Segmentation of Head and Neck Lymph Node Regions for Radiotherapy Planning Using Active Contour-Based Atlas Registration

In this paper, we present the segmentation of the headand neck lymph node regions using a new active contourbased atlas registration model. We propose to segment thelymph node regions without directly including them in theatlas registration process; instead, they are segmentedusing the dense deformation field computed from theregistration of the atlas structures with distinctboundaries. This approach results in robust and accuratesegmentation of the lymph node regions even in thepresence of significant anatomical variations between theatlas-image and the patient's image to be segmented. Wealso present a quantitative evaluation of lymph noderegions segmentation using various statistical as well asgeometrical metrics: sensitivity, specificity, dicesimilarity coefficient and Hausdorff distance. Acomparison of the proposed method with two other state ofthe art methods is presented. The robustness of theproposed method to the atlas selection, in segmenting thelymph node regions, is also evaluated.

Treatment implications of the emerging molecular classification system for melanoma.

Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.

Prospective association of the SHARE-operationalized frailty phenotype with adverse health outcomes: evidence from 60+ community-dwelling Europeans living in 11 countries.

BACKGROUND: Among the many definitions of frailty, the frailty phenotype defined by Fried et al. is one of few constructs that has been repeatedly validated: first in the Cardiovascular Health Study (CHS) and subsequently in other large cohorts in the North America. In Europe, the Survey of Health, Aging and Retirement in Europe (SHARE) is a gold mine of individual, economic and health information that can provide insight into better understanding of frailty across diverse population settings. A recent adaptation of the original five CHS-frailty criteria was proposed to make use of SHARE data and measure frailty in the European population. To test the validity of the SHARE operationalized frailty phenotype, this study aims to evaluate its prospective association with adverse health outcomes. METHODS: Data are from 11,015 community-dwelling men and women aged 60+ participating in wave 1 and 2 of the Survey of Health, Aging and Retirement in Europe, a population-based survey. Multivariate logistic regression analyses were used to assess the 2-year follow up effect of SHARE-operationalized frailty phenotype on the incidence of disability (disability-free at baseline) and on worsening disability and morbidity, adjusting for age, sex, income and baseline morbidity and disability. RESULTS: At 2-year follow up, frail individuals were at increased risk for: developing mobility (OR 3.07, 95% CI, 1.02-9.36), IADL (OR 5.52, 95% CI, 3.76-8.10) and BADL (OR 5.13, 95% CI, 3.53-7.44) disability; worsening mobility (OR 2.94, 95% CI, 2.19- 3.93) IADL (OR 4.43, 95% CI, 3.19-6.15) and BADL disability (OR 4.53, 95% CI, 3.14-6.54); and worsening morbidity (OR 1.77, 95% CI, 1.35-2.32). These associations were significant even among the prefrail, but with a lower magnitude of effect. CONCLUSIONS: The SHARE-operationalized frailty phenotype is significantly associated with all tested health outcomes independent of baseline morbidity and disability in community-dwelling men and women aged 60 and older living in Europe. The robustness of results validate the use of this phenotype in the SHARE survey for future research on frailty in Europe.

Hémorragie digestive haute: utilité des scores pronostiques [Upper gastrointestinal bleeding: usefulness of prognostic scores].

Upper gastrointestinal bleeding is a potentially serious event, usually requiring urgent endoscopic treatment. Better stratification of the risk of complication or death could optimize management and improve patient outcomes, while ensuring adequate resource allocation. Several prognostic scores have been developed, in order to identify high risk patients, who require immediate treatment, and patients at low risk for whom endoscopy may be delayed. An ideal prognostic score should be accurate, simple, reproducible, and prospectively validated in different populations. Published scores meet these requirements only partially, and thus can only be used as part of an integrative diagnostic and therapeutic process.

Cognitive impairment in elderly medical inpatients: detection and associated six-month outcomes.

