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The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation (ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial.BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up.Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 [35%]) versus oral weekly cyclophosphamide (n=44 [52%]). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months [95% CI 16-26] vs 11 months [9-12]; hazard ratio [HR] 0·45 [95% CI 0·31-0·64] log-rank p0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months [95% CI 55-not estimable] vs 52 months [42-60]; log-rank p=0·022; HR 0·56 [0·35-0·90], p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months [52-not estimable] vs 35 months [31-43]; HR 0·37 [0·24-0·57], log-rank p0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT [n=7] vs oral weekly cyclophosphamide [n=5]). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2).Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse.Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK.

The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).

Purpose: To evaluate rheological properties, in vitro dissolution, and in vivo ocular pharmacokinetics of loteprednol etabonate (LE) (submicron) ophthalmic gel 0.38%. Methods: The viscosity of the LE gel 0.38% formulation was measured with a controlled stress rheometer. Dissolution kinetics were evaluated in a fixed-volume and flow-through assay. Rabbits received a single instillation of LE (submicron) gel 0.38% (both eyes), and concentrations of LE in ocular tissues were determined through 24 h by liquid chromatography with tandem mass spectrometry. Where indicated, comparators included micronized LE gel 0.38%, 0.5% (Lotemax® gel), and 0.75%. Results: LE (submicron) gel 0.38% exhibited shear-thinning characteristics similar to LE gel 0.5% with nearly identical yield stress. LE (submicron) gel 0.38% released 2.6-fold more LE into the dissolution medium than micronized LE gel 0.5% over 30 s in the fixed-volume dissolution assay, and submicron LE attained higher concentrations of dissolved LE than micronized LE gel 0.38% in the flow-through dissolution assay. In rabbits, the maximal concentration and area-under-the-curve over 24 h for LE in aqueous humor were 2.5- and 1.8-fold higher, respectively, for LE (submicron) gel 0.38% versus micronized LE gel 0.5% (both P

O Estado Constitucional oportuniza as partes direitos e garantias fundamentais de reserva e participação na construção e no controle das decisões judiciais, representando verdadeiro exercício da democracia. Nesse enfoque, mostra-se de vital importância a motivação e a fundamentação das decisões judiciais. A falta ou deficiência na fundamentação compromete a ampla defesa, bem como outros princípios processuais constitucionais. Em 2018, entrou em vigor a Lei nº 13.655, que introduziu alterações na Lei de Introdução ao Direito Brasileiro (LINDB), com objetivo de conferir maior segurança jurídica, apresentando alguns enfoques que guardam relação com o aperfeiçoamento da fundamentação das decisões judiciais. O presente trabalho tem por objetivo fazer um estudo do princípio constitucional da ampla defesa na esfera do processo civil, fazendo uma análise conjunta das recentes alterações introduzidas na Lei de Introdução ao Direito Brasileiro, sobretudo nos artigos 20 e 21, indagando se as referidas alterações contribuem para a realização desse princípio. Valendo-se dos métodos exploratório e analítico, através de revisão bibliográfica, análise de artigos acadêmicos e das normas, foi realizada uma leitura criteriosa, selecionando os aspectos relevantes para, finalmente, proceder a uma abordagem teórica e analítica do princípio da ampla defesa introduzido na norma base da civil law no Brasil.

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D’un centre d’aide sociale à un service de soins intensifs, d’un lycée à un tribunal pour enfants en passant par un zoo, un abattoir de bovins, un centre de formation de l’armée ou une station de sports d’hiver, Frederick Wiseman a scruté depuis cinquante ans nombre de lieux, d’activités et d’institutions – des États-Unis, essentiellement – à travers l’objectif de sa caméra, composant une œuvre documentaire unique, exigeante, extrêmement riche et diversifiée. National Gallery, son dernier fil...

Compte rendu de Vincent Jarousseau, Les racines de la colère. Deux ans d'enquête dans une France qui n'est pas en marche, Paris, Editions Les Arènes, 2019, 166 p., illustrations d'Eddy Vaccaro, ISBN : 978-2-7112-0126-6.; Au printemps 2016, Emmanuel Macron, alors ministre de François Hollande, lance son mouvement En Marche !. Le choix de ce nom est lourd de sens. C’est une injonction : il faut bouger pour s’en sortir. Quelques semaines avant l’élection d’Emmanuel Macron à la présidence de la République, le photographe Vincent Jarousseau s’est installé à Denain, petite ville de 20 000 habitants dans le nord de la France, afin de suivre le quotidien de familles issues de milieux populaires pour qui la mobilité n’est pas toujours une solution. Pendant deux ans, il a donné la parole à des personnes le plus souvent invisibilisées dans les représentations médiatiques, et tenté de montrer les fractures qui menacent notre modèle démocratique. Il nous livre un documentaire en forme de roman-photo, où tout est vrai. Chaque propos a été enregistré et retranscrit à la virgule près. Les Racines de la colère racontent le quotidien d’une France qui n’est pas « en marche ».

