Whole Brain Radiotherapy and RRx-001: Two Partial Responses in Radioresistant Melanoma Brain Metastases from a Phase I/II Clinical Trial: A TITE-CRM Phase I/II Clinical Trial.

PubMed

Kim, Michelle M; Parmar, Hemant; Cao, Yue; Pramanik, Priyanka; Schipper, Matthew; Hayman, James; Junck, Larry; Mammoser, Aaron; Heth, Jason; Carter, Corey A; Oronsky, Arnold; Knox, Susan J; Caroen, Scott; Oronsky, Bryan; Scicinski, Jan; Lawrence, Theodore S; Lao, Christopher D

2016-04-01

Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial. Published by Elsevier Inc.

Effect of Population III Multiplicity on Dark Star Formation

NASA Technical Reports Server (NTRS)

Stacy, Athena; Pawlik, Andreas H.; Bromm, Volker; Loeb, Abraham

2012-01-01

We numerically study the mutual interaction between dark matter (DM) and Population III (Pop III) stellar systems in order to explore the possibility of Pop III dark stars within this physical scenario. We perform a cosmological simulation, initialized at z approx. 100, which follows the evolution of gas and DM. We analyze the formation of the first mini halo at z approx. 20 and the subsequent collapse of the gas to densities of 10(exp 12)/cu cm. We then use this simulation to initialize a set of smaller-scale 'cut-out' simulations in which we further refine the DM to have spatial resolution similar to that of the gas. We test multiple DM density profiles, and we employ the sink particle method to represent the accreting star-forming region. We find that, for a range of DM configurations, the motion of the Pop III star-disk system serves to separate the positions of the protostars with respect to the DM density peak, such that there is insufficient DM to influence the formation and evolution of the protostars for more than approx. 5000 years. In addition, the star-disk system causes gravitational scattering of the central DM to lower densities, further decreasing the influence of DM over time. Any DM-powered phase of Pop III stars will thus be very short-lived for the typical multiple system, and DM will not serve to significantly prolong the life of Pop III stars.

Novel Agents for Multiple Myeloma to Overcome Resistance in Phase III Clinical Trials

PubMed Central

Orlowski, Robert Z.

2013-01-01

The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free and overall survival in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next five years. PMID:24135408

Synthetic Lethality as a Targeted Approach to Advanced Prostate Cancer

DTIC Science & Technology

2014-05-01

syndrome (MDS) [36-41]. Multiple Phase III trials of tipifarnib monotherapy in acute myeloid leukemia (AML) and in refractory advanced colorectal...cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome . Cancer 2011;117(6):1236-44 42. Harousseau JL...multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome . Blood 2007;109(10):4158

Deferasirox for Treating Patients Who Have Undergone Allogeneic Stem Cell Transplant and Have Iron Overload

ClinicalTrials.gov

2017-11-07

Iron Overload; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

Ondansetron in Preventing Nausea and Vomiting in Patients Undergoing Stem Cell Transplant

ClinicalTrials.gov

2017-04-20

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

HST/COS detection of a Ne VIII absorber towards PG 1407+265: an unambiguous tracer of collisionally ionized hot gas?

NASA Astrophysics Data System (ADS)

Hussain, T.; Muzahid, S.; Narayanan, A.; Srianand, R.; Wakker, B. P.; Charlton, J. C.; Pathak, A.

2015-01-01

We report the detection of Ne VIII in a zabs = 0.599 61 absorber towards the QSO PG1407+265 (zem= 0.94). Besides Ne VIII, absorption from H I Lyman series lines (H I λ1025-λ915), several other low (C II, N II, O II and S II), intermediate (C III, N III, N IV, O III, S IV and S V) and high (S VI, O VI and Ne VIII) ionization metal lines are detected. Disparity in the absorption line kinematics between different ions implies that the absorbing gas comprises of multiple ionization phases. The low and the intermediate ions (except S V) trace a compact (˜410 pc), metal-rich (Z ˜ Z⊙) and overdense (log nH ˜ -2.6) photoionized region that sustained star formation for a prolonged period. The high ions, Ne VIII and O VI, can be explained as arising in a low density (-5.3 ≤ log nH ≤ -5.0), metal-rich (Z ≳ Z⊙) and diffuse (˜180 kpc) photoionized gas. The S V, S VI and C IV [detected in the Faint Object Spectrograph (FOS) spectrum] require an intermediate photoionization phase with -4.2 < log nH < -3.5. Alternatively, a pure collisional ionization model, as used to explain the previous known Ne VIII absorbers, with 5.65 < log T < 5.72, can reproduce the S VI, O VI and Ne VIII column densities simultaneously in a single phase. However, even such models require an intermediate phase to reproduce any observable S V and/or C IV. Therefore, we conclude that when multiple phases are present, the presence of Ne VIII is not necessarily an unambiguous indication of collisionally ionized hot gas.

[Systematic development of a scale for determination of health-related quality of life in multiple trauma patients. The Polytrauma Outcome (POLO) Chart].

PubMed

Pirente, N; Bouillon, B; Schäfer, B; Raum, M; Helling, H J; Berger, E; Neugebauer, E

2002-05-01

Even years after having sustained multiple injuries patients often suffer from its sequelae. These comprise restrictions in physical function, but also pain, social and psychological impairments. Although the Meran Consensus Conference in 1990 defined the contents of "quality of life" (QoL) measures in surgery, still no instrument is available for the valid assessment of all relevant QoL domains in multiple injured patients. This paper describes the systematic development of a modular instrument for the assessment of health related QoL. Within three phases (phase I: generation of items, phase II: item reduction, phase III: pre-testing in 70 multiple injured and control patients) a questionnaire of 57 items was developed, which measures all relevant trauma-related aspects of QoL after acute hospital care. In combination with the Glascow Outcome Scale (GOS), the EUROQOL and the SF-36, the newly developed instrument builds the Polytrauma Outcome Chart (POLO-Chart) which will also be used as "Part E" for outcome assessment within the "Trauma registry" of the German Society for Trauma Surgery. In phase IV, the POLO-Chart will finally be validated in five trauma centres (Celle, Essen, Hanover, Cologne und Munich).

Non-equilibrium phase transition in mesoscopic biochemical systems: from stochastic to nonlinear dynamics and beyond

PubMed Central

Ge, Hao; Qian, Hong

2011-01-01

A theory for an non-equilibrium phase transition in a driven biochemical network is presented. The theory is based on the chemical master equation (CME) formulation of mesoscopic biochemical reactions and the mathematical method of large deviations. The large deviations theory provides an analytical tool connecting the macroscopic multi-stability of an open chemical system with the multi-scale dynamics of its mesoscopic counterpart. It shows a corresponding non-equilibrium phase transition among multiple stochastic attractors. As an example, in the canonical phosphorylation–dephosphorylation system with feedback that exhibits bistability, we show that the non-equilibrium steady-state (NESS) phase transition has all the characteristics of classic equilibrium phase transition: Maxwell construction, a discontinuous first-derivative of the ‘free energy function’, Lee–Yang's zero for a generating function and a critical point that matches the cusp in nonlinear bifurcation theory. To the biochemical system, the mathematical analysis suggests three distinct timescales and needed levels of description. They are (i) molecular signalling, (ii) biochemical network nonlinear dynamics, and (iii) cellular evolution. For finite mesoscopic systems such as a cell, motions associated with (i) and (iii) are stochastic while that with (ii) is deterministic. Both (ii) and (iii) are emergent properties of a dynamic biochemical network. PMID:20466813

Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma.

PubMed

Baertsch, Marc-Andrea; Schlenzka, Jana; Mai, Elias K; Merz, Maximilian; Hillengaß, Jens; Raab, Marc S; Hose, Dirk; Wuchter, Patrick; Ho, Anthony D; Jauch, Anna; Hielscher, Thomas; Kunz, Christina; Luntz, Steffen; Klein, Stefan; Schmidt-Wolf, Ingo G H; Goerner, Martin; Schmidt-Hieber, Martin; Reimer, Peter; Graeven, Ullrich; Fenk, Roland; Salwender, Hans; Scheid, Christof; Nogai, Axel; Haenel, Mathias; Lindemann, Hans W; Martin, Hans; Noppeney, Richard; Weisel, Katja; Goldschmidt, Hartmut

2016-04-25

Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. ISRCTN16345835 (date of registration 2010-08-24).

[Alemtuzumab for relapsing-remitting multiple sclerosis. Results of two randomized controlled phase III studies].

PubMed

Klotz, L; Meuth, S G; Kieseier, B; Wiendl, H

2013-08-01

In November 2012 the results of 2 clinical phase III trials were published which addressed the effects of alemtuzumab in patients with relapsing-remitting multiple sclerosis (MS). In the CARE-MS-I study patients with early untreated MS (EDSS ≤ 3.0, disease duration < 5 years) were included, whereas CARE-MS-II investigated the effects of alemtuzumab in patients with persisting disease activity under standard disease-modifying treatment (EDSS ≤ 5.0, disease duration < 10 years). These groups were compared to patients under treatment with frequently applied interferon β 1a (3 times  44 µg subcutaneous). Both studies clearly demonstrated a superiority of alemtuzumab compared to interferon in terms of reduction of relapse rate as well as the number of new or enlarging T2 lesions and gadolinium-enhancing lesions. Moreover, the CARE-MS-II study showed a significant delay in disease progression by alemtuzumab. The portfolio and the frequency of relevant side effects, such as infusion-related reactions, development of secondary autoimmunity or infections were within the expected range. Taken together these studies confirm the high anti-inflammatory efficacy of alemtuzumab and hence provide the first evidence of superiority of a monotherapy in direct comparison to standard disease-modifying treatment in two phase III trials in relapsing-remitting MS. These data in the context of the mode of action of alemtuzumab provide evidence for the relevance of immune cells, especially T cells, in the pathophysiology of MS. Experience with long-term effects of alemtuzumab, e.g. from the phase II extension trial as well as the side effect profile argue in favor of a sustained reprogramming of the immune system as a consequence of immune cell depletion by alemtuzumab.

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI

PubMed Central

Mainero, C; Benner, T; Radding, A; van der Kouwe, A; Jensen, R; Rosen, B R.; Kinkel, R P.

2009-01-01

Objective: We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data. Methods: We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 × 033 × 1 mm3), and a 3-dimensional magnetization-prepared rapid gradient echo. Results: Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing–remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test). Conclusions: Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability. GLOSSARY ANOVA = analysis of variance; BN = background noise; CNR = contrast-to-noise ratio; DIR = double-inversion recovery; EDSS = Expanded Disability Status Scale; FLAIR = fluid-attenuated inversion recovery; FLASH = fast low-angle shot; GM = gray matter; MPRAGE = magnetization-prepared rapid gradient echo; MR = magnetic resonance; MS = multiple sclerosis; NACGM = normal-appearing cortical gray matter; RF = radiofrequency; ROI = region of interest; RRMS = relapsing–remitting multiple sclerosis; SNR = signal-to-noise ratio; SPMS = secondary progressive multiple sclerosis; TA = time of acquisition; TE = echo time; TR = repetition time; TSE = turbo spin-echo; WM = white matter. PMID:19641168

Mammalian Toxicity of Munition Compounds. Phase II. Effects of Multiple Doses. Part III. 2,6-Dinitrotoluene

DTIC Science & Technology

1976-07-01

Histopathology , Statistical Analysis, and Normal Values ..... ...... ........... 131 I Ii A.mmALIAN TOXICITY OF MUNITION COMPOUNDS PHASE II: Effects of...chemistry tests and histopathology , and the normal values are given in Appendix I. The concentrations of Ca 2+, Mg2 +, Na+ and K+ in serum were determined...mice fed 2,6-DNT included focal epicarditis or myocarditis, focal cystitis, chronic murine pneumonia or bronchopneumonia, metritis and focal myositis

BG 12: BG 00012, BG 12/Oral Fumarate, FAG-201, second-generation fumarate derivative--Fumapharm/Biogen Idec.

PubMed

2005-01-01

Fumapharm AG has developed a second-generation fumarate (fumaric acid) derivative, BG 12 [BG 00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis. Biogen Idec is currently evaluating the product in clinical trials as an oral treatment for multiple sclerosis (phase II) and psoriasis (phase III) trials.BG 12 has an immunomodulatory mechanism of action. It seems that this product has been developed to reduce the adverse effects associated with a first-generation product containing fumaric acid esters (mixed dimethylfumarate and monoethylfumarate salts), Fumaderm. Fumaderm was approved in Germany in August 1994 and is currently the leading oral systemic therapy for moderate-to-severe psoriasis in Germany. One of the problems associated with Fumaderm capsules has been its gastrointestinal adverse effects (including diarrhoea and nausea). In September 2003, Biogen (now Biogen Idec) licensed exclusive worldwide rights (excluding Germany) from Fumapharm to develop and market BG 12. Biogen plans to collaborate with Fumapharm to accelerate phase III development for psoriasis and the registration programme worldwide. Financial terms of the agreement were not disclosed. Development plans for BG 12 include other autoimmune and inflammatory disorders, such as multiple sclerosis. In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Fumapharm completed phase II trials of this second-generation fumarate derivative for psoriasis prior to licensing of the product to Biogen, also with positive results.

Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease (GVHD) After Donor Stem Cell Transplant

ClinicalTrials.gov

2017-01-24

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, Breakpoint Cluster Region-abl Translocation (BCR-ABL) Negative; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Gastrointestinal Complications; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Childhood Rhabdomyosarcoma; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis.

PubMed

Chaudhry, Burhan Z; Cohen, Jeffrey A; Conway, Devon S

2017-10-01

Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer.

PubMed

Paplomata, Elisavet; Nahta, Rita

2018-03-01

Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for 'ABP 980' or 'trastuzumab biosimilar'. 'ABP 980 and breast cancer' or 'trastuzumab biosimilar and breast cancer' were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.

Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial.

PubMed

Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

2010-07-01

Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35. Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs.

Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial

PubMed Central

Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

2010-01-01

Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35. Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978). PMID:20053869

Analysis of navigation and guidance requirements for commercial VTOL operations

NASA Technical Reports Server (NTRS)

Hoffman, W. C.; Zvara, J.; Hollister, W. M.

1975-01-01

The paper presents some results of a program undertaken to define navigation and guidance requirements for commercial VTOL operations in the takeoff, cruise, terminal and landing phases of flight in weather conditions up to and including Category III. Quantitative navigation requirements are given for the parameters range, coverage, operation near obstacles, horizontal accuracy, multiple landing aircraft, multiple pad requirements, inertial/radio-inertial requirements, reliability/redundancy, update rate, and data link requirements in all flight phases. A multi-configuration straw-man navigation and guidance system for commercial VTOL operations is presented. Operation of the system is keyed to a fully automatic approach for navigation, guidance and control, with pilot as monitor-manager. The system is a hybrid navigator using a relatively low-cost inertial sensor with DME updates and MLS in the approach/departure phases.

Job Samples as Tank Gunnery Performance Predictors

DTIC Science & Technology

1980-09-01

previously been obtained ( Maitland , Eaton, and Neff, 1980). Table VI-M. The Table VI-M order of firing and engagement techniques used in Phase III were the... Maitland , Eaton, and Neff (1980) *** <.001 22 Sen 21 ’ )a. datz obtained from ch4 sensing cask was quanti:ied. as in Phase It, by Coti.purtirg the vie.i...of four test weighting methods in multiple regression. Educational and Psychological Measure- ment, 1959, 19, 103-114. Maitland , A. J., Eaton, N. K

Analysis of the Performance of Heat Pipes and Phase-Change Materials with Multiple Localized Heat Sources for Space Applications

DTIC Science & Technology

1989-05-01

NUMERICAL ANALYSIS OF STEFAN PROBLEMS FOR GENERALIZED MULTI- DIMENSIONAL PHASE-CHANGE STRUCTURES USING THE ENTHALPY TRANSFORMING MODEL 4.1 Summary...equation St Stefan number, cs(Tm-Tw)/H or cs(Tm-Ti)/H s circumferential distance coordinate, m, Section III s dimensionless interface position along...fluid, kg/m 3 0 viscous dissipation term in the energy eqn. (1.4), Section I; dummy variable, Section IV r dimensionless time, ta/L 2 a Stefan -Boltzmann

The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients.