OBJECTIVE: The authors examined the relationship of cognitive impairment at hospital admission to 6-month outcome (hospital readmission, nursing home admission, and death) in a cohort of elderly medical inpatients. METHODS: A group of 401 medical inpatients age 75 and older underwent a comprehensive geriatric assessment at hospital admission and were followed up for 6 months. Cognitive impairment was defined as a score <24 on the Mini-Mental State Exam. Detection was assessed through blinded review of discharge summary. Follow-up data were gathered from the centralized billing system (hospital and nursing home admissions) and from proxies (death). RESULTS: Cognitive impairment was present in 129 patients (32.3%). Only 48 (37.2%) were detected; these had more severe impairment than undetected cases. During follow-up, cognitive impairment, whether detected or not, was associated with death and nursing home admission. After adjustment for health, functional, and socioeconomic status, an independent association remained only for nursing home admission in subjects with detected impairment. Those with undetected impairment appeared to be at intermediate risk, but this relationship was not statistically significant. CONCLUSION: In these elderly medical inpatients, cognitive impairment was frequent, rarely detected, and associated with nursing home admission during follow-up. Although this association was stronger in those with detected impairment, these results support the view that acute hospitalization presents an opportunity to better detect cognitive impairment in elderly patients and target further interventions to prevent adverse outcomes such as nursing home admission.

Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours.

AIM: Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements. METHODS: One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates. RESULTS: A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations. CONCLUSION: Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

Efficacy Of Canakinumab (Acz885), A Fully Human Anti-Interleukin (Il)-1beta Monoclonal Antibody, In The Prevention Of Flares In Gout Patients Initiating Allopurinol Therapy

Background: Gout patients initiating urate lowering therapy have an increased risk of flares. Inflammation in gouty arthritis is induced by IL-1b. Canakinumab targets and inhibits IL-1b effectively in clinical studies. This study compared different doses of canakinumab vs colchicine in preventing flares in gout patients initiating allopurinol therapy.Methods: In this 24 week double blind study, gout patients (20-79 years) initiating allopurinol were randomized (1:1:1:1:1:1:2) to canakinumab s.c. single doses of 25, 50, 100, 200, 300 mg, or 150 mg divided in doses every 4 weeks (50+50+25+25 mg [q4wk]) or colchicine 0.5 mg p.o. daily for 16 weeks. Primary outcome was to determine the canakinumab dose giving comparable efficacy to colchicine with respect to the number of gout flares occurring during first 16 weeks. Secondary outcomes included number of patients with gout flares and C-reactive protein (CRP) levels during the first 16 weeks.Results: 432 patients were randomized and 391 (91%) completed the study. All canakinumab doses were better than colchicine in preventing flares and therefore, a canakinumab dose comparable to colchicine could not be determined. Based on a negative binomial model, all canakinumab groups, except 25 mg, reduced the flare rate ratio per patient significantly compared to colchicine group (rate ratio estimates 25 mg 0.60, 50 mg 0.34, 100 mg 0.28, 200 mg 0.37, 300 mg 0.29, q4wk 0.38; p<=0.05). The percentage of patients with flares was lower for all canakinumab groups (25 mg 27.3%, 50 mg 16.7%, 100 mg 14.8%, 200 mg 18.5%, 300 mg 15.1%, q4wk 16.7%) compared to colchicine group (44.4%). All patients taking canakinumab were significantly less likely to experience at least one gout flare than patients taking colchicine (odds ratio range [0.22 - 0.47]; p<=0.05 for all). The median baseline CRP levels were 2.86 mg/L for 25 mg, 3.42 mg/L for 50 mg, 1.76 mg/L for 100 mg, 3.66 mg/L for 200 mg, 3.21 mg/L for 300 mg, 3.23 mg/L for q4wk canakinumab groups and 2.69 mg/L for colchicine group. In all canakinumab groups with median CRP levels above the normal range at baseline, median levels declined within 15 days of treatment and were maintained at normal levels (ULN=3 mg/L) throughout the 16 week period. Adverse events (AEs) occurred in 52.7% (25 mg), 55.6% (50 mg), 51.9% (100 mg), 51.9% (200 mg), 54.7% (300 mg), and 58.5% (q4wk) of patients on canakinumab vs 53.7% of patients on colchicine. Serious AEs (SAE) were reported in 2 (3.6%; 25 mg), 2 (3.7%, 50 mg), 3 (5.6%, 100 mg), 3 (5.6%, 200 mg), 3 (5.7%, 300 mg) and 1 (1.9%, q4wk) patients on canakinumab and in 5 (4.6%) patients on colchicine. One fatal SAE (myocardial infarction, not related to study drug) occurred in colchicine group.Conclusion: In this large randomized, double-blind active controlled study of flare prevention in gout patients initiating allopurinol therapy, treatment with canakinumab led to a statistically significant reduction in flares compared with colchicine (standard of care), and was well tolerated.

