43 research outputs found

    Outcomes in newly diagnosed elderly glioblastoma patients after concomitant temozolomide administration and hypofractionated radiotherapy

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    This study aimed to analyze the treatment and outcomes of older glioblastoma patients. Forty-four patients older than 70 years of age were referred to the Paul Strauss Center for chemotherapy and radiotherapy. The median age was 75.5 years old (range: 70-84), and the patients included 18 females and 26 males. The median Karnofsky index (KI) was 70%. The Charlson indices varied from 4 to 6. All of the patients underwent surgery. O6-methylguanine-DNA methyltransferase (MGMT) methylation status was determined in 25 patients. All of the patients received radiation therapy. Thirty-eight patients adhered to a hypofractionated radiation therapy schedule and six patients to a normofractionated schedule. Neoadjuvant, concomitant and adjuvant chemotherapy regimens were administered to 12, 35 and 20 patients, respectively. At the time of this analysis, 41 patients had died. The median time to relapse was 6.7 months. Twenty-nine patients relapsed, and 10 patients received chemotherapy upon relapse. The median overall survival (OS) was 7.2 months and the one- and two-year OS rates were 32% and 12%, respectively. In a multivariate analysis, only the Karnofsky index was a prognostic factor. Hypofractionated radiotherapy and chemotherapy with temozolomide are feasible and acceptably tolerated in older patients. However, relevant prognostic factors are needed to optimize treatment proposals

    Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

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    Purpose We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks forBRCA1andBRCA2pathogenic variant carriers. Methods Retrospective cohort data on 18,935BRCA1and 12,339BRCA2female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results The ER-negative PRS showed the strongest association with BC risk forBRCA1carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33],P = 3x10(-72)). ForBRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36],P = 7x10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk forBRCA1(HR = 1.32 [95% CI 1.25-1.40],P = 3x10(-22)) andBRCA2(HR = 1.44 [95% CI 1.30-1.60],P = 4x10(-12)) carriers. The associations in the prospective cohort were similar. Conclusion Population-based PRS are strongly associated with BC and EOC risks forBRCA1/2carriers and predict substantial absolute risk differences for women at PRS distribution extremes.Peer reviewe

    ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis

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    Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients.Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6–18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France.Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    Lymphocytes B et lupus (Le phĂ©notype lymphocytaire B peut-il ĂȘtre instructif ?)

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    STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

    Plio-Pleistocene short-term lake-level fluctuations and associated onland landscapes in the West Turkana Rift Basin, Northern Kenya. Consequences on Hominids habitats and culture

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    1 p.The northern end of the Kenya Rift is today occupied by Lake Turkana, the largest lake of the Eastern Branch of the East African Rift System. This lake basin is inherited from an upper Miocene rift basin known as the Turkana Basin, that began to develop as a result of a migration of rift extensive tectonics from Eocene-Oligocene times along East-West and South-North axes. At the northwest end of the Turkana Basin, the 750-m thick Hominid-bearing Nachukui Formation represents 4 Ma of the limnogeological history of the Turkana Basin, in an area where open water and littoral lacustrine deposits interfinger with alluvial fans or delta systems. These detrital bodies develop along the uplifted margin of the basin that reaches elevations of more than 1,000 m above the present-day lake level and is deeply dissected by lateral streams bringing wide quantities of coarse clastic sediments toward the lake. The lateral extension of this fringe of fan/deltaic bodies is directly controlled by climatic/tectonic induced lake-level fluctuations. Archeological investigations conducted in this region by the Mission Préhistorique au Kenya/West Turkana Archaeological Project have produced large number of artefacts and faunal assemblages, as well as Hominid remains, spanning the 2.5-0.7 Ma time period. Paleoenvironmental reconstructions based on limnogeological and paleontological data for these sites demonstrated that Hominids occupation areas were preferentially associated to places connected to stream shorelines (floodplain environment) generally close to a main lacustrine environment. Detailed sedimentological investigations conducted along the Nachukui Formation have revealed series of short-term positive or negative fluctuations in lake level. Transgressive sequences: bioclast-rich beach deposits overlapping deltaic or alluvial fan bodies, then followed by platform margin environments characterized by wide stromatolite bioherms that are in turn overlapped by green massive or laminated shales indicating open deep water conditions. Regressive sequences: stromatolite bioherms overlapped by coarse deposits from bioclast-rich sandstones to conglomerates demonstrating a downward migration of the lake shoreline or a rapid progradation of deltaic environment in response of lake level drop. Such-short terms lake-level fluctuations are linked to rapid changes in water input to the lake from the upper part of the lake watershed, mainly the Omo River to the north. Climatic changes at a regional scale may have directly influenced the localization of Hominids settlements, by restricting the surfaces of potential living areas between the basin margin and the shoreline, thus forcing the populations to migrate in less hospitable areas