PubMed

Heimberger, Amy B; Sampson, John H

2009-08-01

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, resulting in non-specific toxicity. Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells. EGFR variant III (EGFRvIII) is a tumor-specific mutation that is widely expressed in GBM and other neoplasms and its expression enhances tumorigenicity. This in-frame deletion mutation splits a codon, resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction (PEPvIII-KLH/CDX-110) is an efficacious immunotherapy in syngeneic murine models. In this review, we summarize our results in GBM patients targeting this mutation in multiple, multi-institutional Phase II immunotherapy trials. These trials demonstrated that a selected population of GBM patients who received vaccines targeting EGFRvIII had an unexpectedly long survival time. Further therapeutic strategies and potential pitfalls of using this approach are discussed.

Phase III of Early Restoration | NOAA Gulf Spill Restoration

Science.gov Websites

information about this phase of Early Restoration, including fact sheets on each project. The final Phase III 44 projects are documented in a final Record of Decision. Information about Phase III of Early Archive Home Phase III of Early Restoration Phase III of Early Restoration Beach habitat would be restored

Microswitch-aided programs to support physical exercise or adequate ambulation in persons with multiple disabilities.

PubMed

Lancioni, Giulio E; Singh, Nirbhay N; O'Reilly, Mark F; Sigafoos, Jeff; Alberti, Gloria; Perilli, Viviana; Oliva, Doretta; Buono, Serafino

2014-09-01

Three microswitch-aided programs were assessed in three single-case studies to enhance physical exercise or ambulation in participants with multiple disabilities. Study I was aimed at helping a woman who tended to have the head bending forward and the arms down to exercise a combination of appropriate head and arms movements. Study II was aimed at promoting ambulation continuity with a man who tended to have ambulation breaks. Study III was aimed at promoting ambulation with appropriate foot position in a girl who usually showed toe walking. The experimental designs of the studies consisted of a multiple probe across responses (Study I), an ABAB sequence (Study II), and an ABABB(1) sequence (Study III). The last phase of each study was followed by a post-intervention check. The microswitches monitored the target responses selected for the participants and triggered a computer system to provide preferred stimuli contingent on those responses during the intervention phases of the studies. Data showed that the programs were effective with each of the participants who learned to exercise head and arms movements, increased ambulation continuity, and acquired high levels of appropriate foot position during ambulation, respectively. The positive performance levels were retained during the post-intervention checks. The discussion focused on (a) the potential of technology-aided programs for persons with multiple disabilities and (b) the need of replication studies to extend the evidence available in the area. Copyright © 2014 Elsevier Ltd. All rights reserved.

Intravenous immunoglobulin and Alzheimer's disease: what now?

PubMed

Loeffler, David A

2013-06-05

Intravenous immunoglobulin (IVIG) products are prepared from purified plasma immunoglobulins from large numbers of healthy donors. Pilot studies with the IVIG preparations Octagam and Gammagard in individuals with mild-to-moderate Alzheimer's disease (AD) suggested stabilization of cognitive functioning in these patients, and a phase II trial with Gammagard reported similar findings. However, subsequent reports from Octagam's phase II trial and Gammagard's phase III trial found no evidence for slowing of AD progression. Although these recent disappointing results have reduced enthusiasm for IVIG as a possible treatment for AD, it is premature to draw final conclusions; a phase III AD trial with the IVIG product Flebogamma is still in progress. IVIG was the first attempt to use multiple antibodies to treat AD. This approach should be preferable to administration of single monoclonal antibodies in view of the multiple processes that are thought to contribute to AD neuropathology. Development of "AD-specific" preparations with higher concentrations of selected human antibodies and perhaps modified in other ways (such as increasing their anti-inflammatory effects and/or ability to cross the blood-brain barrier) should be considered. Such preparations, if generated with recombinant technology, could overcome the problems of high cost and limited supplies, which have been major concerns relating to the possible widespread use of IVIG in AD patients. This review summarizes the recent AD IVIG trials and discusses the major issues relating to possible use of IVIG for treating AD, as well as the critical questions which remain.

Venetoclax: First Global Approval.

PubMed

Deeks, Emma D

2016-06-01

Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.

Present and future treatment of advanced non-small cell lung cancer.

PubMed

Crinò, Lucio; Cappuzzo, Federico

2002-06-01

Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response rates and suggested an improvement in overall survival. Large phase III trials comparing these second-generation cisplatin regimens indicated a substantial equivalence of new combinations, marginally improving the outcome of patients over the first-generation platinum-based regimens. Phase III trials have not yet shown dramatic advantages for either multiple-drug regimens, with nonoverlapping mechanisms of action and toxicity, or nonplatinum doublets, with efficacy and/or toxicity profiles superior to those of platinum-based chemotherapy. Chemotherapy in advanced non-small cell lung cancer has reached a plateau, and it is clear that new approaches are required. These should include prevention, screening, and early detection, and the use of novel treatments based on our understanding of the biology and molecular biology of this disease. Copyright 2002, Elsevier Science (USA). All rights reserved.

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design.

PubMed

Pujade-Lauraine, Eric; Fujiwara, Keiichi; Dychter, Samuel S; Devgan, Geeta; Monk, Bradley J

2018-03-27

Avelumab is a human anti-PD-L1 checkpoint inhibitor with clinical activity in multiple solid tumors. Here, we describe the rationale and design for JAVELIN Ovarian 200 (NCT02580058), the first randomized Phase III trial to evaluate the role of checkpoint inhibition in women with ovarian cancer. This three-arm trial is comparing avelumab administered alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory recurrent ovarian, fallopian tube or peritoneal cancer. Eligible patients are not preselected based on PD-L1 expression and may have received up to three prior lines of chemotherapy for platinum-sensitive disease, but none for resistant disease. Overall survival and progression-free survival are primary end points, and secondary end points include biomarker evaluations and pharmacokinetics.

Sorption of Ferric Iron from Ferrioxamine B to Synthetic and Biogenic Layer Type Manganese Oxides

NASA Astrophysics Data System (ADS)

Duckworth, O.; John, B.; Sposito, G.

2006-12-01

Siderophores are biogenic chelating agents produced in terrestrial and marine environments to increase the bioavailablity of ferric iron. Recent work has suggested that both aqueous and solid-phase Mn(III) may affect siderophore-mediated iron transport, but no information appears to be available about the effect of solid-phase Mn(IV). To probe the effects of predominantly Mn(IV) oxides, we studied the sorption reaction of ferrioxamine B [Fe(III)HDFOB+, an Fe(III) chelate of the trihydroxamate siderophore desferrioxamine B (DFOB)] with two synthetic birnessites [layer type Mn(III, IV) oxides] and a biogenic birnessite produced by Pseudomonas putida MnB1. We found that all of these predominantly Mn(IV) oxides greatly reduced the aqueous concentration of Fe(III)HDFOB+ over at pH 8. After 72 hours equilibration time, the sorption behavior for the synthetic birnessites could be accurately described by a Langmuir isotherm; for the biogenic oxide, a Freundlich isotherm was best utilized to model the sorption data. To study the molecular nature of the interaction between the Fe(III)HDFOB+ complex and the oxide surface, Fe K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy was employed. Analysis of the EXAFS spectra indicated that Fe(III) associated with the Mn(IV) oxides is not complexed by DFOB as in solution, but instead Fe(III) is specifically adsorbed to into the mineral structure at multiple sites with no evidence of DFOB complexation, thus indicating that the Mn(IV) oxides displaced Fe(III) from the siderophore complex. These results indicate that manganese oxides, including biominerals, may strongly sequester iron from soluble ferric complexes and thus may play a significant role in the biogeochemical cycling of iron in marine and terrestrial environments.

Effect of Laughter Yoga on Psychological Well-being and Physiological Measures.

PubMed

Miles, Cindy; Tait, Elizabeth; Schure, Marc B; Hollis, Marianne

2016-01-01

In 2014, laughter yoga (LY) achieved the intermediate level, tier 2, under the Title III-D Evidence-based Disease Prevention and Health Promotion Program through the Administration on Aging (AOA). Further research is needed to qualify LY under the criteria for the highest tier, tier 3, to assure continued funding for LY classes at senior centers. The study intended to demonstrate further the benefits of LY and to qualify LY as tier 3 under Title III-D. Using a quasi-experimental design, the research team conducted a preintervention/postintervention study in 3 phases. The study was done in a variety of community centers. Phase 1, a pilot phase, was limited to North Carolina, and phase 2 was conducted in multiple states. Phase 3 was held at the North Carolina Area Agency on Aging's annual Volunteer Appreciation meeting. Participants in phases 1 (n = 109) and 2 (n = 247) enrolled in LY classes. Classes were advertised by fliers posted in community and in retirement centers. The ability of participants to participate in a class was based solely on their desire to participate, regardless of age, ability, health status, or physical impairment. Phase 3 (n = 23) was a convenience sample only. All phases were voluntary. The pre- and posttests for all 3 phases were Likert-scale surveys, 10 questions on the Psychological Outcomes of Well-being (POWB) survey. Pulse and other physiological measurements were also assessed pre- and postintervention. Analysis included a t test on each of the 10 POWB and physiological measures for all phases. All 10 POWB measures for phases 1 and 2 showed significant improvements between the pre- and postintervention testing (P < .001). Phase 3, the control, showed no significant improvement. The initial study demonstrated that LY meets the criteria to qualify for tier 3 under the Title III-D Evidence-based Disease Prevention and Health Promotion Program and that a large number of Americans, regardless of age and physical ability, could benefit from LY.

A Community Needs Assessment for the Development of an Interprofessional Palliative Care Training Curriculum.

PubMed

Coats, Heather; Paganelli, Tia; Starks, Helene; Lindhorst, Taryn; Starks Acosta, Anne; Mauksch, Larry; Doorenbos, Ardith

2017-03-01

There is a known shortage of trained palliative care professionals, and an even greater shortage of professionals who have been trained through interprofessional curricula. As part of an institutional Palliative Care Training Center grant, a core team of interprofessional palliative care academic faculty and staff completed a state-wide palliative care educational assessment to determine the needs for an interprofessional palliative care training program. The purpose of this article is to describe the process and results of our community needs assessment of interprofessional palliative care educational needs in Washington state. We approached the needs assessment through a cross-sectional descriptive design by using mixed-method inquiry. Each phase incorporated a variety of settings and subjects. The assessment incorporated multiple phases with diverse methodological approaches: a preparatory phase-identifying key informants; Phase I-key informant interviews; Phase II-survey; and Phase III-steering committee endorsement. The multiple phases of the needs assessment helped create a conceptual framework for the Palliative Care Training Center and developed an interprofessional palliative care curriculum. The input from key informants at multiple phases also allowed us to define priority needs and to refine an interprofessional palliative care curriculum. This curriculum will provide an interprofessional palliative care educational program that crosses disciplinary boundaries to integrate knowledge that is beneficial for all palliative care clinicians. The input from a range of palliative care clinicians and professionals at every phase of the needs assessment was critical for creating an interprofessional palliative care curriculum.

Carbon X-ray absorption in the local ISM: fingerprints in X-ray Novae spectra

NASA Astrophysics Data System (ADS)

Gatuzz, Efraín; Ness, J.-U.; Gorczyca, T. W.; Hasoglu, M. F.; Kallman, Timothy R.; García, Javier A.

2018-06-01

We present a study of the C K-edge using high-resolution LETGS Chandra spectra of four novae during their super-soft-source (SSS) phase. We identified absorption lines due to C II Kα, C III Kα and C III Kβ resonances. We used these astronomical observations to perform a benchmarking of the atomic data, which involves wavelength shifts of the resonances and photoionization cross-sections. We used improved atomic data to estimate the C II and C III column densities. The absence of physical shifts for the absorption lines, the consistence of the column densities between multiple observations and the high temperature required for the SSS nova atmosphere modeling support our conclusion about an ISM origin of the respective absorption lines. Assuming a collisional ionization equilibrium plasma the maximum temperature derived from the ratio of C II/C III column densities of the absorbers correspond to Tmax < 3.05 × 104 K.

Phase diagram and equation of state of praseodymium at high pressures and temperatures

NASA Astrophysics Data System (ADS)

Baer, Bruce J.; Cynn, Hyunchae; Iota, Valentin; Yoo, Choong-Shik; Shen, Guoyin

2003-04-01

The phase diagram for praseodymium (Pr) has been determined for pressures between 5 and 60 GPa and temperatures between 295 and 830 K using both in situ energy- and angle-dispersive x-ray diffraction with externally heated diamond-anvil cells. Mineral oil and argon were alternatively used as pressure media in order to compare conflicting results in the literature and to ensure the validity of mineral oil as an inert medium. Evidence for the presence of an, as yet, unidentified phase (denoted Pr-VI) above 675 K has been observed, whereas no compelling evidence has been observed for the existence of the recently reported monoclinic phase (Pr-V). The new constraints of the phase diagram, therefore, suggest that the phase transitions occur as Pr-I(dhcp)→Pr-II(fcc)→Pr-VI→Pr-IV(α-U) above approximately 700 K. Additionally, there is a Pr-III(distorted fcc), Pr-VI, and Pr-IV triple point at approximately 675 K and 23.8 GPa. Temperature-dependent equations of state have been determined, allowing the temperature-dependent volume collapse at the transition between Pr-III and Pr-IV to be calculated. We report a linear decrease of the volume collapse along the Pr-III to Pr-IV boundary with temperature, ΔV/V (%)=16.235-0.0156[T(K)]; the extrapolation indicates that the volume collapse should vanish well below the melting point. With the temperature-dependent equation of state data and new phase diagram we demonstrate that the volume collapse can be accounted for by a change in the multiplicity of Pr atoms as the f electrons go from localized to itinerant.

Methods for improved growth of group III nitride buffer layers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melnik, Yurity; Chen, Lu; Kojiri, Hidehiro

Methods are disclosed for growing high crystal quality group III-nitride epitaxial layers with advanced multiple buffer layer techniques. In an embodiment, a method includes forming group III-nitride buffer layers that contain aluminum on suitable substrate in a processing chamber of a hydride vapor phase epitaxy processing system. A hydrogen halide or halogen gas is flowing into the growth zone during deposition of buffer layers to suppress homogeneous particle formation. Some combinations of low temperature buffers that contain aluminum (e.g., AlN, AlGaN) and high temperature buffers that contain aluminum (e.g., AlN, AlGaN) may be used to improve crystal quality and morphologymore » of subsequently grown group III-nitride epitaxial layers. The buffer may be deposited on the substrate, or on the surface of another buffer. The additional buffer layers may be added as interlayers in group III-nitride layers (e.g., GaN, AlGaN, AlN).« less

Phase III Early Restoration Public Meetings | NOAA Gulf Spill Restoration

Science.gov Websites

Archive Home Phase III Early Restoration Public Meetings Phase III Early Restoration Public Meetings share Posted on December 6, 2013 | Assessment and Early Restoration Restoration Area Title: Phase III Early on the draft plan for the third phase of Early Restoration, which proposes more than $625 million in

Using phase II data for the analysis of phase III studies: An application in rare diseases.

PubMed

Wandel, Simon; Neuenschwander, Beat; Röver, Christian; Friede, Tim

2017-06-01

Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

Apatinib: a promising oral antiangiogenic agent in the treatment of multiple solid tumors.

PubMed

Scott, A J; Messersmith, W A; Jimeno, A

2015-04-01

Aberrant proangiogenic pathways have long been implicated in tumorigenesis and metastasis. Antiangiogenic therapies have shown efficacy in the treatment of a variety of solid tumors including lung, breast, colon, glioblastomas, and other solid tumor types. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), is an orally bioavailable agent currently being studied in multiple tumor types. Apatinib has shown a survival benefit in gastric cancer in a phase III trial and non-small cell lung cancer in a phase II trial. With a favorable side effect profile and improved outcomes, apatinib has demonstrated a substantial potential to augment therapeutic options in a variety of tumor types. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

Can harmonized regulation overcome intra-European differences? Insights from a European Phase III stem cell trial.