Success of referral for alcohol dependent patients from a general hospital : predictive value of patient and process characteristics

RESUME: Introduction L'objectif de cette étude prospective de cohorte était d'estimer l'efficacité d'un processus de prise en charge standardisé de patients dépendants de l'alcool dans le contexte d'un hôpital universitaire de soins généraux. Ce modèle de prise en charge comprenait une évaluation multidisciplinaire puis des propositions de traitements individualisées et spécifiques (« projet thérapeutique »). Patients et méthode 165 patients alcoolo-dépendants furent recrutés dans différents services de l'hôpital universitaire, y compris la policlinique de médecine. Ils furent dans un premier temps évalués par une équipe multidisciplinaire (médecin interniste, psychiatre, assistant social), puis un projet thérapeutique spécialisé et individualisé leur fut proposé lors d'une rencontre réunissant le patient et l'équipe. Tous les patients éligibles acceptant de participer à l'étude (n=68) furent interrogés au moment de l'inclusion puis 2 et 6 mois plus tard par une psychologue. Des informations standardisées furent recueillies sur les caractéristiques des patients, le processus de prise en charge et l'évolution à 6 mois. Les critères de succès utilisés à 6 mois furent: l'adhérence au traitement proposé et l'abstinence d'alcool. Résultats Lors de l'évaluation à 6 mois, 43% des patients étaient toujours en traitement et 28% étaient abstinents. Les variables prédictrices de succès parmi les caractéristiques des patients étaient un âge de plus de 45 ans, ne pas vivre seul, avoir un travail et être motivé pour un traitement (RAATE-A <18). Pour les variables dépendantes du processus de prise en charge, un sevrage complet de l'alcool lors de la rencontre multidisciplinaire ainsi que la présence de tous les membres de l'équipe à cette réunion étaient des facteurs associés au succès. Conclusion L'efficacité de ce modèle d'intervention pour patients dépendants de l'alcool en hôpital de soins généraux s'est montrée satisfaisante, en particulier pour le critère de succès adhérence au traitement. Des variables associées au succès ou à l'échec à 6 mois ont pu être mises en évidence, permettant d'identifier des populations de patients évoluant différemment. Des stratégies de prise en charge tenant compte de ces éléments pourraient donc être développées, permettant de proposer des traitements plus adaptés ainsi qu'une meilleure rétention des patients alcooliques dans les programmes thérapeutiques. ABSTRACT. To assess the effectiveness of a multidisciplinary evaluation and referral process in a prospective cohort of general hospital patients with alcohol dependence, alcohol-dependent patients were identified in the wards of the general hospital and its primary care center. They were evaluated and then referred to treatment by a multidisciplinary team; those patients who accepted to participate in this cohort study were consecutively included and followed for 6 months. Not included patients were lost for follow-up, whereas all included patients were assessed at time of inclusion, 2 and 6 months later by a research psychologist in order to collect standardized baseline patients' characteristics, process salient features and patients outcomes (defined as treatment adherence and abstinence). Multidisciplinary evaluation and therapeutic referral was feasible and effective, with a success rate of 43% for treatment adherence and 28% for abstinence at 6 months. Among patients' characteristics, predictors of success were an age over 45, not living alone, being employed and being motivated to treatment (RAATE-A score < 18), whereas successful process characteristics included detoxification of the patient at time of referral and a full multidisciplinary referral meeting. This multidisciplinary model of evaluation and referral of alcohol dependent patients of a general hospital had a satisfactory level of effectiveness. Predictors of success and failure allow the identification of subsets of patients for whom new strategies of motivation and treatment referral should be designed.