    New considerations on the stratigraphy and environmental context of the oldest (2.34 Ma) Lokalalei archaeological site complex of the Nachukui Formation, West Turkana, northern Kenya Rift

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    International audienceAt the northwest end of the Lake Turkana Basin (northern Kenya Rift), intensive fieldwork conducted on the Plio-Pleistocene fluvio-lacustrine Nachukui Formation by the National Museums of Kenya and the West Turkana Archaeological Project (WTAP), led to the discovery of more than 50 archaeological sites aged between 2.4 and 0.7 Ma. Among them is the Lokalalei archaeological site complex, which includes the two oldest archaeological sites (2.34 Ma) found in the Kenyan segment of the East African Rift System. The environmental background of the two sites was described as a succession of ephemeral streams with floodplain palaeosols in which the archaeological sites are situated, bordering the western bank of a large axial meandering river flowing southward. The Lokalalei 1 (LA1) and Lokalalei 2C (LA2C) archaeological sites are of extreme importance in terms of knowledge of hominins' knapping activities. The stratigraphic position of the LA1 and LA2C sites as well as implications on the technical differences between the two sites have been successively discussed by (Roche et al., 1999), (Brown and Gathogo, 2002) and (Delagnes and Roche, 2005). In terms of stratigraphic position, Lokalalei 2C was estimated to be slightly higher in the section (i.e. younger) than Lokalalei 1. An alternative stratigraphic correlation was proposed by Brown and Gathogo (2002), who suggested that LA2C site should have been approximately 100,000 years younger than LA1. New considerations on the stratigraphy and environmental context of the Lokalalei sites have been developed following controversy on the stratigraphic position and time interval between the LA1 and LA2C sites. High-resolution lithostratigraphic work based on bed-to-bed field correlations, facies sedimentology and tephra geochemistry confirms that the LA2C site is slightly higher in the section than the LA1 site by about 11.20 m. This represents a time interval of not, vert, similar74,000 years based on an assumed sedimentation rate of 152 mm/ka. Sedimentary facies analysis indicates that the hominin occupation sites were situated in the vicinity of a lagoon/embayment environment close to the shoreline of an open lake. This lake was part of the broad lake development described across East Africa during the 2.7-2.4 Ma period. Palaeontological data associated with the sites suggest at the LA1 site a lake margin habitat, and at the LA2 sites an habitat with poor and sparse vegetation along channels of an alluvial fan system landward of the lake margin. They also confirm the aridity trend mentioned at the global scale for this period, which is demonstrated in the upper Lokalalei sediment sequence by progradation of an alluvial fan environment over the lake shoreline. Associated conglomeratic deposits could have been the source from which the knappers collected their raw materials. In addition, rapid variations from humid to arid episodes in a unique environment such as the East African Rift may have had a major influence in controlling hominin evolution

    SÉMINAIRE DOCTORAL LIMINAL (5): <br />Migrations en Afghanistan: culture, dĂ©cisions et politiques