PubMed

Hauskeller, Christine

2017-09-01

Harmonized regulation of research with human stem cells in Europe has shaped innovation in regenerative medicine. Findings from a Phase III academic clinical trial of an autologous cell procedure illustrate the obstacles that a multinational trial faces. A typology of the obstacles encountered, may help other teams embarking upon trials. The findings throw light on the situation of clinician-scientists in clinical innovation, as the expertise to run scientific trials is very complex. The innovation route of clinical translation takes insufficient account of the interdependencies between multiple social and cultural factors from outside the laboratory and the clinic. For ethical reasons, however, academic and business routes to stem cell treatments ought to be enabled by the regulators. Suggestions arise, how academics can prepare for trials, that academic research needs better institutional support and that new models of medical innovation may need to be developed for regenerative medicine.

Enhanced visible light activity of nano-titanium dioxide doped with multiple ions: Effect of crystal defects

NASA Astrophysics Data System (ADS)

Jaimy, Kanakkanmavudi B.; Ghosh, Swapankumar; Gopakumar Warrier, Krishna

2012-12-01

Titanium dioxide photocatalysts co-doped with iron(III) and lanthanum(III) have been prepared through a modified sol-gel method. Doping with Fe3+ resulted in a relatively lower anatase to rutile phase transformation temperature, while La3+ addition reduced the crystal growth and thus retarded the phase transformation of titania nanoparticles. The presence of Fe3+ ions shifted the absorption profile of titania to the longer wavelength side of the spectrum and enhanced the visible light activity. On the other hand, La3+ addition improved the optical absorption of titania nanoparticles. Both the dopants improved the life time of excitons by proper transferring and trapping of photoexcited charges. In the present work, considerable enhancement in photocatalytic activity under visible light was achieved through synergistic effect of optimum concentrations of the two dopants and associated crystal defects.

Microscopic studies of polycrystalline nanoparticle growth in free space

NASA Astrophysics Data System (ADS)

Mohan, A.; Kaiser, M.; Verheijen, M. A.; Schropp, R. E. I.; Rath, J. K.

2017-06-01

We have extensively studied by multiple microscopic techniques the growth and crystallization of silicon nanoparticles in pulsed SiH4/Ar plasmas. We observe that the crystallinity of the particles can be tuned from amorphous to crystalline by altering the plasma ON time, tON. Three phases can be identified as a function of tON. Microscopic studies reveal that, in the initial gas phase (phase I) single particles of polycrystalline nature are formed which according to our hypothesis grow out of a single nucleus. The individual crystallites of the polycrystalline particles become bigger crystalline regions which marks the onset of cauliflower shaped particles (phase II). At longer tON (phase III) distinct cauliflower particles are formed by the growth of these crystalline regions by local epitaxy.

Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy.

PubMed

Rapoport, Bernardo; Schwartzberg, Lee; Chasen, Martin; Powers, Dan; Arora, Sujata; Navari, Rudolph; Schnadig, Ian

2016-04-01

Rolapitant, a novel neurokinin-1 receptor antagonist (RA), was shown to protect against delayed chemotherapy-induced nausea and vomiting (CINV) during the first cycle of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in randomized, double-blind trials. This analysis explored the efficacy and safety of rolapitant in preventing CINV over multiple cycles of MEC or HEC. Patients in one phase III MEC, one phase II HEC, and two phase III HEC clinical trials were randomized to receive oral rolapitant (180 mg) or placebo in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Regardless of response in cycle 1, patients could continue the same antiemetic treatment for up to six cycles. On days 6-8 of each subsequent chemotherapy cycle, patients reported the incidence of emesis and/or nausea interfering with normal daily life. Post hoc analyses of pooled safety and efficacy data from the four trials were performed for cycles 2-6. Significantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 (p = 0.006), 3 (p < 0.001), 4 (p = 0.001), and 5 (p = 0.021). Over cycles 1-6, time-to-first emesis was significantly longer with rolapitant than with control (p < 0.001). The incidence of treatment-related adverse events during cycles 2-6 was similar in rolapitant (5.5%) and control (6.8%) arms. No cumulative toxicity was observed. Over multiple cycles of MEC or HEC, rolapitant provided superior CINV protection and reduced emesis and nausea interfering with daily life compared with control and remained well tolerated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study

PubMed Central

Nnoaham, Kelechi E.; Hummelshoj, Lone; Kennedy, Stephen H.; Jenkinson, Crispin; Zondervan, Krina T.

2012-01-01

Objective To generate and validate symptom-based models to predict endometriosis among symptomatic women prior to undergoing their first laparoscopy. Design Prospective, observational, two-phase study, in which women completed a 25-item questionnaire prior to surgery. Setting Nineteen hospitals in 13 countries. Patient(s) Symptomatic women (n = 1,396) scheduled for laparoscopy without a previous surgical diagnosis of endometriosis. Intervention(s) None. Main Outcome Measure(s) Sensitivity and specificity of endometriosis diagnosis predicted by symptoms and patient characteristics from optimal models developed using multiple logistic regression analyses in one data set (phase I), and independently validated in a second data set (phase II) by receiver operating characteristic (ROC) curve analysis. Result(s) Three hundred sixty (46.7%) women in phase I and 364 (58.2%) in phase II were diagnosed with endometriosis at laparoscopy. Menstrual dyschezia (pain on opening bowels) and a history of benign ovarian cysts most strongly predicted both any and stage III and IV endometriosis in both phases. Prediction of any-stage endometriosis, although improved by ultrasound scan evidence of cyst/nodules, was relatively poor (area under the curve [AUC] = 68.3). Stage III and IV disease was predicted with good accuracy (AUC = 84.9, sensitivity of 82.3% and specificity 75.8% at an optimal cut-off of 0.24). Conclusion(s) Our symptom-based models predict any-stage endometriosis relatively poorly and stage III and IV disease with good accuracy. Predictive tools based on such models could help to prioritize women for surgical investigation in clinical practice and thus contribute to reducing time to diagnosis. We invite other researchers to validate the key models in additional populations. PMID:22657249

Recent trends in 30-day mortality in patients with blunt splenic injury: A nationwide trauma database study in Japan.

PubMed

Tanaka, Chie; Tagami, Takashi; Matsumoto, Hisashi; Matsuda, Kiyoshi; Kim, Shiei; Moroe, Yuta; Fukuda, Reo; Unemoto, Kyoko; Yokota, Hiroyuki

2017-01-01

Splenic injury frequently occurs after blunt abdominal trauma; however, limited epidemiological data regarding mortality are available. We aimed to investigate mortality rate trends after blunt splenic injury in Japan. We retrospectively identified 1,721 adults with blunt splenic injury (American Association for the Surgery of Trauma splenic injury scale grades III-V) from the 2004-2014 Japan Trauma Data Bank. We grouped the records of these patients into 3 time phases: phase I (2004-2008), phase II (2009-2012), and phase III (2013-2014). Over the 3 phases, we analysed 30-day mortality rates and investigated their association with the prevalence of certain initial interventions (Mantel-Haenszel trend test). We further performed multiple imputation and multivariable analyses for comparing the characteristics and outcomes of patients who underwent TAE or splenectomy/splenorrhaphy, adjusting for known potential confounders and for within-hospital clustering using generalised estimating equation. Over time, there was a significant decrease in 30-day mortality after splenic injury (p < 0.01). Logistic regression analysis revealed that mortality significantly decreased over time (from phase I to phase II, odds ratio: 0.39, 95% confidence interval: 0.22-0.67; from phase I to phase III, odds ratio: 0.34, 95% confidence interval: 0.19-0.62) for the overall cohort. While the 30-day mortality for splenectomy/splenorrhaphy diminished significantly over time (p = 0.01), there were no significant differences regarding mortality for non-operative management, with or without transcatheter arterial embolisation (p = 0.43, p = 0.29, respectively). In Japan, in-hospital 30-day mortality rates decreased significantly after splenic injury between 2004 and 2014, even after adjustment for within-hospital clustering and other factors independently associated with mortality. Over time, mortality rates decreased significantly after splenectomy/splenorrhaphy, but not after non-operative management. This information is useful for clinicians when making decisions about treatments for patients with blunt splenic injury.

Efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A phase II/III, multicenter, randomized, evaluator-blinded, active-controlled trial and a phase III, multicenter, open trial.

PubMed

Suzuki, Kazuyuki; Endo, Ryujin; Takikawa, Yasuhiro; Moriyasu, Fuminori; Aoyagi, Yutaka; Moriwaki, Hisataka; Terai, Shuji; Sakaida, Isao; Sakai, Yoshiyuki; Nishiguchi, Shuhei; Ishikawa, Toru; Takagi, Hitoshi; Naganuma, Atsushi; Genda, Takuya; Ichida, Takafumi; Takaguchi, Koichi; Miyazawa, Katsuhiko; Okita, Kiwamu

2018-05-01

The efficacy and safety of rifaximin in the treatment of hepatic encephalopathy (HE) are widely known, but they have not been confirmed in Japanese patients with HE. Thus, two prospective, randomized studies (a phase II/III study and a phase III study) were carried out. Subjects with grade I or II HE and hyperammonemia were enrolled. The phase II/III study, which was a randomized, evaluator-blinded, active-comparator, parallel-group study, was undertaken at 37 institutions in Japan. Treatment periods were 14 days. Eligible patients were randomized to the rifaximin group (1200 mg/day) or the lactitol group (18-36 g/day). The phase III study was carried out in the same patients previously enrolled in the phase II/III study, and they were all treated with rifaximin (1200 mg/day) for 10 weeks. In the phase II/III study, 172 patients were enrolled. Blood ammonia (B-NH 3 ) concentration was significantly improved in the rifaximin group, but the difference between the two groups was not significant. The portal systemic encephalopathy index (PSE index), including HE grade, was significantly improved in both groups. In the phase III study, 87.3% of enrolled patients completed the treatment. The improved B-NH 3 concentration and PSE index were well maintained from the phase II/III study during the treatment period of the phase III study. Adverse drug reactions (ADRs) were seen in 13.4% of patients who received rifaximin, but there were no severe ADRs leading to death. The efficacy of rifaximin is sufficient and treatment is well tolerated in Japanese patients with HE and hyperammonemia. © 2017 The Japan Society of Hepatology.

Adaptive Clinical Trials: Advantages and Disadvantages of Various Adaptive Design Elements.

PubMed

Korn, Edward L; Freidlin, Boris

2017-06-01

There is a wide range of adaptive elements of clinical trial design (some old and some new), with differing advantages and disadvantages. Classical interim monitoring, which adapts the design based on early evidence of superiority or futility of a treatment arm, has long been known to be extremely useful. A more recent application of interim monitoring is in the use of phase II/III designs, which can be very effective (especially in the setting of multiple experimental treatments and a reliable intermediate end point) but do have the cost of having to commit earlier to the phase III question than if separate phase II and phase III trials were performed. Outcome-adaptive randomization is an older technique that has recently regained attention; it increases trial complexity and duration without offering substantial benefits to the patients in the trial. The use of adaptive trials with biomarkers is new and has great potential for efficiently identifying patients who will be helped most by specific treatments. Master protocols in which trial arms and treatment questions are added to an ongoing trial can be especially efficient in the biomarker setting, where patients are screened for entry into different subtrials based on evolving knowledge about targeted therapies. A discussion of three recent adaptive clinical trials (BATTLE-2, I-SPY 2, and FOCUS4) highlights the issues. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.

Upright and Inverted Single-Junction GaAs Solar Cells Grown by Hydride Vapor Phase Epitaxy

DOE PAGES

Simon, John; Schulte, Kevin L.; Jain, Nikhil; ...

2016-10-19

Hydride vapor phase epitaxy (HVPE) is a low-cost alternative to conventional metal-organic vapor phase epitaxy (MOVPE) growth of III-V solar cells. In this work, we show continued improvement of the performance of HVPE-grown single-junction GaAs solar cells. We show over an order of magnitude improvement in the interface recombination velocity between GaAs and GaInP layers through the elimination of growth interrupts, leading to increased short-circuit current density and open-circuit voltage compared with cells with interrupts. One-sun conversion efficiencies as high as 20.6% were achieved with this improved growth process. Solar cells grown in an inverted configuration that were removed frommore » the substrate showed nearly identical performance to on-wafer cells, demonstrating the viability of HVPE to be used together with conventional wafer reuse techniques for further cost reduction. As a result, these devices utilized multiple heterointerfaces, showing the potential of HVPE for the growth of complex and high-quality III-V devices.« less

Collaborative Research: Robust Climate Projections and Stochastic Stability of Dynamical Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ilya Zaliapin

This project focused on conceptual exploration of El Nino/Southern Oscillation (ENSO) variability and sensitivity using a Delay Differential Equation developed in the project. We have (i) established the existence and continuous dependence of solutions of the model (ii) explored multiple models solutions, and the distribution of solutions extrema, and (iii) established and explored the phase locking phenomenon and the existence of multiple solutions for the same values of model parameters. In addition, we have applied to our model the concept of pullback attractor, which greatly facilitated predictive understanding of the nonlinear model's behavior.

Bleeding and infection with external ventricular drainage: a systematic review in comparison with adjudicated adverse events in the ongoing Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-III IHV) trial.

PubMed

Dey, Mahua; Stadnik, Agnieszka; Riad, Fady; Zhang, Lingjiao; McBee, Nichol; Kase, Carlos; Carhuapoma, J Ricardo; Ram, Malathi; Lane, Karen; Ostapkovich, Noeleen; Aldrich, Francois; Aldrich, Charlene; Jallo, Jack; Butcher, Ken; Snider, Ryan; Hanley, Daniel; Ziai, Wendy; Awad, Issam A

2015-03-01

Retrospective series report varied rates of bleeding and infection with external ventricular drainage (EVD). There have been no prospective studies of these risks with systematic surveillance, threshold definitions, or independent adjudication. To analyze the rate of complications in the ongoing Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) trial, providing a comparison with a systematic review of complications of EVD in the literature. Patients were prospectively enrolled in the CLEAR III trial after placement of an EVD for obstructive intraventricular hemorrhage and randomized to receive recombinant tissue-type plasminogen activator or placebo. We counted any detected new hemorrhage (catheter tract hemorrhage or any other distant hemorrhage) on computed tomography scan within 30 days from the randomization. Meta-analysis of published series of EVD placement was compiled with STATA software. Growing or unstable hemorrhage was reported as a cause of exclusion from the trial in 74 of 5707 cases (1.3%) screened for CLEAR III. The first 250 patients enrolled have completed adjudication of adverse events. Forty-two subjects (16.8%) experienced ≥1 new bleeds or expansions, and 6 of 250 subjects (2.4%) suffered symptomatic hemorrhages. Eleven cases (4.4%) had culture-proven bacterial meningitis or ventriculitis. Risks of bleeding and infection in the ongoing CLEAR III trial are comparable to those previously reported in EVD case series. In the present study, rates of new bleeds and bacterial meningitis/ventriculitis are very low despite multiple daily injections, blood in the ventricles, the use of thrombolysis in half the cases, and generalization to >60 trial sites.

Los Angeles International Airport Runway Incursion Studies: Phase III--Center-Taxiway Simulation

NASA Technical Reports Server (NTRS)

Madson, Michael D.

2004-01-01

Phase III of the Los Angeles International Airport Runway Incursion Studies was conducted, under an agreement with HNTB Corporation, at the NASA Ames FutureFlight Central (FFC) facility in June 2003. The objective of the study was the evaluation of a new center-taxiway concept at LAX. This study is an extension of the Phase I and Phase II studies previously conducted at FFC. This report presents results from Phase III of the study, in which a center-taxiway concept between runways 25L and 25R was simulated and evaluated. Phase III data were compared objectively against the Baseline data. Subjective evaluations by participating LAX controllers were obtained with regard to workload, efficiency, and safety criteria. To facilitate a valid comparison between Baseline and Phase III data, the same scenarios were used for Phase III that were tested during Phases I and II. This required briefing participating controllers on differences in airport and airline operations between 2001 and today.

Quality of reporting in oncology phase II trials: A 5-year assessment through systematic review.

PubMed

Langrand-Escure, Julien; Rivoirard, Romain; Oriol, Mathieu; Tinquaut, Fabien; Rancoule, Chloé; Chauvin, Frank; Magné, Nicolas; Bourmaud, Aurélie

2017-01-01

Phase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials. A literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010-2015). All articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer. Quality of reporting was assessed using the Key Methodological Score. 557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001). Screening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate. This literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles.

