 8.83), the presence of erosions at inclusion (OR 3.47) and increasing age (OR 1.06/year) were significantly associated with severity, whereas RF and anti-CCP were not significant predictors. Persistent arthritis was present in up to 84% of patients; autoantibodies were specific but poorly sensitive predictors of this outcome. We conclude that assays for antibodies against citrullinated antigens differ in their ability to predict poorer outcomes in patients with EPA. In our EPA cohort treated in accordance with current standards, detection of anti-Sa but not of RF or anti-CCP antibodies, in combination with clinical and radiological variables present at the first encounter, allowed the identification of a subgroup of EPA patients suffering more rapid and more severe joint damage over 30 months

Radio telemetry devices to monitor breathing in non-sedated animals

Radio telemetry equipment has significantly improved over the last 10-15 years and is increasingly being used in research for monitoring a variety of physiological parameters in non-sedated animals. The aim of this review is to provide an update on the current state of development of radio telemetry for recording respiration. Our literature review found only rare reports of respiratory studies via radio telemetry. Much of this article will hence report our experience with our custom-built radio telemetry devices designed for recording respiratory signals, together with numerous other physiological signals in lambs. Our current radio telemetry system allows to record 24 simultaneous signals 24h/day for several days. To our knowledge, this is the highest number of physiological signals, which can be recorded wirelessly. Our devices have been invaluable for studying respiration in our ovine models of preterm birth, reflux laryngitis, postnatal exposure to cigarette smoke, respiratory syncytial virus infection and nasal ventilation, all of which are relevant to neonatal respiratory problems

Overview of the assessment practices of occupational therapists working in Quebec

Description. L'évaluation du client est primordiale dans la pratique de l'ergothérapie, notamment pour établir les priorités de traitement et pour vérifier l'efficacité des interventions. Les pratiques évaluatives des ergothérapeutes sont cependant peu documentées. But. Dresser un portrait des pratiques évaluatives des ergothérapeutes du Québec selon les dimensions personne-environnement-occupation et les clientèles. Méthodologie. Une enquête transversale a été réalisée à l'aide d'un sondage en ligne envoyé aux ergothérapeutes du Québec. Résultats. En pédiatrie, les ergothérapeutes utilisent majoritairement des outils standardisés des aptitudes physiques et neurologiques. L'évaluation d'adultes cible principalement les aptitudes physiques et la productivité. Auprès des aînés, l'évaluation repose surtout sur les aspects fonctionnels, particulièrement les aptitudes physiques, les soins personnels et la sécurité à domicile, et sur le dépistage des difficultés cognitives. Implications pour la pratique. L'évaluation ergothérapique serait généralement axée sur les aptitudes physiques. Pour assurer une approche holistique, l'occupation et l'environnement devraient être davantage considérés dans l'évaluation.Abstract : Background. In occupational therapy practice, client assessments are essential for establishing treatment priorities and determining the effectiveness of interventions. However, occupational therapists' assessment practices are not well documented. Purpose. This work aimed to provide an overview of the assessment practices of Quebec occupational therapists based on the person–environment–occupation components and clienteles. Method. A cross-sectional survey was conducted using an online survey that was sent to occupational therapists in Quebec. Findings. In paediatrics, occupational therapists tend to use standardized tools to assess physical and neurological abilities. Adult assessment focuses mainly on physical abilities and productivity. For seniors, assessment focuses mainly on functional aspects (physical abilities, personal care, and home safety) and screening for cognitive difficulties. Implications. Occupational therapy assessment mostly focuses on physicial abilities. To ensure a holistic approach, more occupational and environmental components should be included in the assessment practices

Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials

PURPOSE: The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS: Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality. RESULTS: Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION: ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.</p