Diabète de type 2: n'oubliez pas les troubles du comportement alimentaire [Patient with type 2 diabetes: don't forget eating disorders!]

The coexistence of diabetes and eating disorder (ED) is more prevalent than we think; indeed it seems to occur in 10 to 20% of cases. Therefore ED deserve attention to be detected and treated in order to permit a decreased in morbidity and better outcomes in body weight loss. The association of type 2 diabetes and ED is frequently seen in younger, overweighed or obese patients suffering of at least one psychiatric co-morbidities and frequently in a difficult psychosocial setting. To succeed in ED treatment, a multidisciplinary and specialised team in eating disorder is requested, however these patients are highly fragile and complex and therapeutic failure has to be feared.

Vitamin C supplementation in the critically ill patient.

PURPOSE OF REVIEW: Vitamin C is not only an essential nutrient involved in many anabolic pathways, but also an important player of the endogenous antioxidant defense. Low plasma levels are very common in critical care patients and may reflect severe deficiency states. RECENT FINDINGS: Vitamin C scavenges reactive oxygen species such as superoxide and peroxynitrite in plasma and cells (preventing damage to proteins, lipids and DNA), prevents occludin dephosphorylation and loosening of the tight junctions. Ascorbate improves microcirculatory flow impairment by inhibiting tumor-necrosis-factor-induced intracellular adhesion molecule expression, which triggers leukocyte stickiness and slugging. Clinical trials in sepsis, trauma and major burns testing high-dose vitamin C show clinical benefit. Restoration of normal plasma levels in inflammatory patients requires the administration of 3 g/day for several days, which is 30 times the daily recommended dose. SUMMARY: The recent research on the modulation of oxidative stress and endothelial protection offer interesting therapeutic perspectives, based on the biochemical evidence, with limited or even absent side-effects.

Clinical Prognostic Factors Predicting Outcomes Of Patients With Recurrent Gbm And Nomograms

BACKGROUND: Prognostic models and nomograms were recently developed to predict survival of patients with newly diagnosed glioblastoma multiforme (GBM).1 To improve predictions, models should be updated with the most recent patient and disease information. Nomograms predicting patient outcome at the time of disease progression are required. METHODS: Baseline information from 299 patients with recurrent GBM recruited in 8 phase I or II trials of the EORTC Brain Tumor Group was used to evaluate clinical parameters as prognosticators of patient outcome. Univariate (log rank) and multivariate (Cox models) analyses were made to assess the ability of patients' characteristics (age, sex, performance status [WHO PS], and MRC neurological deficit scale), disease history (prior treatments, time since last treatment or initial diagnosis, and administration of steroids or antiepileptics) and disease characteristics (tumor size and number of lesions) to predict progression free survival (PFS) and overall survival (OS). Bootstrap technique was used for models internal validation. Nomograms were computed to provide individual patients predictions. RESULTS: Poor PS and more than 1 lesion had a significant prognostic impact for both PFS and OS. Antiepileptic drug use was significantly associated with worse PFS. Larger tumors (split by the median of the largest tumor diameter >42.5 mm) and steroid use had shorter OS. Age, sex, neurologic deficit, prior therapies, and time since last therapy or initial diagnosis did not show independent prognostic value for PFS or OS. CONCLUSIONS: This analysis confirms that PS but not age is a major prognostic factor for PFS and OS. Multiple or large tumors and the need to administer steroids significantly increase the risk of progression and death. Nomograms at the recurrence could be used to obtain accurate predictions for the design of new targeted therapy trials or retrospective analyses. (1. T. Gorlia et al., Nomograms for predicting survival of patients with newly diagnosed glioblastoma. Lancet Oncol 9 (1): 29-38, 2008.)

The neuro-ICU patient and electroencephalography paroxysms: if and when to treat.