Quality of reporting in oncology phase II trials: A 5-year assessment through systematic review

PubMed Central

Langrand-Escure, Julien; Rivoirard, Romain; Oriol, Mathieu; Tinquaut, Fabien; Rancoule, Chloé; Chauvin, Frank; Magné, Nicolas; Bourmaud, Aurélie

2017-01-01

Background Phase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials. Data sources A literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010–2015). Study eligibility criteria All articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer. Intervention Quality of reporting was assessed using the Key Methodological Score. Results 557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001). Limitations Screening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate. Conclusions & implications of key findings This literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles. PMID:29216190

A review of ipratropium bromide/fenoterol hydrobromide (Berodual) delivered via Respimat Soft Mist Inhaler in patients with asthma and chronic obstructive pulmonary disease.

PubMed

Kässner, Frank; Hodder, Rick; Bateman, Eric D

2004-01-01

Asthma and chronic obstructive pulmonary disease (COPD) can be effectively treated by the use of bronchodilator therapies delivered by inhalation. Berodual is a fixed combination of the anticholinergic agent ipratropium bromide (IB) and the beta2-adrenergic agonist fenoterol hydrobromide (FEN). IB/FEN has been available for the treatment of asthma and COPD in a pressurised metered dose inhaler (MDI) [pMDI] formulation for many years. The pMDI is the most widely used device for the delivery of inhaled medications, such as IB/FEN. However, most conventional pMDIs contain chlorofluorocarbon (CFC) propellants, which are currently being withdrawn because of their detrimental effects on the environment. This has resulted in alternative methods of drug delivery being developed. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that generates a fine, slow-moving cloud (the Soft Mist) which can be easily inhaled. Scintigraphic studies have shown that this improves deposition of drugs in the lung and results in less oropharyngeal deposition than the CFC-MDI. A clinical development programme has been conducted to compare the efficacy and safety of IB/FEN delivered via Respimat SMI with that of IB/FEN via CFC-MDI in the treatment of patients with asthma or COPD. Five clinical studies (two phase II and three phase III) investigated dosages of IB/FEN 5/12.5 microg to 320/800 microg via Respimat SMI in single and multiple dose administration regimens. Four of the trials were conducted in patients with asthma (three in adults and one in children), while one phase III trial was conducted in patients with COPD. In phase III, 2058 patients participated, with a total of 1112 patients treated with IB/FEN via Respimat SMI. In the phase III studies, each dose from Respimat SMI was given in one actuation compared with two actuations with the CFC-MDI. In the paediatric asthma phase III study, all CFC-MDI doses were delivered via a spacer device. The results of the trials demonstrated that IB/FEN via Respimat SMI allows a reduction in the nominal dose of IB/FEN, while offering similar therapeutic efficacy and safety to a CFC-MDI. In children, Respimat SMI obviates the need for a spacer.

The PEP-3-KLH (CDX-110) vaccine in glioblastoma multiforme patients

PubMed Central

Heimberger, Amy B.; Sampson, John H

2009-01-01

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively resulting in non-specific toxicity. Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation that is widely expressed on GBM and other neoplasms and its expression enhances tumorigenicity. This in-frame deletion mutation splits a codon resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction (PEPvIII-KLH/CDX-110) is an efficacious immunotherapy in syngeneic murine models. In this review, we summarize our results in GBM patients targeting this mutation in multiple, multi-institutional Phase II immunotherapy trials. These trials demonstrated that a selected population of GBM patients who received the vaccines targeting EGFRvIII had an unexpectedly long survival time. Further therapeutic strategies and potential pitfalls using this approach are discussed. PMID:19591631

Measurement of backbone hydrogen-deuterium exchange in the type III secretion system needle protein PrgI by solid-state NMR

NASA Astrophysics Data System (ADS)

Chevelkov, Veniamin; Giller, Karin; Becker, Stefan; Lange, Adam

2017-10-01

In this report we present site-specific measurements of amide hydrogen-deuterium exchange rates in a protein in the solid state phase by MAS NMR. Employing perdeuteration, proton detection and a high external magnetic field we could adopt the highly efficient Relax-EXSY protocol previously developed for liquid state NMR. According to this method, we measured the contribution of hydrogen exchange on apparent 15N longitudinal relaxation rates in samples with differing D2O buffer content. Differences in the apparent T1 times allowed us to derive exchange rates for multiple residues in the type III secretion system needle protein.

Installation Restoration Program. Phase II: Stage 1 Problem Confirmation Study, Duluth International Airport, Duluth, Minnesota.

DTIC Science & Technology

1984-10-01

8 iii "i t-. Table of Contents (cont.) Section Title Page -APPENDIX A Acronyms, Definitions, Nomenclature and Units of Measure B Scope of Work, Task...Identification/Records Search Phase II - Problem Confirmation and Quantification Phase III - Technology Base Development Phase IV - Corrective Action Only...Problem Identification/Records Search Phase II - Problem Confirmation and Quantification Phase III - Technology Base Development Phase IV - Corrective

Motilin-induced gastric contractions signal hunger in man.

PubMed

Tack, J; Deloose, E; Ang, D; Scarpellini, E; Vanuytsel, T; Van Oudenhove, L; Depoortere, I

2016-02-01

Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. In fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (β=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. Motilin-induced gastric phase III is a hunger signal from GIT in man. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Initiation of phase III contractions in the jejunum by atropine, hexamethonium and xylocaine in conscious dogs.

PubMed

Tohara, K; Uchida, Y; Suzuki, H; Itoh, Z

2000-02-01

Mechanisms of initiation of phase III contractions in the jejunum during the digestive state are not well understood. To test whether phase III can be induced by a local injection of various agents in a jejunal segment, a polyethylene tube was chronically placed in a branch of the jejunal artery, and force transducers were chronically placed in the upper jejunum. Local injection of atropine, hexamethonium and xylocaine induced caudal-migrating phase III in the injected segment only in the digestive state, and simultaneous intra-arterial infusions of L-arginine, an NK-1 antagonist, or 5-hydroxytryptamine (5-HT) 1P and 3 antagonists inhibited the induced phase III. Intravenous atropine and hexamethonium also inhibited xylocaine-induced phase III contractions. Atropine and hexamethonium-induced phase III were brought about by inhibition of neural transmission at nicotinic receptors in the inhibitory pathway to NO neurones. NK-1, 5-HT1P and 5-HT3 receptors are present in the excitatory but not the inhibitory pathway to NO neurones. Xylocaine appears to stop neuronal transmission from mechanoreceptors to NO neurones. Thus, the initiation of spontaneous occurrence of phase III in the digestive jejunum is likely to be brought about by transient cessation of postprandial contractions in a segment of the jejunum.

Infection Prophylaxis and Management in Treating Cytomegalovirus (CMV) Infection in Patients With Hematologic Malignancies Previously Treated With Donor Stem Cell Transplant

ClinicalTrials.gov

2015-06-03

Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenstrom Macroglobulinemia

PandaX-III neutrinoless double beta decay experiment

NASA Astrophysics Data System (ADS)

Wang, Shaobo; PandaX-III Collaboration

2017-09-01

The PandaX-III experiment uses high pressure Time Projection Chambers (TPCs) to search for neutrinoless double-beta decay of Xe-136 with high energy resolution and sensitivity at the China Jin-Ping underground Laboratory II (CJPL-II). Fine-pitch Microbulk Micromegas will be used for charge amplification and readout in order to reconstruct both the energy and track of the neutrinoless double-beta decay event. In the first phase of the experiment, the detector, which contains 200 kg of 90% Xe-136 enriched gas operated at 10 bar, will be immersed in a large water tank to ensure 5 m of water shielding. For the second phase, a ton-scale experiment with multiple TPCs will be constructed to improve the detection probability and sensitivity. A 20-kg scale prototype TPC with 7 Micromegas modules has been built to optimize the design of Micromegas readout module, study the energy calibration of TPC and develop algorithm of 3D track reconstruction.

Invasive Cortical Stimulation to Promote Recovery of Function After Stroke

PubMed Central

Plow, Ela B.; Carey, James R.; Nudo, Randolph J.; Pascual-Leone, Alvaro

2011-01-01

Background and Purpose Residual motor deficits frequently linger after stroke. Search for newer effective strategies to promote functional recovery is ongoing. Brain stimulation, as a means of directing adaptive plasticity, is appealing. Animal studies and Phase I and II trials in humans have indicated safety, feasibility, and efficacy of combining rehabilitation and concurrent invasive cortical stimulation. However, a recent Phase III trial showed no advantage of the combination. We critically review results of various trials and discuss the factors that contributed to the distinctive result. Summary of Review Regarding cortical stimulation, it is important to determine the (1) location of peri-infarct representations by integrating multiple neuroanatomical and physiological techniques; (2) role of other mechanisms of stroke recovery; (3) viability of peri-infarct tissue and descending pathways; (4) lesion geometry to ensure no alteration/displacement of current density; and (5) applicability of lessons generated from noninvasive brain stimulation studies in humans. In terms of combining stimulation with rehabilitation, we should understand (1) the principle of homeostatic plasticity; (2) the effect of ongoing cortical activity and phases of learning; and (3) that subject-specific intervention may be necessary. Conclusions Future cortical stimulation trials should consider the factors that may have contributed to the peculiar results of the Phase III trial and address those in future study designs. PMID:19359643

Quantifying Acoustic Impacts on Marine Mammals and Sea Turtles: Methods and Analytical Approach for Phase III Training and Testing

DTIC Science & Technology

2017-06-16

Acoustic Impacts on Marine Mammals and Sea Turtles: Methods and Analytical Approach for Phase III Training and Testing Sarah A. Blackstock Joseph O...December 2017 4. TITLE AND SUBTITLE Quantifying Acoustic Impacts on Marine Mammals and Sea Turtles: Methods and Analytical Approach for Phase III...Navy’s Phase III Study Areas as described in each Environmental Impact Statement/ Overseas Environmental Impact Statement and describes the methods

SURFACE CHEMKIN-III: A Fortran package for analyzing heterogeneous chemical kinetics at a solid-surface - gas-phase interface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coltrin, M.E.; Kee, R.J.; Rupley, F.M.

1996-05-01

This document is the user`s manual for the SURFACE CHEMKIN-III package. Together with CHEMKIN-III, this software facilitates the formation, solution, and interpretation of problems involving elementary heterogeneous and gas-phase chemical kinetics in the presence of a solid surface. The package consists of two major software components: an Interpreter and a Surface Subroutine Library. The Interpreter is a program that reads a symbolic description of a user-specified chemical reaction mechanism. One output from the Interpreter is a data file that forms a link to the Surface Subroutine Library, which is a collection of about seventy modular Fortran subroutines that may bemore » called from a user`s application code to return information on chemical production rates and thermodynamic properties. This version of SURFACE CHEMKIN-III includes many modifications to allow treatment of multi-fluid plasma systems, for example modeling the reactions of highly energetic ionic species with a surface. Optional rate expressions allow reaction rates to depend upon ion energy rather than a single thermodynamic temperature. In addition, subroutines treat temperature as an array, allowing an application code to define a different temperature for each species. This version of SURFACE CHEMKIN-III allows use of real (non-integer) stoichiometric coefficients; the reaction order with respect to species concentrations can also be specified independent of the reaction`s stoichiometric coefficients. Several different reaction mechanisms can be specified in the Interpreter input file through the new construct of multiple materials.« less

[Clinical patterns and stages of multiple organ failure in the elderly].

PubMed

Wang, S

1990-05-01

Multiple organ failure in the elderly (MOFE) is a new clinical syndrome different from multiple organ failure (MOF) caused by trauma occurring most often in young and mid-aged persons. The authors retrospectively analysed 158 cases of MOFE hospitalized in the past 12 years and commented on its definition, diagnostic criteria, clinical patterns and stages. The suggested definition of MOFE is the sequential 2 or more organs failure within a short period in the elderly patients (greater than or equal to 60 years old) with multiple organ chronic diseases in the presence of aging of organs and age-related malfunction. The most common precipitating factors are pulmonary infections and acute attack of chronic cardiac, cerebral and renal diseases. The interval between failures of various organs is mostly less than 10 days and seldom longer than 1 month. MOFE has 3 different patterns: rapid pattern with single phase; delayed pattern with two phases and recurrent pattern with multiple phase. In the last pattern the patients suffer from multiple attacks of multiple organ failure. It is only seen in MOFE, but not in MOF. The presentation of this particular pattern is related to the following facts: (1). A few organs or only the heart and lungs are involved. (2) Kidney, brain and hemopoietic system etc. usually with poor prognosis are not involved. (3) The age of patients are relatively younger. (4) More resuscitation experiences have been accumulated and better resuscitation measures are available. The clinical course of MOFE can be divided into 3 stages: prefailure stage (stage I), failure compensations stage (stage II) and decompensation stage (stage III).(ABSTRACT TRUNCATED AT 250 WORDS)

Growth of III-V films by control of MBE growth front stoichiometry

NASA Technical Reports Server (NTRS)

Grunthaner, Frank J. (Inventor); Liu, John K. (Inventor); Hancock, Bruce R. (Inventor)

1992-01-01

For the growth of strain-layer materials and high quality single and multiple quantum wells, the instantaneous control of growth front stoichiometry is critical. The process of the invention adjusts the offset or phase of molecular beam epitaxy (MBE) control shutters to program the instantaneous arrival or flux rate of In and As4 reactants to grow InAs. The interrupted growth of first In, then As4, is also a key feature.

A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma.

PubMed

Mahé, M A; Fumoleau, P; Fabbro, M; Guastalla, J P; Faurous, P; Chauvot, P; Chetanoud, L; Classe, J M; Rouanet, P; Chatal, J F

1999-10-01

Standard treatment of advanced ovarian cancer is a combination of surgery and chemotherapy. Additional therapies using the i.p. route are considered as a potential means of improving the locoregional control rate. This Phase II study evaluated the efficacy of i.p. radioimmunotherapy (RIT) in patients with minimal residual ovarian adenocarcinoma after primary treatment with surgery and chemotherapy. Between February 1995 and March 1996, six patients with residual macroscopic (<5 mm) or microscopic disease as demonstrated by laparotomy and multiple biopsies received i.p. RIT. All had initial stage III epithelial carcinoma and were treated with debulking surgery and one line (four patients) or two lines (two patients) of chemotherapy. RIT was performed with 60 mg of OC 125 F(ab')2 monoclonal antibody labeled with 4.44 GBq (120 mCi) of 131I injected 5-10 days after the surgical procedure. Systematic laparoscopy or laparotomy with multiple biopsies performed 3 months after RIT in five patients (clinical progression was seen in one patient) showed no change in three patients and progression in two patients. Toxicity was mainly hematological, with grade III neutropenia and thrombocytopenia in two patients. Human antimouse antibody production was demonstrated in all six patients. This study showed little therapeutic benefit from i.p. RIT in patients with residual ovarian carcinoma.

Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting, 2017.

PubMed

Terpos, Evangelos

2018-05-01

The novel clinical data for myeloma that were presented in the 2017 Annual Meeting of the American Society of Hematology are summarized here. Studies with curative approach (CESAR) or prolonging progression-free survival (CENTAURUS) for patients with high-risk smoldering multiple myeloma (SMM) are described. Updated data from large phase III studies for patients with newly diagnosed MM (NDMM) who are eligible for autologous stem cell transplantation (ASCT) (EMN02, MRC XI) are described, along with the results of studies using novel anti-myeloma drug combinations for induction, consolidation, and maintenance as first-line therapy. The role of minimal residual disease for patients with MM is also discussed. We also present the results of novel phase III studies in patients with NDMM who are not eligible for ASCT (ALCYONE) and new data for their treatment. Recent updates of important studies in the field of relapsed/refractory MM (ASPIRE, POLLUX) along with novel immunotherapy approaches (anti-BCMA monoclonal antibodies, CART cells) are also reported. Finally, levofloxacin prophylaxis reduces febrile episodes and death events in NDMM, whereas 2 doses of high-dose influenza vaccine seem to maintain higher rates of seroprotection compared with those who received standard vaccination. All these data provide the basis for possible changes in the way we manage myeloma in the near future trying to "cure" the disease in many patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical Transformations in Proto-Cytoplasmic Media. Phosphorus Coupling in the Silica Hydrogel Phase

PubMed Central

Gorrell, Ian B.; Henderson, Timothy W.; Albdeery, Kamal; Savage, Philip M.; Kee, Terence P.