The High Performance Computing (HPC) domain aims to optimize code to use the latest multicore and parallel technologies including specific processor instructions. In this computing framework, portability and reproducibility are key concepts. A way to handle these requirements is to use Linux containers. These "light virtual machines" allow users to encapsulate applications within its environment in processes. Containers have been recently highlighted because they provide multi-infrastructure environnement for both developers and system administrators. Furthermore, they offer reproducibility due to image building files. Two container solutions are emerging: Docker for micro-services and Singularity for computing applications. We present here the Com-puteOps project which investigates the container benefits for HPC applications.

To correlate intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) parameters with the enhancement patterns of bone marrow and focal lesion obtained on whole-body (WB) dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) images in patients with stage-III multiple myeloma (MM) before and after systemic therapy.Twenty-seven patients with MM were retrospectively included in this institutional review board-approved study. Requirement for written informed consent was waived. All patients underwent WB DCE MR imaging before treatment and 18 patients underwent repeat MR imaging 3 months after treatment. A transverse IVIM DWI sequence with 10 b values (0, 10, 20, 30, 50, 80, 100, 200, 400, and 800 sec/mm(2)) was acquired within bone marrow and focal lesions. The IVIM parameters (perfusion fraction [f], molecular diffusion coefficient [D], and perfusion-related D [D*]) and apparent diffusion coefficient (ADC) were extracted for both focal lesions and bone marrow and correlated with focal lesions and maximal bone marrow enhancement (BMEmax) (Spearman correlation coefficient) at baseline and at follow-up (Wilcoxon signed-rank test).D and ADC values positively correlated with BMEmax (r = 0.7, P.001; and r = 0.455, P = .0435, respectively). Patients with increased BMEmax showed significantly increased ADC and D within bone marrow versus patients who did not have increased BMEmax (ADC, 0.67 × 10(-3) mm(2)/sec vs 0.54 × 10(-3) mm(2)/sec, P = .03; D, 0.58 × 10(-3) mm(2)/sec vs 0.42 × 10(-3) mm(2)/sec, P.001). Within focal lesions, f was the maximum in lesions that showed enhancement followed by washout. After treatment in good responders, the significant decrease in maximal enhancement value of focal lesions (baseline vs after treatment, 213.9% ± 78.7 [standard deviation] vs 131% ± 53.6, respectively; P.001) was accompanied by a significant decrease in f (baseline vs after treatment, 11% ± 3.8 vs 5.8% ± 4.7, respectively; P.001).Diffuse bone marrow involvement is associated with increased D. Hypervascular focal lesions with high maximal enhancement value of focal lesions also show high f value. Likewise, the decreased maximal enhancement value of focal lesions after treatment is accompanied by decreased f.

There is a significant unmet need in effective therapy for relapsed myeloma patients once they become refractory to bortezomib and lenalidomide. While data from the front line setting suggest bendamustine is superior to melphalan, there is no information defining optimal bendamustine dose in multiply-treated patients. We report a multi-centre randomized two-stage phase 2 trial simultaneously assessing deliverability and activity of two doses of bendamustine (60 mg/m2 vs. 100 mg/m2) days 1 and 8, thalidomide (100 mg) days 1-21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28-d cycle. Ninety-four relapsing patients were treated on trial, with a median three prior treatment lines. A pre-planned interim deliverability and activity assessment led to closure of the 100 mg/m2 arm due to excess cytopenias, and led to amendment of entry criteria for cytopenias. Non-haematological toxicities including thromboembolism and neurotoxicity were infrequent. In the 60 mg/m2 arm, treatment was deliverable in 61.1% subjects and the partial response rate was 46.3% in the study eligible population, with 7.5 months progression-free survival. This study demonstrates bendamustine at 60 mg/m2 twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pre-treated myeloma patients and has substantial clinical activity.