PURPOSE OF REVIEW: To review recent clinical data and summarize actual recommendations for the management of electrographic seizures and status epilepticus in neuro-ICU patients. RECENT FINDINGS: Electrographic, 'nonconvulsive', seizures are frequent in neuro-ICU patients including traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage and hypoxic-ischemic encephalopathy. Continuous electroencephalography monitoring is thus of great potential utility. The impact of electrographic seizures on outcome however is not entirely established and it is also unclear what type of electroencephalography paroxysms require treatment and when and how exactly to treat them. Evidence from randomized studies is lacking and will not be available in the near future. Given robust animal and human evidence showing the potential negative impact of seizures on secondary cerebral damage and outcome, treatment of seizures appears reasonable, particularly if related to status epilepticus. On the contrary, over-aggressive antiepileptic therapy entails risks. The management of seizures should therefore be guided individually, based on the underlying cause, the severity of illness and patient comorbidities. SUMMARY: We provide a pragmatic approach for the management of electrographic seizures in neuro-ICU patients. International consensus guidelines on continuous electroencephalography monitoring and seizure therapy are needed and would represent the rationale for a future multicenter randomized trial.

The Mixed Management of Patients' Medical Records: Responsibility Sharing Between the Patient and the Physician

Through this article, we propose a mixed management of patients' medical records, so as to share responsibilities between the patient and the Medical Practitioner by making Patients responsible for the validation of their administrative information, and MPs responsible for the validation of their Patients' medical information. Our proposal can be considered a solution to the main problem faced by patients, health practitioners and the authorities, namely the gathering and updating of administrative and medical data belonging to the patient in order to accurately reconstitute a patient's medical history. This method is based on two processes. The aim of the first process is to provide a patient's administrative data, in order to know where and when the patient received care (name of the health structure or health practitioner, type of care: out patient or inpatient). The aim of the second process is to provide a patient's medical information and to validate it under the accountability of the Medical Practitioner with the help of the patient if needed. During these two processes, the patient's privacy will be ensured through cryptographic hash functions like the Secure Hash Algorithm, which allows pseudonymisation of a patient's identity. The proposed Medical Record Search Engines will be able to retrieve and to provide upon a request formulated by the Medical ractitioner all the available information concerning a patient who has received care in different health structures without divulging the patient's identity. Our method can lead to improved efficiency of personal medical record management under the mixed responsibilities of the patient and the MP.