2017-01-01

It has been proposed that prebiotic chemical studies on the emergence of primitive life would be most relevant when performed in a hydrogel, rather than an aqueous, environment. In this paper we describe the ambient temperature coupling of phosphorus oxyacids [Pi] mediated by Fe(II) under aerobic conditions within a silica hydrogel (SHG) environment. We have chosen to examine SHGs as they have considerable geological precedence as key phases in silicification en route to rock formation. Following a description of the preparation and characterization studies on our SHG formulations, coupling experiments between Pi species are described across multiple permutations of (i) Pi compound; (ii) gel formulation; (iii) metal salt additive; and (iv) pH-modifying agent. The results suggest that successful Pi coupling, indicated by observation of pyrophosphate [PPi(V)] via 31P-NMR spectroscopy, takes place when the following components are present: (i) a mixture of mixture of Pi(III) and Pi(V) or pure PPi(III– V); (ii) Fe(II); (iii) acetic or formic acid (not hydrochloric acid); (iv) aerobic conditions or the presence of H2O2 as an oxidant; and (v) the presence of a gel system. On the basis of these, and aqueous control reactions, we suggest mechanistic possibilities. PMID:29156594

77 FR 40936 - 60-Day Notice of Proposed Information Collection: Passport Demand Forecasting Study Phase III

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-11

...: Passport Demand Forecasting Study Phase III ACTION: Notice of request for public comments. SUMMARY: The... of 1995. Title of Information Collection: Passport Demand Forecasting Study Phase III. OMB Control... Consular Affairs/Passport Services (CA/PPT) Form Number: SV-2012-0006. Respondents: A national...

Haploidentical Donor Bone Marrow Transplant in Treating Patients With High-Risk Hematologic Cancer

ClinicalTrials.gov

2017-04-10

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hematopoietic/Lymphoid Cancer; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2015-03-05

Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Disease, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma

Quality of reporting of outcomes in phase III studies of pulmonary tuberculosis: a systematic review.

PubMed

Bonnett, Laura Jayne; Ken-Dror, Gie; Davies, Geraint Rhys

2018-02-21

Despite more than 60 years of clinical trials, tuberculosis (TB) still causes a high global burden of mortality and morbidity. Treatment currently requires multiple drugs in combination, taken over a prolonged period. New drugs are needed to shorten treatment duration, prevent resistance and reduce adverse events. However, to improve on current methodology in drug development, a more complete understanding of the existing clinical evidence base is required. A systematic review was undertaken to summarise outcomes reported in phase III trials of patients with newly diagnosed pulmonary TB. A systematic search of databases (PubMed, MEDLINE, EMBASE, CENTRAL and LILACs) was conducted on 30 November 2017 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. Of 248 included studies, 229 considered "on-treatment" outcomes whilst 148 reported "off-treatment" outcomes. There was wide variation and ambiguity in the definition of reported outcomes, including their relationship to treatment and in the time points evaluated. Additional challenges were observed regarding the analysis approach taken (per protocol versus intention to treat) and the varying durations of "intensive" and "continuation" phases of treatment. Bacteriological outcomes were most frequently reported but radiological and clinical data were often included as an implicit or explicit component of the overall definition of outcome. Terminology used to define long-term outcomes in phase III trials is inconsistent, reflecting evolving differences in protocols and practices. For successful future cumulative meta-analysis, the findings of this review suggest that greater availability of individual patient data and the development of a core outcome set would be desirable. In the meantime, we propose a simple and logical approach which should facilitate combination of key evidence and inform improvements in the methodology of TB drug development and clinical trials.

Irreversible multitargeted ErbB family inhibitors for therapy of lung and breast cancer.

PubMed

Subramaniam, Deepa; He, Aiwu Ruth; Hwang, Jimmy; Deeken, John; Pishvaian, Michael; Hartley, Marion L; Marshall, John L

2015-01-01

Overactivation of the ErbB protein family, which is comprised of 4 receptor tyrosine kinase members (ErbB1/epidermal growth factor receptor [EGFR]/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4), can drive the development and progression of a wide variety of malignancies, including colorectal, head and neck, and certain non-small cell lung cancers (NSCLCs). As a result, agents that target a specific member of the ErbB family have been developed for the treatment of cancer. These agents include the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib; the EGFR-targeting monoclonal antibodies cetuximab and panitumumab; and the HER2-targeting monoclonal antibody trastuzumab. Lapatinib is a dual TKI that targets both EGFR and HER2. In addition, TKIs that inhibit multiple members of the ErbB family and also bind their targets irreversibly are under evaluation for the treatment of cancer. Three such compounds have progressed into clinical studies: the EGFR, HER2, and HER4 inhibitors afatinib, dacomitinib, and neratinib. Phase I studies of these agents have shown clinical activity in NSCLC, breast cancer, and other malignancies. Currently, afatinib is approved for EGFR mutation-positive NSCLC and is in development for squamous NSCLC, and dacomitinib is in phase III of clinical development for NSCLC, neratinib is in phase III of clinical development for the treatment of breast cancer, and afatinib is also in phase III development in head and neck cancer. Final results from clinical trials may lead to the potential approval of these agents in a variety of solid tumor malignancies.

Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis.

PubMed

Miller, Aaron E

2015-10-01

The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in ≥2% of patients and ≥2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Oral Disease-Modifying Therapies for Multiple Sclerosis

PubMed Central

Kim, Woojun; Zandoná, Manuella Edler; Kim, Su-Hyun

2015-01-01

Classical multiple sclerosis (MS) treatments using first-line injectable drugs, although widely applied, remain a major concern in terms of therapeutic adherence and efficacy. New oral drugs recently approved for MS treatment represent significant advances in therapy. The oral route of administration clearly promotes patient satisfaction and increases therapeutic compliance. However, these drugs may also have safety and tolerability issues, and a thorough analysis of the risks and benefits is required. Three oral drugs have been approved by regulatory agencies for MS treatment: fingolimod, teriflunomide, and dimethyl fumarate. This article reviews the mechanisms of action, safety, and efficacy of these drugs and two other drugs that have yielded positive results in phase III trials: cladribine and laquinimod. PMID:25628732

Development of Levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis

PubMed Central

Stockmann, Chris; Sherwin, Catherine M.T.; Ampofo, Krow; Spigarelli, Michael G.

2017-01-01

Inhaled therapies allow for the targeted delivery of antimicrobials directly into the lungs and have been widely used in the treatment of cystic fibrosis (CF) acute pulmonary exacerbations. Nebulized levofloxacin solution (MP-376) is a novel therapy that is currently being evaluated in phase I, II, and III clinical trials among patients with stable CF and recent isolation of Pseudomonas aeruginosa from sputum. Phase I studies have investigated the single and multiple-dose pharmacokinetics of MP-376 and shown that it is rapidly absorbed from the lungs and results in low systemic concentrations. A subsequent phase IB study found that MP-376 pharmacokinetics were comparable among adults and children 6–16 years of age. Further phase II studies reported that sputum P. aeruginosa density decreased in a dose-dependent manner among patients who were randomized to MP-376 when compared with patients who received placebo. Improvements in pulmonary function and a decrease in the need for other antipseudomonal antibiotics were also reported for patients who received inhaled levofloxacin. The most common adverse event was dysgeusia (abnormal taste sensation), which was reported by nearly half of the participants who received MP-376. No serious drug-related adverse events were reported. These findings are encouraging; however, data from the two ongoing phase III trials are needed to determine whether MP-376 demonstrates substantial evidence of safety and efficacy as a chronic CF maintenance therapy and therefore may be useful in routine clinical practice. PMID:24334337

Multiple pathways in pressure-induced phase transition of coesite

NASA Astrophysics Data System (ADS)

Liu, Wei; Wu, Xuebang; Liang, Yunfeng; Liu, Changsong; Miranda, Caetano R.; Scandolo, Sandro

2017-12-01

High-pressure single-crystal X-ray diffraction method with precise control of hydrostatic conditions, typically with helium or neon as the pressure-transmitting medium, has significantly changed our view on what happens with low-density silica phases under pressure. Coesite is a prototype material for pressure-induced amorphization. However, it was found to transform into a high-pressure octahedral (HPO) phase, or coesite-II and coesite-III. Given that the pressure is believed to be hydrostatic in two recent experiments, the different transformation pathways are striking. Based on molecular dynamic simulations with an ab initio parameterized potential, we reproduced all of the above experiments in three transformation pathways, including the one leading to an HPO phase. This octahedral phase has an oxygen hcp sublattice featuring 2 × 2 zigzag octahedral edge-sharing chains, however with some broken points (i.e., point defects). It transforms into α-PbO2 phase when it is relaxed under further compression. We show that the HPO phase forms through a continuous rearrangement of the oxygen sublattice toward hcp arrangement. The high-pressure amorphous phases can be described by an fcc and hcp sublattice mixture.

Phenomenology of Polymorphism, III: p, TDiagram and Stability of Piracetam Polymorphs

NASA Astrophysics Data System (ADS)

Céolin, R.; Agafonov, V.; Louër, D.; Dzyabchenko, V. A.; Toscani, S.; Cense, J. M.

1996-02-01

The nootropic drug Piracetam is known to crystallize in three phases. In order to obtain their stability hierarchy from sublimation pressure inequalities, the drawing of a topologicalp,Tdiagram was attempted. For such a purpose and also for quality control, crystallographic and thermodynamic data were required. Powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC) were used. Molecular energy calculations were performed. Phase I melts at 426 K (ΔfusH(I) = +180 J·g-1). Phase II transforms into Phase I at 399 K (Δ(II→I)H= +24 J·g-1). Phase III transforms into phase I at 392 K (Δ(III→I)H= +28 J·g-1) or melts at 412 K (ΔfusH(III) = +210 J·g-1). Thep,Tdiagram shows that phase I is stable at higher temperature and phase II at lower temperature, like phase III, which is stable under high pressure. At room temperature, phase II is the more stable form, and phase I the less stable one. This agrees with the spontaneous I → II transformation observed at 298 K within a few hours, and with lattice energies, calculated previously. Molecular energy calculations and crystal structure comparison show how intermolecular hydrogen bonds and H-bonded dimers, in phases II and III, may stabilize conformations higher in energy than those of the isolated molecule and of phase I.

Security Quality Requirements Engineering (SQUARE): Case Study Phase III

DTIC Science & Technology

2006-05-01

Security Quality Requirements Engineering (SQUARE): Case Study Phase III Lydia Chung Frank Hung Eric Hough Don Ojoko-Adams Advisor...Engineering (SQUARE): Case Study Phase III CMU/SEI-2006-SR-003 Lydia Chung Frank Hung Eric Hough Don Ojoko-Adams Advisor Nancy R. Mead...1 1.1 The SQUARE Process ............................................................................... 1 1.2 Case Study Clients

Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury.

PubMed

Howard, Randy B; Sayeed, Iqbal; Stein, Donald G

2017-06-01

To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.

Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy.

PubMed

de Haas, Sanne; Delmar, Paul; Bansal, Aruna T; Moisse, Matthieu; Miles, David W; Leighl, Natasha; Escudier, Bernard; Van Cutsem, Eric; Carmeliet, Peter; Scherer, Stefan J; Pallaud, Celine; Lambrechts, Diether

2014-10-01

Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified. We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome. The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene. This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.

Sorafenib in Treating Patients With Metastatic or Unresectable Solid Tumors, Multiple Myeloma, or Non-Hodgkin's Lymphoma With or Without Impaired Liver or Kidney Function

ClinicalTrials.gov

2013-01-04

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

PubMed

Vogl, Dan T; Martin, Thomas G; Vij, Ravi; Hari, Parameswaran; Mikhael, Joseph R; Siegel, David; Wu, Ka Lung; Delforge, Michel; Gasparetto, Cristina

2017-08-01

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m 2 . Dose-limiting toxicities (DLTs) at 2.4 mg/m 2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis.

PubMed

Zettl, Uwe K; Rommer, Paulus; Hipp, Petra; Patejdl, Robert

2016-01-01

Spasticity, one of the main symptoms of multiple sclerosis (MS), can affect more than 80% of MS patients during the course of their disease and is often not treated adequately. δ-9-Tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray is a plant-derived, standardized cannabinoid-based oromucosal spray medicine for add-on treatment of moderate to severe, resistant multiple sclerosis-induced spasticity. This article reviews the current evidence for the efficacy and safety, with dizziness and fatigue as the most common treatment-related adverse events, being mostly mild to moderate in severity. Results from both randomized controlled phase III studies involving about,1600 MS patients or 1500 patient-years and recently published studies on everyday clinical practice involving more than 1000 patients or more than,1000 patient-years are presented.

Enhanced Night Visibility Series, Volume XII : Overview of Phase II and Development of Phase III Experimental Plan

DOT National Transportation Integrated Search

2005-12-01

This volume provides an overview of the six studies that compose Phase II of the Enhanced Night Visibility project and the experimental plan for its third and final portion, Phase III. The Phase II studies evaluated up to 12 vision enhancement system...

Lot-to-lot consistency of a tetravalent dengue vaccine in healthy adults in Australia: a randomised study.

PubMed

Torresi, Joseph; Heron, Leon G; Qiao, Ming; Marjason, Joanne; Chambonneau, Laurent; Bouckenooghe, Alain; Boaz, Mark; van der Vliet, Diane; Wallace, Derek; Hutagalung, Yanee; Nissen, Michael D; Richmond, Peter C

2015-09-22

The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV) has undergone extensive clinical trials. Here safety and consistency of immunogenicity of phase III manufacturing lots of CYD-TDV were evaluated and compared with a phase II lot and placebo in a dengue-naïve population. Healthy 18-60 year-olds were randomly assigned in a 3:3:3:3:1 ratio to receive three subcutaneous doses of either CYD-TDV from any one of three phase III lots or a phase II lot, or placebo, respectively in a 0, 6, 12 month dosing schedule. Neutralising antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were compared in sera collected 28 days after the third vaccination-equivalence among lots was demonstrated if the lower and upper limits of the two-sided 95% CIs of the GMT ratio were ≥0.5 and ≤2.0, respectively. 712 participants received vaccine or placebo and 614 (86%) completed the study; 17 (2.4%) participants withdrew after adverse events. Equivalence of phase III lots was demonstrated for 11 of 12 pairwise comparisons. One of three comparisons for serotype 2 was not statistically equivalent. GMTs for serotype 2 in phase III lots were close to each other (65.9, 44.1 and 58.1, respectively). Phase III lots can be produced in a consistent manner with predictable immune response and acceptable safety profile similar to previously characterised phase II lots. The phase III lots may be considered as not clinically different as statistical equivalence was shown for serotypes 1, 3 and 4 across the phase III lots. For serotype 2, although equivalence was not shown between two lots, the GMTs observed in the phase III lots were consistently higher than those for the phase II lot. As such, in our view, biological equivalence for all serotypes was demonstrated. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy.

PubMed

Haussmann, Ursula; Fischer, Joachim; Eber, Stefan; Scherer, Franziska; Seger, Reinhard; Gungor, Tayfun

2006-06-01

Hepatic veno-occlusive disease (VOD) remains a serious complication after hematopoietic stem cell transplantation (HSCT). Based on a protective effect of antithrombin III (ATIII) on endothelial cells, we assessed the incidence of VOD after pre-emptive ATIII replacement and the outcome of VOD after combined high dose defibrotide (DF) and ATIII therapy. This prospective case series comprised two phases. In the first phase 71 children did not receive any specific VOD prophylaxis or therapy (controls). In the second phase 91 children were given pre-emptive ATIII replacement in case of decreased ATIII activity (< or =70%). If VOD was diagnosed clinically (according to modified Seattle criteria), high dose defibrotide (60 mg/day) and ATIII replacement therapy were combined. The severity of VOD was determined according to the degree of multiple organ dysfunction. The incidence of VOD was similar in both groups (13/71, 18% vs. 14/91, 15%). All 14 patients in the second group who developed VOD showed decreased ATIII activity not more than 1 day prior to the clinical diagnosis of VOD. The resulting short duration of pre-emptive ATIII therapy failed to prevent VOD (OR 0.96). None of the patients (n=72) maintaining normal ATIII levels developed VOD. All 14 patients with VOD who received combined therapy achieved complete remission and 93 % (13/14) survived until day +100, compared to six survivors (46%) in the first group. Pre-emptive ATIII administration did not alter the incidence of VOD. Combination treatment with ATIII and defibrotide was safe and yielded excellent remission and survival rates.