SIGNIFICANCE The α2-adrenergic receptor agonist brimonidine has been reported to induce conjunctival blanching in cataract, strabismus, laser refractive, and filtration procedures. Clinicians are often faced with red eyes with no apparent underlying pathology. Low-dose brimonidine reduced ocular redness in such subjects with efficacy maintained over 1 month and negligible rebound redness. PURPOSE The aim of this study was to evaluate the safety and efficacy of brimonidine tartrate ophthalmic solution 0.025% for the treatment of ocular redness. METHODS In this single-center, double-masked, phase 3 clinical trial, adult subjects with baseline redness of more than 1 unit in both eyes (0- to 4-unit scale) were randomized 2:1 to brimonidine 0.025% or vehicle. A single dose was administered in-office (day 1); thereafter subjects instilled treatment four times a day for 4 weeks, with clinic visits on days 15, 29, and 36 (7 days post-treatment). Efficacy end points included investigator-evaluated redness 5 to 240 minutes post-instillation on day 1 (primary); investigator-evaluated change from baseline 1, 360, and 480 minutes post-instillation on day 1, and 1 and 5 minutes post-instillation on days 15 and 29; total clearance of redness, and subject-assessed redness. Safety/tolerability measures included adverse events, rebound redness, and drop comfort. RESULTS Sixty subjects were randomized (n = 40 brimonidine, n = 20 vehicle). Investigator-assessed redness was lower with brimonidine versus vehicle over the 5- to 240-minute post-instillation period (mean [SE], 0.62 [0.076] vs. 1.49 [0.108]; P < .0001) and at each time point within that period (P < .0001). At 1, 360, and 480 minutes post-instillation, respectively, the mean differences (95% confidence interval) between treatments were −0.73 (−1.05 to −0.41), −0.57 (−0.84 to −0.29), and −0.39 (−0.67 to −0.10), respectively. No tachyphylaxis was evident with brimonidine on days 15 and 29, and minimal rebound redness was observed following discontinuation. Adverse events were infrequent, and brimonidine was rated as very comfortable. CONCLUSIONS Brimonidine 0.025% appeared safe and effective for reduction of ocular redness, with an 8-hour duration of action, no evidence of tachyphylaxis, and negligible rebound redness.

Introduction: Guidelines provide recommendations on the management of multiple myeloma (MM), but there are no standard algorithms for the choice and sequencing of treatments. As a result, there is widespread variation in the interpretation and implementation of these guidelines. Areas covered: This review will cover: the real-world data on MM treatment patterns; the approved agents available for the treatment of MM; a comparative summary of the national and international clinical guidelines; a discussion on the impact reimbursement decisions have on treatment availability. Expert commentary: In the future, treatment choices may become even more complex as clonal heterogeneity is better understood in the context of response to treatment, and next-generation agents become available. Although information on real-world practice patterns can provide further guidance, to date, few studies have generated data on patients treated with the newer agents in real-world settings. Furthermore, the translation of guideline recommendations into clinical practice across Europe is inconsistent. Additional real-world data are therefore vital to understanding current clinical practice patterns, so that new agents can be effectively incorporated into existing treatment strategies. Such information may aid the development of better guidance, which will ultimately help to ensure that patients receive the best possible care. © 2018 Informa UK Limited, trading as Taylor & Francis Group.

To evaluate both in vivo and in phantom studies, dose reduction, and image quality of body CT reconstructed with model-based iterative reconstruction (MBIR), performed during patient follow-ups for lymphoma.This study included 40 patients (mean age 49 years) with lymphoma. All underwent reduced-dose CT during follow-up, reconstructed using MBIR or 50 % advanced statistical iterative reconstruction (ASIR). All had previously undergone a standard dose CT with filtered back projection (FBP) reconstruction. The volume CT dose index (CTDIvol), the density measures in liver, spleen, fat, air, and muscle, and the image quality (noise and signal to noise ratio, SNR) (ANOVA) observed using standard or reduced-dose CT were compared both in patients and a phantom study (Catphan 600) (Kruskal Wallis).The CTDIvol was decreased on reduced-dose body CT (4.06 mGy vs. 15.64 mGy p 0.0001). SNR was higher in reduced-dose CT reconstructed with MBIR than in 50 % ASIR or than standard dose CT with FBP (patients, p ≤ 0.01; phantoms, p = 0.003). Low contrast detectability and spatial resolution in phantoms were not altered on MBIR-reconstructed CT (p ≥ 0.11).Reduced-dose CT with MBIR reconstruction can decrease radiation dose delivered to patients with lymphoma, while keeping an image quality similar to that obtained on standard-dose CT.• In lymphoma patients, CT dose reduction is a major concern. • Reduced-dose body CT provides a fourfold radiation dose reduction. • Optimized CT reconstruction techniques (MBIR) can maintain image quality.