Cellular immune responses against mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) infection is known to have two main outcomes: latent infection (LTBI) where the pathogen is in a dormant form or active tuberculosis disease (TB), which is, most of the time, highly transmissible. Over one-third of the world's population asymptomatically harbours a latent form of Mtb with a 10% risk of disease reactivation. Efficient vaccine strategies remain unknown and the existing BCG vaccine is believed to protect against only some forms of TB (extra-pulmonary TB in children). Moreover, timely identification of TB remains complex with the actual diagnosis based on clinical observations associated to low efficient tests. Furthermore, current therapies are expensive, heavy and long for patients, and present lesser and lesser efficiency against new drug-resistant strains of Mtb. It is thus important to develop our knowledge on host -Mtb relationship to propose new vaccines, diagnosis tools and medications for the future. This thesis aims at improving our understanding of human immunology in the field of TB. All along this work, the same algorithm has been used and points towards the discovery of new correlates of protection through the comparison of T-cell immune responses in patients with LTBI or TB. We performed a comprehensive analysis of T-cell immune responses to Mtb using polychromatic flow cytometiy to study the functional profile of Μ/ό-specific CD4 Τ cells. We observed a polyfunctional profile in LTBI where CD4 Τ cells mainly co-produced IFN-γ, TNF-α and IL-2. In contrast, in TB, Mtó-specific CD4 Τ cells were mostly single TNF-a positive. Thus, analysis of the cytokine profiles was a strong immunological measure discriminating TB and LTBI. We next analyzed Thl7 cells. Mtò-specific Thl7 cells lacked immediate {i.e. ex vivo) IL-17A effector function in both LTBI and TB individuals. Moreover, they were also absent in bronchoalveolar lavages (BALs). Interestingly, we noticed that Mtb- specific Thl7 cells from LTBI but not from TB subjects acquired the ability to produce IL- 17A following Mtb-specific T-cell expansion. We finally performed a comprehensive characterization of Mfè-specific CD8 Τ cells that were detected in most (60%) TB patients and few (15%) LTBI subjects. We observed differences in the phenotype, the cytotoxicity and the proliferative capacities but not in the cytokine profile of Mtò-specific CD8 Τ cells between LTBI and TB. We concluded that the activity of Mtb infection (i.e. latent versus active) and the clinical presentation were associated to distinct profiles of Mtó-specific CD8 T-cell responses. To conclude, a multiparametric analysis including both CD4 and CD8 T-cell responses to Mtb lead to the development of a significantly improved diagnostic test discriminating between LTBI and TB. All together, these results provide new insights into the interaction between Mtb and the host immune response and expand upon our prior knowledge of tuberculosis. - L'infection par Mycobacterium tuberculosis peut résulter en une infection tuberculeuse latente et asymptomatique ou encore en une forme active et la plupart du temps contagieuse, la tuberculose. Un tiers de la population mondiale serait infectée de manière chronique avec 10 % de risques de développer la maladie durant la vie. Il n'existe actuellement aucun vaccin efficace, le BCG ne conférant qu'une protection partielle contre certaines formes extrapulmonaires de la maladie chez l'enfant. D'autre part, il n'existe pas de méthode diagnostique fiable et rapide, celle-ci se basant dans un premier temps sur l'analyse de la situation clinique des patients. Enfin, les thérapies actuelles sont couteuses et contraignantes pour les patients et tendent à ne plus être efficaces contre les souches émergentes de mycobactérie multi-résistantes. Aussi, il est important de bien comprendre la relation hôte-pathogène de manière à pouvoir proposer de nouveaux outils vaccinaux, diagnostiques et thérapeutiques. Ce manuscrit s'inscrit dans cette direction et vise à améliorer nos connaissances de la réponse immunitaire humaine dans le cadre de la tuberculose. Nous avons suivi un algorithme similaire tout au long des études proposées en comparant les réponses immunes des patients latents à celles des patients actifs, et ce, dans le but de mettre en évidence de potentiels corrélats de protection. Nous avons réalisé par cytométrie en flux une analyse du profil fonctionnel des cellules lymphocytaires CD4 dans la réponse au pathogène. Dans le cas de la tuberculose active, les cellules CD4 sécrètent majoritairement du TNF-α quand, au contraire, elles sécrètent à la fois du TNF-α, de l'IFN-γ et de l'IL-2 (poly-fonctionnalité) dans l'infection latente. Cette observation nous a permis de proposer un nouveau test diagnostique de la maladie active. Nous avons aussi étudié les cellules CD4 Thl7, impliquées dans la réponse immunitaire cellulaire contre les pathogènes extracellulaires et les champignons. Nous avons souligné une variation dans la production d'IL-17 entre infection latente et tuberculose active qui pourrait être impliquée dans la protection de l'individu contre le pathogène. D'autre part, ce manuscrit propose une caractérisation des cellules Τ CD8 dites cytotoxiques dans la tuberculose. Des divergences dans la fréquence des réponses observées, le phénotype mais aussi les capacités prolifératives et cytotoxiques ont pu être mises en évidence entre latence et tuberculose active. Ces observations soulignent le rôle important de ce groupe cellulaire dans l'évolution de la maladie et permettent de proposer une amélioration de l'outil diagnostic précédemment proposé et se basant à la fois sur le profil fonctionnel des cellules Τ CD4 ainsi que sur la présence potentielle d'une réponse CD8 spécifique au pathogène. Ces diverses études réalisées sur les cellules Τ humaines répondant spécifiquement à Mtb nous permettent de faire un pas supplémentaire dans la compréhension de notre réponse immunitaire face à ce pathogène particulièrement dangereux qui continue à l'heure actuelle à tuer chaque année des millions de personnes. - La tuberculose (TB) résulte d'une infection bactérienne par Mycobacterium tuberculosis (Mtb) et existe sous deux formes majeures: une forme latente, lorsque la bactérie est en phase de dormance ainsi qu'une forme active durant laquelle la bactérie se divise activement, entraînant les symptômes de la maladie. La personne infectée devient alors contagieuse dans la plupart des cas. Aujourd'hui des études épidémiologiques assument que plus d'un tiers de la population mondiale serait infectée par la forme latente de la bactérie et que 10% des cas réactiveront donnant lieu à diverses présentations de la maladie. Il n'existe actuellement aucun vaccin réellement efficace chez l'adulte. D'autre part, les traitements antibiotiques utilisés sont très lourds pour les patients et les cliniciens doivent faire face à l'émergence de nouvelles souches bactériennes multi-résistantes non affectées par les thérapies existantes. Les autorités sanitaires sont, d'autre part, confrontées à l'absence d'un outil diagnostique rapide, fiable et efficace. En effet, la méthode de référence reste la culture microbiologique du pathogène qui prend généralement plusieurs semaines, pendant lesquelles le patient pourra contaminer d'autres personnes. En résumé, la lutte contre la tuberculose doit passer par l'élaboration d'un vaccin efficace, de nouvelles thérapies, mais aussi par la mise en place de nouveaux tests diagnostics plus rapides afin d'éviter la dissémination de la maladie. Aussi, la relation hôte-bactérie qui n'est actuellement que peu comprise doit être investiguée. Ce travail de thèse a pour but d'étudier la réponse immunitaire chez l'homme infecté par Mtb et vise plus particulièrement l'étude d'une population clé de cellules immunitaires: les lymphocytes T. L'étude des cellules Τ CD4 nous a permis dans un premier temps de proposer un nouveau test diagnostic de la maladie active. Nous avons aussi analysé plus en détail une population spécifique des cellules Τ CD4 (les cellules Thl7), nous permettant d'associer leur fonction avec un possible état physiologique de protection contre le pathogène. En second lieu nous avons réalisé une caractérisation des cellules Τ CD8, à la fois chez les personnes avec des infections latentes et chez les personnes malades. Nous avons mis en évidence des différences fonctionnelles chez les deux groupes de patients, nous permettant ainsi une meilleure compréhension de l'immunité contre Mtb. Enfin, nous avons combiné les différents profils immunologiques obtenus pour développer un test diagnostic plus performant et sensible que celui proposé antérieurement. Ces diverses études réalisées sur les cellules Τ humaines nous permettent de faire un pas supplémentaire dans la compréhension de la réponse immunitaire face à ce pathogène particulièrement dangereux qui continue à tuer chaque année des millions de personnes.