Cannabis-based medicines--GW pharmaceuticals: high CBD, high THC, medicinal cannabis--GW pharmaceuticals, THC:CBD.

PubMed

2003-01-01

GW Pharmaceuticals is undertaking a major research programme in the UK to develop and market distinct cannabis-based prescription medicines [THC:CBD, High THC, High CBD] in a range of medical conditions. The cannabis for this programme is grown in a secret location in the UK. It is expected that the product will be marketed in the US in late 2003. GW's cannabis-based products include selected phytocannabinoids from cannabis plants, including D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). The company is investigating their use in three delivery systems, including sublingual spray, sublingual tablet and inhaled (but not smoked) dosage forms. The technology is protected by patent applications. Four different formulations are currently being investigated, including High THC, THC:CBD (narrow ratio), THC:CBD (broad ratio) and High CBD. GW is also developing a specialist security technology that will be incorporated in all its drug delivery systems. This technology allows for the recording and remote monitoring of patient usage to prevent any potential abuse of its cannabis-based medicines. GW plans to enter into agreements with other companies following phase III development, to secure the best commercialisation terms for its cannabis-based medicines. In June 2003, GW announced that exclusive commercialisation rights for the drug in the UK had been licensed to Bayer AG. The drug will be marketed under the Sativex brand name. This agreement also provides Bayer with an option to expand their license to include the European Union and certain world markets. GW was granted a clinical trial exemption certificate by the Medicines Control Agency to conduct clinical studies with cannabis-based medicines in the UK. The exemption includes investigations in the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive cancer, dystonias, cerebral vascular accident and spina bifida, as well as for the relief of pain and inflammation in rheumatoid arthritis and also pain relief in brachial plexus injury. The UK Government stated that it would be willing to amend the Misuse of Drugs Act 1971 to permit the introduction of a cannabis-based medicine. GW stated in its 2002 Annual Report that it was currently conducting five phase III trials of its cannabis derivatives, including a double-blind, placebo-controlled trial with a sublingual spray containing High THC in more than 100 patients with cancer pain in the UK. Also included is a phase III trial of THC:CBD (narrow ratio) being conducted in patients with severe pain due to brachial plexus injury, as are two more phase III trials of THC:CBD (narrow ratio) targeting spasticity and bladder dysfunction in multiple sclerosis patients. Another phase III trial of THC:CBD (narrow ratio) in patients with spinal cord injury is also being conducted. Results from the trials are expected during 2003. Three additional trials are also in the early stages of planning. These trials include a phase I trial of THC:CBD (broad ratio) in patients with inflammatory bowel disease, a phase I trial of High CBD in patients with psychotic disorders such as schizophrenia, and a preclinical trial of High CBD in various CNS disorders (including epilepsy, stroke and head injury). GW Pharmaceuticals submitted an application for approval of cannabis-based medicines to UK regulatory authorities in March 2003. Originally GW hoped to market cannabis-based prescription medicines by 2004, but is now planning for a launch in the UK towards the end of 2003. Several trials for GW's cannabis derivatives have also been completed, including four randomised, double-blind, placebo-controlled phase III clinical trials conducted in the UK. The trials were initiated by GW in April 2002, to investigate the use of a sublingual spray containing THC:CBD (narrow ratio) in the following medical conditions: pain in spinal cord injury, pain and sleep in MS and spinal cord injury, neuropathic pain in MS and general neuropathic pain (presented as allodynia). Results from these trials show that THC:CBD (narrow ratio) caused statistically significant reductions in neuropathic pain in patients with MS and other conditions. In addition, improvements in other MS symptoms were observed as well. Phase II studies of THC:CBD (narrow ratio) have also been completed in patients with MS, spinal cord injury, neuropathic pain and a small number of patients with peripheral neuropathy secondary to diabetes mellitus or AIDS. A phase II trial of THC:CBD (broad ratio) has also been completed in a small number of patients with rheumatoid arthritis, as has a trial of High CBD in patients with neurogenic symptoms. A phase II trial has also been evaluated with High THC in small numbers of patients for the treatment of perioperative pain. The phase II trials provided positive results and confirmed an excellent safety profile for cannabis-based medicines. GW Pharmaceuticals received an IND approval to commence phase II clinical trials in Canada in patients with chronic pain, multiple sclerosis and spinal cord injury in 2002. Following meetings with the US FDA, Drug Enforcement Agency (DEA), the Office for National Drug Control Policy, and National Institute for Drug Abuse, GW was granted an import license from the DEA and has imported its first cannabis extracts into the US. Preclinical research with these extracts in the US is ongoing.

Effects of step-feeding and intermittent aeration on organics and nitrogen removal in a horizontal subsurface flow constructed wetland.

PubMed

Patil, Sagar; Chakraborty, Saswati

2017-03-21

The effect of step feed strategy and intermittent aeration on removal of chemical oxygen demand (COD) and nitrogen was investigated in a laboratory scale horizontal subsurface flow constructed wetland (HSSFCW). Wetland was divided into four zones along the length (zone I to IV), and influent was introduced into first and third zones by step feeding. Continuous study was carried out in four phases. In phases I to III, 30% of influent was bypassed to zone III for denitrification along with organics removal. Intermittent aeration was provided only in zone II at 2.5 L/min for 4 h/day, during phases II, III and IV. In phase I, 87% COD and 43% NH 4 + -N (ammonia-nitrogen) removal were obtained from influents of 331 and 30 mg/L, respectively. In phase II study, external aeration resulted in 97% COD and 71% NH 4 + -N removal in the wetland. In phase IV, 40% of feed was delivered to zone III. Higher supply of organic in zone III resulted in higher denitrification, and total nitrogen removal rate increased to 70% from 56%. In the final effluent, concentration of NO 3 - -N was 9-11 mg/L in phase I to III and decreased to 4 mg/L in phase IV. Batch study showed that COD and NH 4 + -N removal followed first order kinetics in different zones of wetland.

Unraveling the Mystery of the Blue Fog: Structure, Properties, and Applications of Amorphous Blue Phase III.

PubMed

Gandhi, Sahil Sandesh; Chien, Liang-Chy

2017-12-01

The amorphous blue phase III of cholesteric liquid crystals, also known as the "blue fog," are among the rising stars in materials science that can potentially be used to develop next-generation displays with the ability to compete toe-to-toe with disruptive technologies like organic light-emitting diodes. The structure and properties of the practically unobservable blue phase III have eluded scientists for more than a century since it was discovered. This progress report reviews the developments in this field from both fundamental and applied research perspectives. The first part of this progress report gives an overview of the 130-years-long scientific tour-de-force that very recently resulted in the revelation of the mysterious structure of blue phase III. The second part reviews progress made in the past decade in developing electrooptical, optical, and photonic devices based on blue phase III. The strong and weak aspects of the development of these devices are underlined and criticized, respectively. The third- and-final part proposes ideas for further improvement in blue phase III technology to make it feasible for commercialization and widespread use. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The epidemiology of pelvic floor disorders and childbirth: an update

PubMed Central

Hallock, Jennifer L.; Handa, Victoria L.

2015-01-01

SYNOPSIS Using a life span model, this article presents new scientific findings regarding risk factors for pelvic floor disorders (PFDs), with a focus on the role of childbirth in the development of single or multiple co-existing PFDs. Phase I of the life span model includes predisposing factors such as genetic predisposition and race. Phase II of the model includes inciting factors such as obstetric events. Prolapse, urinary incontinence (UI) and fecal incontinence (FI) are more common among vaginally parous women, although the impact of vaginal delivery on risk of FI is less dramatic than for prolapse and UI. Finally, Phase III includes intervening factors such as age and obesity. Both age and obesity are associated with prevalence of PFDs. The prevention and treatment of obesity is an important component to PFD prevention. PMID:26880504

Failures in Phase III: Causes and Consequences.

PubMed

Seruga, Bostjan; Ocana, Alberto; Amir, Eitan; Tannock, Ian F

2015-10-15

Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from early-phase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients. ©2015 American Association for Cancer Research.

Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.

PubMed

Levin, Bruce; Thompson, John L P; Chakraborty, Bibhas; Levy, Gilberto; MacArthur, Robert; Haley, E Clarke

2011-08-01

TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III. (1) To review the trial design and comprehensive type I error rate simulations and (2) to discuss issues raised during regulatory review, to facilitate future approval of similar designs. In phase II, an early (24-h) outcome and adaptive sequential procedure selected one of three tenecteplase doses for phase III comparison with rt-PA. Decision rules comparing this dose to rt-PA would cause stopping for futility at phase II end, or continuation to phase III. Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale. Assuming no early termination, four interim analyses and one final analysis of 1908 patients provided an experiment-wise type I error rate of <0.05. Over 1,000 distribution scenarios, each involving 40,000 replications, the maximum type I error in phase III was 0.038. Inflation from the dose selection was more than offset by the one-half continuity correction in the test statistics. Inflation from repeated interim analyses was more than offset by the reduction from the clinical stopping rules for futility at the first interim analysis. Design complexity and evolving regulatory requirements lengthened the review process. (1) The design was innovative and efficient. Per protocol, type I error was well controlled for the co-primary phase III hypothesis tests, and experiment-wise. (2a) Time must be allowed for communications with regulatory reviewers from first design stages. (2b) Adequate type I error control must be demonstrated. (2c) Greater clarity is needed on (i) whether this includes demonstration of type I error control if the protocol is violated and (ii) whether simulations of type I error control are acceptable. (2d) Regulatory agency concerns that protocols for futility stopping may not be followed may be allayed by submitting interim analysis results to them as these analyses occur.

Enobosarm (GTx-024, S-22): a potential treatment for cachexia.

PubMed

Srinath, Reshmi; Dobs, Adrian

2014-02-01

Muscle loss and wasting occurs with aging and in multiple disease states including cancer, heart failure, chronic obstructive pulmonary disease, end-stage liver disease, end-stage renal disease and HIV. Cachexia is defined as a multifactorial syndrome that is associated with anorexia, weight loss and increased catabolism, with increased morbidity and mortality. Currently no therapy is approved for the treatment or prevention of cachexia. Different treatment options have been suggested but many have proven to be ineffective or associated with adverse events. Nonsteroidal selective androgen receptor modulators (SARMs) are a new class of anabolic agents that bind the androgen receptor and exhibit tissue selectivity. Enobosarm (GTx-024, S-22) is a recently developed SARM, developed by GTx, Inc. (TN, USA), which has been tested in Phase I, II and III trials with promising results in terms of improving lean body mass and measurements of physical function and power. Enobosarm has received fast track designation by the US FDA and results from the Phase III trials POWER1 and POWER2 will help determine approval for use in the prevention and treatment of muscle wasting in patients with non-small-cell lung cancer. This article provides an introduction to enobosarm as a new therapeutic strategy for the prevention and treatment of cachexia. A review of the literature was performed using search terms 'cachexia', 'sarcopenia', 'SARM', 'enobosarm' and 'GTx-024' in September 2013 using multiple databases as well as online resources.

Methods for synthesizing semiconductor quality chalcopyrite crystals for nonlinear optical and radiation detection applications and the like

DOEpatents

Stowe, Ashley; Burger, Arnold

2016-05-10

A method for synthesizing I-III-VI.sub.2 compounds, including: melting a Group III element; adding a Group I element to the melted Group III element at a rate that allows the Group I and Group III elements to react thereby providing a single phase I-III compound; and adding a Group VI element to the single phase I-III compound under heat, with mixing, and/or via vapor transport. The Group III element is melted at a temperature of between about 200 degrees C. and about 700 degrees C. Preferably, the Group I element consists of a neutron absorber and the group III element consists of In or Ga. The Group VI element and the single phase I-III compound are heated to a temperature of between about 700 degrees C. and about 1000 degrees C. Preferably, the Group VI element consists of S, Se, or Te. Optionally, the method also includes doping with a Group IV element activator.

Enantioselective separation of racemic juvenile hormone III by normal-phase high-performance liquid chromatography and preparation of [(2)H(3)]juvenile hormone III as an internal standard for liquid chromatography-mass spectrometry quantification.

PubMed

Ichikawa, Akio; Ono, Hiroshi; Furuta, Kenjiro; Shiotsuki, Takahiro; Shinoda, Tetsuro

2007-08-17

Juvenile hormone III (JH III) racemate was prepared from methyl (2E,6E)-farnesoate via epoxidation with 3-chloroperbenzoic acid (mCPBA). Enantioselective separation of JH III was conducted using normal-phase high-performance liquid chromatography (HPLC) on a chiral stationary phase. [(2)H(3)]Methyl (2E,6E)-farnesoate was also prepared from (2E,6E)-farnesoic acid and [(2)H(4)]methanol (methanol-d(4)) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP); the conjugated double bond underwent isomerization to some degree. Epoxidation of [(2)H(3)]methyl (2E,6E)-farnesoate with mCPBA gave a novel deuterium-substituted internal standard [(2)H(3)]JH III (JH III-d(3)). The standard curve was produced by linear regression using the peak area ratios of JH III and JH III-d(3) in liquid chromatography-mass spectrometry (LC-MS).

Innovations in Clinical Trial Design in the Era of Molecular Profiling.

PubMed

Wulfkuhle, Julia D; Spira, Alexander; Edmiston, Kirsten H; Petricoin, Emanuel F

2017-01-01

Historically, cancer has been studied, and therapeutic agents have been evaluated based on organ site, clinical staging, and histology. The science of molecular profiling has expanded our knowledge of cancer at the cellular and molecular level such that numerous subtypes are being described based on biomarker expression and genetic mutations rather than traditional classifications of the disease. Drug development has experienced a concomitant revolution in response to this knowledge with many new targeted therapeutic agents becoming available, and this has necessitated an evolution in clinical trial design. The traditional, large phase II and phase III adjuvant trial models need to be replaced with smaller, shorter, and more focused trials. These trials need to be more efficient and adaptive in order to quickly assess the efficacy of new agents and develop new companion diagnostics. We are now seeing a substantial shift from the traditional multiphase trial model to an increase in phase II adjuvant and neoadjuvant trials in earlier-stage disease incorporating surrogate endpoints for long-term survival to assess efficacy of therapeutic agents in shorter time frames. New trial designs have emerged with capabilities to assess more efficiently multiple disease types, multiple molecular subtypes, and multiple agents simultaneously, and regulatory agencies have responded by outlining new pathways for accelerated drug approval that can help bring effective targeted therapeutic agents to the clinic more quickly for patients in need.