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    [00:00:00:00 Ă  00:04:17:23] Introduction par Marie-Caroline SAGLIO YATZIMIRSKY (ANR LIMINAL, CESSMA, INALCO) et HĂ©lĂšne THIOLLET (CERI, Sciences Po) [00:04:17:23 Ă  00:05:10:09] PrĂ©sentation par Azita BATHAIE (Anthropologue, ANR LIMINAL) [00:05:10:09 Ă  00:28:23:10] Liza SCHUSTER (University of London) : Politique migratoire en Afghanistan [00:28:23:10 Ă  00:45:11:14] Discutante : Azita BATHAIE (Anthropologue, ANR LIMINAL) [00:45:11:14 Ă  01:12:49:17] Discussion [01:12:49:17 Ă  01:41:20:23] Belgheis ALAVI JAFARI (Afghanistan Center at Kabul University – ACKU) : Parcours des familles afghanes et reprĂ©sentations de la migration [01:41:20:23 Ă  01:58:49:02] Intervention de Liza SCHUSTER (University of London) [01:58:49:02 Ă  02:02:04:09] Discutante : Azita BATHAIE (Anthropologue, ANR LIMINAL) [02:02:04:09 Ă  02:11:27:00] Discussion [02:11:27:00 Ă  fin] Discussion avec Mohamad Reza SAHIBDAD, rĂ©alisateur de Welcome to Paristan, de (2017 – 75 min). PrĂ©sentation de l’ANR LIMINAL :Le programme LIMINAL portĂ© par l’INALCO et financĂ© par l’Agence Nationale de la Recherche traite des interactions et mĂ©diations langagiĂšres et culturelles entre acteurs en situation de crise migratoire et humanitaire, telle que celle-ci se dĂ©veloppe en France depuis 2015 (crĂ©ation de camps et campements d’ampleur, dĂ©veloppement de centres d’accueil). Il mobilise des chercheurs de diffĂ©rentes disciplines en SHS (linguistique et sociolinguistique, sĂ©miotique, anthropologie, sociologie, Ă©tudes sur la migration, psychologie) pour mener conjointement en cinq langues (urdu, dari, farsi, amharique, arabe) des Ă©tudes de terrain sur les pratiques de mĂ©diation linguistique et interculturelle dans des camps et des lieux d’accueil et d’hĂ©bergement diversifiĂ©s, formels et informels, auprĂšs d’une pluralitĂ© d’acteurs sociaux (institutionnels, associatifs, populations migrantes). Son objectif scientifique est d’étudier les enjeux thĂ©oriques et pratiques des stratĂ©gies d’interaction et de mĂ©diation, les malentendus ou insuffisances (usages inappropriĂ©s, mĂ©comprĂ©hensions interculturelles, situations bloquĂ©es, Ă©motions dysphoriques) et de proposer, Ă  terme, des outils Ă  destination de la recherche, des acteurs sociaux et des services publics (glossaires lexico-terminologiques multilingues, documentations textuelles et audiovisuelles, portail web, outils pĂ©dagogiques). Ce programme de recherche offrira l’opportunitĂ© de valoriser compĂ©tences linguistiques, dispositifs de solidaritĂ©, co-actions ; de circonscrire les difficultĂ©s ; d’apporter le concours d’une recherche plurilingue et pluridisciplinaire Ă  des Ă©lĂ©ments de formation et de documentation destinĂ©s Ă  un large public (recherche, associatif, ONG, travailleurs sociaux, bĂ©nĂ©voles et exilĂ©s). Hypotheses de l’ANR LIMINAL"> Lien vers le carnet Hypotheses de l’ANR LIMINAL <br /

    The Multi-phase Cold Fountain in M82 Revealed by a Wide, Sensitive Map of the Molecular Interstellar Medium

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    International audienceWe present a wide area (≈8 × 8 kpc), sensitive map of CO (2-1) emission around the nearby starburst galaxy M82. Molecular gas extends far beyond the stellar disk, including emission associated with the well-known outflow as far as 3 kpc from M82's midplane. Kinematic signatures of the outflow are visible in both the CO and H i emission: both tracers show a minor axis velocity gradient and together they show double peaked profiles, consistent with a hot outflow bounded by a cone made of a mix of atomic and molecular gas. Combining our CO and H i data with observations of the dust continuum, we study the changing properties of the cold outflow as it leaves the disk. While H2 dominates the ISM near the disk, the dominant phase of the cool medium changes as it leaves the galaxy and becomes mostly atomic after about a kpc. Several arguments suggest that regardless of phase, the mass in the cold outflow does not make it far from the disk; the mass flux through surfaces above the disk appears to decline with a projected scale length of ≈1-2 kpc. The cool material must also end up distributed over a much wider angle than the hot outflow based on the nearly circular isophotes of dust and CO at low intensity and the declining rotation velocities as a function of height from the plane. The minor axis of M82 appears so striking at many wavelengths because the interface between the hot wind cavity and the cool gas produces Hα, hot dust, polycyclic aromatic hydrocarbon emission, and scattered UV light. We also show the level at which a face-on version of M82 would be detectable as an outflow based on unresolved spectroscopy. Finally, we consider multiple constraints on the CO-to-H2 conversion factor, which must change across the galaxy but appears to be only a factor of ≈2 lower than the Galactic value in the outflow
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