Derivation and validation of a prognostic model for pulmonary embolism.

RATIONALE: An objective and simple prognostic model for patients with pulmonary embolism could be helpful in guiding initial intensity of treatment. OBJECTIVES: To develop a clinical prediction rule that accurately classifies patients with pulmonary embolism into categories of increasing risk of mortality and other adverse medical outcomes. METHODS: We randomly allocated 15,531 inpatient discharges with pulmonary embolism from 186 Pennsylvania hospitals to derivation (67%) and internal validation (33%) samples. We derived our prediction rule using logistic regression with 30-day mortality as the primary outcome, and patient demographic and clinical data routinely available at presentation as potential predictor variables. We externally validated the rule in 221 inpatients with pulmonary embolism from Switzerland and France. MEASUREMENTS: We compared mortality and nonfatal adverse medical outcomes across the derivation and two validation samples. MAIN RESULTS: The prediction rule is based on 11 simple patient characteristics that were independently associated with mortality and stratifies patients with pulmonary embolism into five severity classes, with 30-day mortality rates of 0-1.6% in class I, 1.7-3.5% in class II, 3.2-7.1% in class III, 4.0-11.4% in class IV, and 10.0-24.5% in class V across the derivation and validation samples. Inpatient death and nonfatal complications were <or= 1.1% among patients in class I and <or= 1.9% among patients in class II. CONCLUSIONS: Our rule accurately classifies patients with pulmonary embolism into classes of increasing risk of mortality and other adverse medical outcomes. Further validation of the rule is important before its implementation as a decision aid to guide the initial management of patients with pulmonary embolism.