An emerging treatment option for glaucoma: Rho kinase inhibitors

PubMed Central

Wang, Sean K; Chang, Robert T

2014-01-01

Rho kinase (ROCK) inhibitors are a novel potential class of glaucoma therapeutics with multiple compounds currently in Phase II and III US Food and Drug Administration trials in the United States. These selective agents work by relaxing the trabecular meshwork through inhibition of the actin cytoskeleton contractile tone of smooth muscle. This results in increased aqueous outflow directly through the trabecular meshwork, achieving lower intraocular pressures in a range similar to prostaglandins. There are also animal studies indicating that ROCK inhibitors may improve blood flow to the optic nerve, increase ganglion cell survival, and reduce bleb scarring in glaucoma surgery. Given the multiple beneficial effects for glaucoma patients, ROCK inhibitors are certainly a highly anticipated emerging treatment option for glaucoma. PMID:24872673

Impact of heat-shock protein 90 on cancer metastasis

PubMed Central

Tsutsumi, Shinji; Beebe, Kristin; Neckers, Len

2009-01-01

Cancer metastasis is the result of complex processes, including alteration of cell adhesion/motility in the microenvironment and neoangiogenesis, that are necessary to support cancer growth in tissues distant from the primary tumor. The molecular chaperone heat-shock protein 90 (Hsp90), also termed the ‘cancer chaperone’, plays a crucial role in maintaining the stability and activity of numerous signaling proteins involved in these processes. Small-molecule Hsp90 inhibitors display anticancer activity both in vitro and in vivo, and multiple Phase II and Phase III clinical trials of several structurally distinct Hsp90 inhibitors are currently underway. In this review, we will highlight the importance of Hsp90 in cancer metastasis and the therapeutic potential of Hsp90 inhibitors as antimetastasis drugs. PMID:19519207

Unusual Enhancement of Magnetization by Pressure in the Antiferro-Quadrupole-Ordered Phase in CeB6

NASA Astrophysics Data System (ADS)

Ikeda, Suguru; Sera, Masafumi; Hane, Shingo; Uwatoko, Yoshiya; Kosaka, Masashi; Kunii, Satoru

2007-06-01

The effect of pressure on CeB6 was investigated by the measurement of the magnetization (M) under pressure, and we obtained the following results. The effect of pressure on M in phase I is very small. By applying pressure, TQ is enhanced, but TN and the critical field from the antiferromagnetic (AFM) phase III to the antiferro-quadrupole (AFQ) phase II (HcIII--II) are suppressed, as previously reported. The magnetization curve in phase III shows the characteristic shoulder at H˜ HcIII--II/2 at ambient pressure. This shoulder becomes much more pronounced by applying pressure. Both HcIII--II and the magnetic field, where a shoulder is seen in the magnetization curve in phase III, are largely suppressed by pressure. In phase II, the M-T curve at a low magnetic field exhibits an unusual concave temperature dependence below TQ down to TN. Thus, we found that the lower the magnetic field, the larger the enhancement of M in both phases III and II. To clarify the origin of the unusual pressure effect of M, we performed a mean-field calculation for the 4-sublattice model using the experimental results of dTQ/dP>0 and dTN/dP<0 and assuming the positive pressure dependence of the Txyz-antiferro-octupole (AFO) interaction. The characteristic features of the pressure effect of M obtained by the experiments could be reproduced well by the mean-field calculation. We found that the origin of the characteristic effect of pressure on CeB6 is the change in the subtle balance between the AFM interaction and the magnetic field-induced-effective FM interaction induced by the coexistence of the Oxy-AFQ and Txyz-AFO interactions under pressure.

Pore-scale characterization of biogeochemical controls on iron and uranium speciation under flow conditions.

PubMed

Pearce, Carolyn I; Wilkins, Michael J; Zhang, Changyong; Heald, Steve M; Fredrickson, Jim K; Zachara, John M

2012-08-07

Etched silicon microfluidic pore network models (micromodels) with controlled chemical and redox gradients, mineralogy, and microbiology under continuous flow conditions are used for the incremental development of complex microenvironments that simulate subsurface conditions. We demonstrate the colonization of micromodel pore spaces by an anaerobic Fe(III)-reducing bacterial species (Geobacter sulfurreducens) and the enzymatic reduction of a bioavailable Fe(III) phase within this environment. Using both X-ray microprobe and X-ray absorption spectroscopy, we investigate the combined effects of the precipitated Fe(III) phases and the microbial population on uranium biogeochemistry under flow conditions. Precipitated Fe(III) phases within the micromodel were most effectively reduced in the presence of an electron shuttle (AQDS), and Fe(II) ions adsorbed onto the precipitated mineral surface without inducing any structural change. In the absence of Fe(III), U(VI) was effectively reduced by the microbial population to insoluble U(IV), which was precipitated in discrete regions associated with biomass. In the presence of Fe(III) phases, however, both U(IV) and U(VI) could be detected associated with biomass, suggesting reoxidation of U(IV) by localized Fe(III) phases. These results demonstrate the importance of the spatial localization of biomass and redox active metals, and illustrate the key effects of pore-scale processes on contaminant fate and reactive transport.

Safety and tolerability review of lorcaserin in clinical trials.

PubMed

Greenway, F L; Shanahan, W; Fain, R; Ma, T; Rubino, D

2016-10-01

Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations. © 2016 World Obesity.

Prevalence of multiple organ dysfunction in the pediatric intensive care unit: Pediatric Risk of Mortality III versus Pediatric Logistic Organ Dysfunction scores for mortality prediction

PubMed Central

Hamshary, Azza Abd Elkader El; Sherbini, Seham Awad El; Elgebaly, HebatAllah Fadel; Amin, Samah Abdelkrim

2017-01-01

Objectives To assess the frequency of primary multiple organ failure and the role of sepsis as a causative agent in critically ill pediatric patients; and calculate and evaluate the accuracy of the Pediatric Risk of Mortality III (PRISM III) and Pediatric Logistic Organ Dysfunction (PELOD) scores to predict the outcomes of critically ill children. Methods Retrospective study, which evaluated data from patients admitted from January to December 2011 in the pediatric intensive care unit of the Children's Hospital of the University of Cairo. Results Out of 237 patients in the study, 72% had multiple organ dysfunctions, and 45% had sepsis with multiple organ dysfunctions. The mortality rate in patients with multiple organ dysfunction was 73%. Independent risk factors for death were mechanical ventilation and neurological failure [OR: 36 and 3.3, respectively]. The PRISM III score was more accurate than the PELOD score in predicting death, with a Hosmer-Lemeshow X2 (Chi-square value) of 7.3 (df = 8, p = 0.5). The area under the curve was 0.723 for PRISM III and 0.78 for PELOD. Conclusion A multiple organ dysfunctions was associated with high mortality. Sepsis was the major cause. Pneumonia, diarrhea and central nervous system infections were the major causes of sepsis. PRISM III had a better calibration than the PELOD for prognosis of the patients, despite the high frequency of the multiple organ dysfunction syndrome. PMID:28977260

Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant

ClinicalTrials.gov

2018-05-16

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Isolated Plasmacytoma of Bone; Monoclonal Gammopathy of Undetermined Significance; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Primary Myelofibrosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

Galvanic Liquid Applied Coating Development for Protection of Steel in Concrete

NASA Technical Reports Server (NTRS)

Curran, Joseph John; Curran, Jerry; MacDowell, Louis

2004-01-01

Corrosion of reinforcing steel in concrete is a major problem affecting NASA facilities at Kennedy Space Center (KSC), other government agencies, and the general public. Problems include damage to KSC launch support structures, transportation and marine infrastructures, as well as building structures. A galvanic liquid applied coating was developed at KSC in order to address this problem. The coating is a non-epoxy metal rich ethyl silicate liquid coating. The coating is applied as a liquid from initial stage to final stage. Preliminary data shows that this coating system exceeds the NACE 100 millivolt shift criterion. The remainder of the paper details the development of the coating system through the following phases: Phase I: Development of multiple formulations of the coating to achieve easy application characteristics, predictable galvanic activity, long-term protection, and minimum environmental impact. Phase II: Improvement of the formulations tested in Phase I including optimization of metallic loading as well as incorporation of humectants for continuous activation. Phase III: Application and testing of improved formulations on the test blocks. Phase IV: Incorporation of the final formulation upgrades onto large instrumented structures (slabs).

The motilin receptor agonist erythromycin stimulates hunger and food intake through a cholinergic pathway.

PubMed

Deloose, Eveline; Vos, Rita; Janssen, Pieter; Van den Bergh, Omer; Van Oudenhove, Lukas; Depoortere, Inge; Tack, Jan

2016-03-01

Motilin-induced phase III contractions have been identified as a hunger signal. These phase III contractions occur as part of the migrating motor complex (MMC), a contractility pattern of the gastrointestinal tract during fasting. The mechanism involved in this association between subjective hunger feelings and gastrointestinal motility during the MMC is largely unknown, however, as is its ability to stimulate food intake. We sought to 1) investigate the occurrence of hunger peaks and their relation to phase III contractions, 2) evaluate whether this relation was cholinergically driven, and 3) assess the ability of the motilin receptor agonist erythromycin to induce food intake. An algorithm was developed to detect hunger peaks. The association with phase III contractions was studied in 14 healthy volunteers [50% men; mean ± SEM age: 25 ± 2 y; mean ± SEM body mass index (BMI; in kg/m(2)): 23 ± 1]. The impact of pharmacologically induced phase III contractions on the occurrence of hunger peaks and the involvement of a cholinergic pathway were assessed in 14 healthy volunteers (43% men; age: 29 ± 3 y; BMI: 23 ± 1). Last, the effect of erythromycin administration on food intake was examined in 15 healthy volunteers (40% men; age: 28 ± 3 y; BMI: 22 ± 1). The occurrence of hunger peaks and their significant association with phase III contractions was confirmed (P < 0.0001). Pharmacologically induced phase III contractions were also significantly associated with hunger peaks (P < 0.05), and this association involved a cholinergic pathway. Administering erythromycin significantly stimulated food intake compared with placebo (53% ± 13% compared with 10% ± 5%; P < 0.05). Motilin-induced phase III contractions induced hunger feelings through a cholinergic pathway. Moreover, erythromycin stimulated food intake, suggesting a physiologic role of motilin as an orexigenic signal from the gastrointestinal tract. This trial was registered at www.clinicaltrials.gov as NCT02633579. © 2016 American Society for Nutrition.

Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis

PubMed Central

Zettl, Uwe K.; Rommer, Paulus; Hipp, Petra; Patejdl, Robert

2016-01-01

Spasticity, one of the main symptoms of multiple sclerosis (MS), can affect more than 80% of MS patients during the course of their disease and is often not treated adequately. δ-9-Tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray is a plant-derived, standardized cannabinoid-based oromucosal spray medicine for add-on treatment of moderate to severe, resistant multiple sclerosis-induced spasticity. This article reviews the current evidence for the efficacy and safety, with dizziness and fatigue as the most common treatment-related adverse events, being mostly mild to moderate in severity. Results from both randomized controlled phase III studies involving about,1600 MS patients or 1500 patient-years and recently published studies on everyday clinical practice involving more than 1000 patients or more than,1000 patient-years are presented. PMID:26788128

Monterey-Salinas Transit ITS Augmentation Project : Phase III Evaluation Report

DOT National Transportation Integrated Search

2009-12-01

The purpose of this document is to present the findings from Phase II and Phase III of the Evaluation of the Intelligent Transportation Systems (ITS) Augmentation Project that was implemented at the Monterey-Salinas Transit (MST) in Monterey, Califor...

The Mississippi Catalog of Competencies for Public Elementary and Secondary Physical Education.

ERIC Educational Resources Information Center

Mississippi State Dept. of Education, Jackson.

Phase III of a five-phase project which has implications for the improvement of instructional programs in Mississippi's elementary and secondary schools is described. In phase III, specifically stated objectives or competencies in physical education, designed to accomplish the objectives stated in phase II, are cataloged. The competencies are…

The use of dihexyldithiocarbamate in reverse-phase HPLC of metal chelates

NASA Astrophysics Data System (ADS)

Fatimah, S. S.; Bahti, H. H.; Hastiawan, I.; Permanasari, A.

2018-05-01

Dialkyldithiocarbamates have long been used as chelating agents in reverse-phase HPLC of transition metals. In the previous study, an alkyl homolog of this type of ligand, namely dihexyldithiocarbamate (DHDTC), was synthesized and characterized. The use of this particular ligand in the revese-phase HPLC of some selected transition metal ions is now reported for the first time. The mobile phase comprising of the flow rate and of the detection, in the separation of the metal chelates of Cd (II), Fe (III), Cu (II), and Co (III), were investigated on a C-18 column. The results showed that dihexylditiocarbamate could be used for separating Cd (II), Fe(III), Cu(II), and Co(III). Therefore, it could be used in simultaneous analysis.

A phase II flexible screening design allowing for interim analysis and comparison with historical control.

PubMed

Wu, Wenting; Bot, Brian; Hu, Yan; Geyer, Susan M; Sargent, Daniel J

2013-07-01

Sargent and Goldberg [1] proposed a randomized phase II flexible screening design (SG design) which took multiple characteristics of candidate regimens into consideration in selecting a regimen for further phase III testing. In this paper, we extend the SG design by including provisions for an interim analysis and/or a comparison to a historical control. By including a comparison with a historical control, a modified SG design not only identifies a more promising treatment but also assures that the regimen has a clinically meaningful level of efficacy as compared to a historical control. By including an interim analysis, a modified SG design could reduce the number of patients exposed to inferior treatment regimens. When compared to the original SG design, the modified designs increase the sample size moderately, but expand the utility of the flexible screening design substantially. Copyright © 2013 Elsevier Inc. All rights reserved.

High-temperature deformation and microstructural analysis for silicon nitride-scandium(III) oxide

NASA Technical Reports Server (NTRS)

Cheong, Deock-Soo; Sanders, William A.

1992-01-01

It was indicated that Si3N4 doped with Sc2O3 may exhibit high temperature mechanical properties superior to Si3N4 systems with various other oxide sintered additives. High temperature deformation of samples was studied by characterizing the microstructures before and after deformation. It was found that elements of the additive, such as Sc and O, exist in small amounts at very thin grain boundary layers and most of them stay in secondary phases at tripple and multiple grain boundary junctions. These secondary phases are devitrified as crystalline Sc2Si2O7. Deformation of the samples was dominated by cavitational processes rather than movements of dislocations. Thus the excellent deformation resistance of the samples at high temperature can be attributed to the very small thickness of the grain boundary layers and the crystalline secondary phase.

Multiple pathways in pressure-induced phase transition of coesite

PubMed Central

Liu, Wei; Wu, Xuebang; Liu, Changsong; Miranda, Caetano R.; Scandolo, Sandro

2017-01-01

High-pressure single-crystal X-ray diffraction method with precise control of hydrostatic conditions, typically with helium or neon as the pressure-transmitting medium, has significantly changed our view on what happens with low-density silica phases under pressure. Coesite is a prototype material for pressure-induced amorphization. However, it was found to transform into a high-pressure octahedral (HPO) phase, or coesite-II and coesite-III. Given that the pressure is believed to be hydrostatic in two recent experiments, the different transformation pathways are striking. Based on molecular dynamic simulations with an ab initio parameterized potential, we reproduced all of the above experiments in three transformation pathways, including the one leading to an HPO phase. This octahedral phase has an oxygen hcp sublattice featuring 2 × 2 zigzag octahedral edge-sharing chains, however with some broken points (i.e., point defects). It transforms into α-PbO2 phase when it is relaxed under further compression. We show that the HPO phase forms through a continuous rearrangement of the oxygen sublattice toward hcp arrangement. The high-pressure amorphous phases can be described by an fcc and hcp sublattice mixture. PMID:29162690

Recent trends in 30-day mortality in patients with blunt splenic injury: A nationwide trauma database study in Japan

PubMed Central

Tanaka, Chie; Matsumoto, Hisashi; Matsuda, Kiyoshi; Kim, Shiei; Moroe, Yuta; Fukuda, Reo; Unemoto, Kyoko; Yokota, Hiroyuki

2017-01-01

Background Splenic injury frequently occurs after blunt abdominal trauma; however, limited epidemiological data regarding mortality are available. We aimed to investigate mortality rate trends after blunt splenic injury in Japan. Methods We retrospectively identified 1,721 adults with blunt splenic injury (American Association for the Surgery of Trauma splenic injury scale grades III–V) from the 2004–2014 Japan Trauma Data Bank. We grouped the records of these patients into 3 time phases: phase I (2004–2008), phase II (2009–2012), and phase III (2013–2014). Over the 3 phases, we analysed 30-day mortality rates and investigated their association with the prevalence of certain initial interventions (Mantel-Haenszel trend test). We further performed multiple imputation and multivariable analyses for comparing the characteristics and outcomes of patients who underwent TAE or splenectomy/splenorrhaphy, adjusting for known potential confounders and for within-hospital clustering using generalised estimating equation. Results Over time, there was a significant decrease in 30-day mortality after splenic injury (p < 0.01). Logistic regression analysis revealed that mortality significantly decreased over time (from phase I to phase II, odds ratio: 0.39, 95% confidence interval: 0.22–0.67; from phase I to phase III, odds ratio: 0.34, 95% confidence interval: 0.19–0.62) for the overall cohort. While the 30-day mortality for splenectomy/splenorrhaphy diminished significantly over time (p = 0.01), there were no significant differences regarding mortality for non-operative management, with or without transcatheter arterial embolisation (p = 0.43, p = 0.29, respectively). Conclusions In Japan, in-hospital 30-day mortality rates decreased significantly after splenic injury between 2004 and 2014, even after adjustment for within-hospital clustering and other factors independently associated with mortality. Over time, mortality rates decreased significantly after splenectomy/splenorrhaphy, but not after non-operative management. This information is useful for clinicians when making decisions about treatments for patients with blunt splenic injury. PMID:28910356

Polarized neutron scattering study of the multiple order parameter system NdB 4 [Polarized neutron scattering study on multiple order parameter system NdB 4

DOE Office of Scientific and Technical Information (OSTI.GOV)

Metoki, Naoto; Yamauchi, Hiroki; Matsuda, Masaaki

Neutron polarization analysis has been carried out in order to clarify the magnetic structures of multiple order parameter f-electron system NdB 4. We confirmed the noncollinear “all-in all-out” structure (Γ 4) of the in-plane moment, which is in good agreement with our previous neutron powder diffraction study. We found that the magnetic moment along the c-axis m c showed diagonally antiferromagnetic structure (Γ 10), inconsistent with previously reported “vortex” structure (Γ 2). The microscopic mixture of these two structures with →q 0=(0,0,0) appears in phase II and remains stable in phases III and IV, where an incommensurate modulation coexists. Themore » unusual magnetic ordering is phenomenologically understood via Landau theory with the primary order parameter Γ 4 coupled with higher-order secondary order parameter Γ 10. The magnetic moments were estimated to be 1.8 ± 0.2 and 0.2 ± 0.05μ B at T = 7.5K for Γ 4 and Γ 10, respectively. We also found a long-period incommensurate modulation of the →q 1=(0,0,1/2) antiferromagnetic structure of mc with the propagation →q s1=(0.14,0.14,0.1) and →q s2=(0.2,0,0.1) in phase III and IV, respectively. The amplitude of sinusoidal modulation was about m c=1.0 ± 0.2μ B at T=1.5 K. The local (0,0,1/2) structure consists of in-plane ferromagnetic and out-of-plane antiferromagnetic coupling of m c, opposite to the coexisting Γ 10. The mc of Γ 10 is significantly enhanced up to 0.6μ B at T=1.5 K, which is accompanied by the incommensurate modulations. As a result, the Landau phenomenological approach indicates that the higher-order magnetic and/or multipole interactions based on the pseudoquartet f-electron state play important roles.« less

Polarized neutron scattering study of the multiple order parameter system NdB 4 [Polarized neutron scattering study on multiple order parameter system NdB 4

DOE PAGES

Metoki, Naoto; Yamauchi, Hiroki; Matsuda, Masaaki; ...