Listeria monocytogenes is a food borne pathogen responsible for a number of life-threatening infections of humans. During an infection it invades epithelial cells before spreading from the intestine to the cells of the liver and spleen. This requires an ability to adapt to varying oxygen levels. Here we demonstrate that L. monocytogenes has two terminal oxidases, a cytochrome bd-type (CydAB) and a cytochrome aa3 -type menaquinol oxidase (QoxAB) and that both are used for respiration under different oxygen tensions. Furthermore, we show that possession of both terminal oxidases is important in infection. In air, the CydAB bd-type oxidase is essential for aerobic respiration and intracellular replication, and cydAB mutants are highly attenuated in mice. In contrast, the QoxAB aa3 -type oxidase is neither required for aerobic respiration in air nor for intracellular growth. However, the qoxAB mutants are attenuated in mice with both a delay in the onset of disease signs and with increased survival time, indicating a role for the QoxAB aa3 -type oxidase in the initial stages of infection. Growth of bacteria under defined oxygen conditions revealed that at 1% (v/v) both oxidases are functional and the presence of either is sufficient for aerobic respiration and intracellular replication. However at 0.2% (v/v) both oxidases are necessary for maximum growth. These findings are consistent with the ability of L. monocytogenes to switch between terminal oxidases under different oxygen conditions providing an exquisite adaptation to different conditions encountered within the infected host.

Listeria monocytogenes is a food borne pathogen responsible for a number of life-threatening infections of humans. During an infection it invades epithelial cells before spreading from the intestine to the cells of the liver and spleen. This requires an ability to adapt to varying oxygen levels. Here we demonstrate that L. monocytogenes has two terminal oxidases, a cytochrome bd-type (CydAB) and a cytochrome aa3 -type menaquinol oxidase (QoxAB) and that both are used for respiration under different oxygen tensions. Furthermore, we show that possession of both terminal oxidases is important in infection. In air, the CydAB bd-type oxidase is essential for aerobic respiration and intracellular replication, and cydAB mutants are highly attenuated in mice. In contrast, the QoxAB aa3 -type oxidase is neither required for aerobic respiration in air nor for intracellular growth. However, the qoxAB mutants are attenuated in mice with both a delay in the onset of disease signs and with increased survival time, indicating a role for the QoxAB aa3 -type oxidase in the initial stages of infection. Growth of bacteria under defined oxygen conditions revealed that at 1% (v/v) both oxidases are functional and the presence of either is sufficient for aerobic respiration and intracellular replication. However at 0.2% (v/v) both oxidases are necessary for maximum growth. These findings are consistent with the ability of L. monocytogenes to switch between terminal oxidases under different oxygen conditions providing an exquisite adaptation to different conditions encountered within the infected host.

Listeria monocytogenes is a foodborne pathogen responsible for a number of life-threatening infections of humans. During an infection, it invades epithelial cells before spreading from the intestine to the cells of the liver and spleen. This requires an ability to adapt to varying oxygen levels. Here, we demonstrate that L. monocytogenes has two terminal oxidases, a cytochrome bd-type (CydAB) and a cytochrome aa(3)-type menaquinol (QoxAB) oxidase, and that both are used for respiration under different oxygen tensions. Furthermore, we show that possession of both terminal oxidases is important in infection. In air, the CydAB bd-type oxidase is essential for aerobic respiration and intracellular replication, and cydAB mutants are highly attenuated in mice. In contrast, the QoxAB aa(3)-type oxidase is required neither for aerobic respiration in air nor for intracellular growth. However, the qoxAB mutants are attenuated in mice, with a delay in the onset of disease signs and with increased survival time, indicating a role for the QoxAB aa(3)-type oxidase in the initial stages of infection. Growth of bacteria under defined oxygen conditions revealed that at 1% (vol/vol), both oxidases are functional, and the presence of either is sufficient for aerobic respiration and intracellular replication. However, at 0.2% (vol/vol), both oxidases are necessary for maximum growth. These findings are consistent with the ability of L. monocytogenes to switch between terminal oxidases under different oxygen conditions, providing exquisite adaptation to different conditions encountered within the infected host. MRC [G0601205] info:eu-repo/semantics/publishedVersion