2018-05-17

Neutron polarization analysis has been carried out in order to clarify the magnetic structures of multiple order parameter f-electron system NdB 4. We confirmed the noncollinear “all-in all-out” structure (Γ 4) of the in-plane moment, which is in good agreement with our previous neutron powder diffraction study. We found that the magnetic moment along the c-axis m c showed diagonally antiferromagnetic structure (Γ 10), inconsistent with previously reported “vortex” structure (Γ 2). The microscopic mixture of these two structures with →q 0=(0,0,0) appears in phase II and remains stable in phases III and IV, where an incommensurate modulation coexists. Themore » unusual magnetic ordering is phenomenologically understood via Landau theory with the primary order parameter Γ 4 coupled with higher-order secondary order parameter Γ 10. The magnetic moments were estimated to be 1.8 ± 0.2 and 0.2 ± 0.05μ B at T = 7.5K for Γ 4 and Γ 10, respectively. We also found a long-period incommensurate modulation of the →q 1=(0,0,1/2) antiferromagnetic structure of mc with the propagation →q s1=(0.14,0.14,0.1) and →q s2=(0.2,0,0.1) in phase III and IV, respectively. The amplitude of sinusoidal modulation was about m c=1.0 ± 0.2μ B at T=1.5 K. The local (0,0,1/2) structure consists of in-plane ferromagnetic and out-of-plane antiferromagnetic coupling of m c, opposite to the coexisting Γ 10. The mc of Γ 10 is significantly enhanced up to 0.6μ B at T=1.5 K, which is accompanied by the incommensurate modulations. As a result, the Landau phenomenological approach indicates that the higher-order magnetic and/or multipole interactions based on the pseudoquartet f-electron state play important roles.« less

A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).

PubMed

Phillips, Patrick P J; Dooley, Kelly E; Gillespie, Stephen H; Heinrich, Norbert; Stout, Jason E; Nahid, Payam; Diacon, Andreas H; Aarnoutse, Rob E; Kibiki, Gibson S; Boeree, Martin J; Hoelscher, Michael

2016-03-23

The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world's greatest infectious disease killer. We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.

Cloud point extraction: an alternative to traditional liquid-liquid extraction for lanthanides(III) separation.

PubMed

Favre-Réguillon, Alain; Draye, Micheline; Lebuzit, Gérard; Thomas, Sylvie; Foos, Jacques; Cote, Gérard; Guy, Alain

2004-06-17

Cloud point extraction (CPE) was used to extract and separate lanthanum(III) and gadolinium(III) nitrate from an aqueous solution. The methodology used is based on the formation of lanthanide(III)-8-hydroxyquinoline (8-HQ) complexes soluble in a micellar phase of non-ionic surfactant. The lanthanide(III) complexes are then extracted into the surfactant-rich phase at a temperature above the cloud point temperature (CPT). The structure of the non-ionic surfactant, and the chelating agent-metal molar ratio are identified as factors determining the extraction efficiency and selectivity. In an aqueous solution containing equimolar concentrations of La(III) and Gd(III), extraction efficiency for Gd(III) can reach 96% with a Gd(III)/La(III) selectivity higher than 30 using Triton X-114. Under those conditions, a Gd(III) decontamination factor of 50 is obtained.

School Improvement Efforts: Qualitative Data from Four Naturally Occurring Experiments in Phase III of the Louisiana School Effectiveness Study.

ERIC Educational Resources Information Center

Stringfield, Sam; And Others

Phase III of the Louisiana School Effectiveness Study (LSES-III) was designed in part to obtain rich, qualitative data on the characteristics of more and less effective schools in the Gulf South. Data were gathered on eight matched outlier pairs of schools during the 1984-1985 school year. Of the eight historically ineffective schools in LSES-III,…

Fe(II) sorption on pyrophyllite: Effect of structural Fe(III) (impurity) in pyrophyllite on nature of layered double hydroxide (LDH) secondary mineral formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Starcher, Autumn N.; Li, Wei; Kukkadapu, Ravi K.

Fe(II)-Al(III)-LDH (layered double hydroxide) phases have been shown to form from reactions of aqueous Fe(II) with Fe-free Al-bearing minerals (phyllosilicate/clays and Al-oxides). To our knowledge, the effect of small amounts of structural Fe(III) impurities in “neutral” clays on such reactions, however, were not studied. In this study to understand the role of structural Fe(III) impurity in clays, laboratory batch studies with pyrophyllite (10 g/L), an Al-bearing phyllosilicate, containing small amounts of structural Fe(III) impurities and 0.8 mM and 3 mM Fe(II) (both natural and enriched in 57Fe) were carried out at pH 7.5 under anaerobic conditions (4% H2 – 96%more » N2 atmosphere). Samples were taken up to 4 weeks for analysis by Fe-X-ray absorption spectroscopy and 57Fe Mössbauer spectroscopy. In addition to the precipitation of Fe(II)-Al(III)-LDH phases as observed in earlier studies with pure minerals (no Fe(III) impurities in the minerals), the analyses indicated formation of small amounts of Fe(III) containing solid(s), most probably hybrid a Fe(II)-Al(III)/Fe(III)-LDH phase. The mechanism of Fe(II) oxidation was not apparent but most likely was due to interfacial electron transfer from the sorbed Fe(II) to the structural Fe(III) and/or surface-sorption-induced electron-transfer from the sorbed Fe(II) to the clay lattice. Increase in the Fe(II)/Al ratio of the LDH with reaction time further indicated the complex nature of the samples. This research provides evidence for the formation of both Fe(II)-Al(III)-LDH and Fe(II)-Fe(III)/Al(III)-LDH-like phases during reactions of Fe(II) in systems that mimic the natural environments. Better understanding Fe phase formation in complex laboratory studies will improve models of natural redox systems.« less

Methodology of clinical trials evaluating the incorporation of new drugs in the first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review.

PubMed

Iacoboni, G; Zucca, E; Ghielmini, M; Stathis, A

2018-05-01

The first-line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been carried out over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Reports of phase III trials evaluating the addition of molecularly targeted agents or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phases I and II trials which preceded these phase III trials were also reviewed. Among six phase III trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary end point. The other five trials did not show an improved outcome with the addition of the new agent. The preceding phases I and II trials were very heterogeneous in their end points and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase III trials. The standard of care for DLBCL is still R-CHOP. Phase I/II trials failed to predict the results of subsequent phase III trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase II trials evaluating new agents in DLBCL needs to be better defined in the future.

76 FR 52658 - State Program Requirements; Approval of Application for Program Revision to the National...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-23

... (ADEC) in four phases. Phases I-III have been transferred from the EPA to ADEC. In March 2011, ADEC made a submission for approval for a one year extension of the transfer of Phase IV of the APDES program... facilities not previously transferred in Phases I-III. The EPA approved the one year extension for Phase IV...

Pore-Scale Characterization of Biogeochemical Controls on Iron and Uranium Speciation under Flow Conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pearce, Carolyn I.; Wilkins, Michael J.; Zhang, Changyong

2012-09-17

Etched silicon microfluidic pore network models (micromodels) with controlled chemical and redox gradients, mineralogy, and microbiology under continuous flow conditions are used for the incremental development of complex microenvironments that simulate subsurface conditions. We demonstrate the colonization of micromodel pore spaces by an anaerobic Fe(III)-reducing bacterial species (Geobacter sulfurreducens) and the enzymatic reduction of a bioavailable Fe(III) phase within this environment. Using both X-ray Microprobe and X-ray Absorption Spectroscopy, we investigate the combined effects of the precipitated Fe(III) phases and the microbial population on uranium biogeochemistry under flow conditions. Precipitated Fe(III) phases within the micromodel were most effectively reduced inmore » the presence of an electron shuttle (AQDS), and Fe(II) ions adsorbed onto the precipitated mineral surface without inducing any structural change. In the absence of Fe(III), U(VI) was effectively reduced by the microbial population to insoluble U(IV), which was precipitated in discrete regions associated with biomass. In the presence of Fe(III) phases, however, both U(IV) and U(VI) could be detected associated with biomass, suggesting re-oxidation of U(IV) by localized Fe(III) phases. These results demonstrate the importance of the spatial localization of biomass and redox active metals, and illustrate the key effects of pore-scale processes on contaminant fate and reactive transport.« less

Gas phase condensation of superparamagnetic iron oxide-silica nanoparticles - control of the intraparticle phase distribution

NASA Astrophysics Data System (ADS)

Stötzel, C.; Kurland, H.-D.; Grabow, J.; Müller, F. A.

2015-04-01

Spherical, softly agglomerated and superparamagnetic nanoparticles (NPs) consisting of maghemite (γ-Fe2O3) and amorphous silica (SiO2) were prepared by CO2 laser co-vaporization (CoLAVA) of hematite powder (α-Fe2O3) and quartz sand (SiO2). The α-Fe2O3 portion of the homogeneous starting mixtures was gradually increased (15 mass%-95 mass%). It was found that (i) with increasing iron oxide content the NPs' morphology changes from a nanoscale SiO2 matrix with multiple γ-Fe2O3 inclusions to Janus NPs consisting of a γ-Fe2O3 and a SiO2 hemisphere to γ-Fe2O3 NPs each carrying one small SiO2 lens on its surface, (ii) the multiple γ-Fe2O3 inclusions accumulate at the NPs' inner surfaces, and (iii) all composite NPs are covered by a thin layer of amorphous SiO2. These morphological characteristics are attributed to (i) the phase segregation of iron oxide and silica within the condensed Fe2O3-SiO2 droplets, (ii) the temperature gradient within these droplets which arises during rapid cooling in the CoLAVA process, and (iii) the significantly lower surface energy of silica when compared to iron oxide. The proposed growth mechanism of these Fe2O3-SiO2 composite NPs during gas phase condensation can be transferred to other systems comprising a glass-network former and another component that is insoluble in the regarding glass. Thus, our model will facilitate the development of novel functional composite NPs for applications in biomedicine, optics, electronics, or catalysis.Spherical, softly agglomerated and superparamagnetic nanoparticles (NPs) consisting of maghemite (γ-Fe2O3) and amorphous silica (SiO2) were prepared by CO2 laser co-vaporization (CoLAVA) of hematite powder (α-Fe2O3) and quartz sand (SiO2). The α-Fe2O3 portion of the homogeneous starting mixtures was gradually increased (15 mass%-95 mass%). It was found that (i) with increasing iron oxide content the NPs' morphology changes from a nanoscale SiO2 matrix with multiple γ-Fe2O3 inclusions to Janus NPs consisting of a γ-Fe2O3 and a SiO2 hemisphere to γ-Fe2O3 NPs each carrying one small SiO2 lens on its surface, (ii) the multiple γ-Fe2O3 inclusions accumulate at the NPs' inner surfaces, and (iii) all composite NPs are covered by a thin layer of amorphous SiO2. These morphological characteristics are attributed to (i) the phase segregation of iron oxide and silica within the condensed Fe2O3-SiO2 droplets, (ii) the temperature gradient within these droplets which arises during rapid cooling in the CoLAVA process, and (iii) the significantly lower surface energy of silica when compared to iron oxide. The proposed growth mechanism of these Fe2O3-SiO2 composite NPs during gas phase condensation can be transferred to other systems comprising a glass-network former and another component that is insoluble in the regarding glass. Thus, our model will facilitate the development of novel functional composite NPs for applications in biomedicine, optics, electronics, or catalysis. Electronic supplementary information (ESI) available: Infrared absorption of the raw powders hematite and quartz (section S1), TEM investigation of the spatial distribution of the γ-Fe2O3 inclusions (section S2), particle size distributions of the Fe2O3@SiO2 nanopowder samples (section S3), ζ-potentials of aqueous dispersions of all γ-Fe2O3@SiO2 nanopowder samples (section S4), silanization of Fe2O3@SiO2 composite nanopowders with [3-(2,3-epoxypropoxy)-propyl]trimethoxysilane (section S5), and animation composed of TEM micrographs of Fe2O3@SiO2 NPs recorded at incrementally altered tilt angles (``Rotating Fe2O3@SiO2 NP.avi''). See DOI: 10.1039/c5nr00845j

Changing interdigestive migrating motor complex in rats under acute liver injury.

PubMed

Liu, Mei; Zheng, Su-Jun; Xu, Weihong; Zhang, Jianying; Chen, Yu; Duan, Zhongping

2014-01-01

Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC) is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by d-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders.

Effects of Combined Phase III and Phase II Cardiac Exercise Therapy for Middle-aged Male Patients with Acute Myocardial Infarction

PubMed Central

Lee, Chih-Wei; Wang, Ji-Hung; Hsieh, Jen-Che; Hsieh, Tsung-Cheng; Huang, Chien-Hui

2013-01-01

[Purpose] To investigate the effects of cardiac exercise therapy (CET) on exercise capacity and coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Methods] Patients who participated in an 8-week supervised, hospital-based phase II and 6-month home-based phase III CET with monthly telephone and/or home visits were defined as the exercise group (EG) (n=20), while those who did not receive phase II or phase III CET were defined as the no-exercise group (NEG) (n=10). CRFs were evaluated pre- and post-phase II and eight months after discharge. One and two-way repeated measures ANOVA were used to perform intra- and inter-group comparisons. [Results] Thirty men with AMI aged 49.3 ± 8.3 years were studied. EG increased their exercise capacity (METs) (6.8 ± 1.6 vs.10.0 ± 1.9) after phase II CET and was able to maintain it at 8-month follow-up. Both groups had significantly fewer persons who kept on smoking compared to the first examination. High density lipoprotein cholesterol (HDL-C) increased from 38.1 ± 11.0 to 43.7 ± 8.7 mg/dl at follow-up in EG while no significant difference was noted in NEG. [Conclusion] After phase III CET subjects had maintained the therapeutic effects of smoking cessation, and increasing exercise capacity obtained in phase II CET. HDL-C in EG continued to improve during phase III CET. PMID:24396201

Phase III Simplified Integrated Test (SIT) results - Space Station ECLSS testing

NASA Technical Reports Server (NTRS)

Roberts, Barry C.; Carrasquillo, Robyn L.; Dubiel, Melissa Y.; Ogle, Kathryn Y.; Perry, Jay L.; Whitley, Ken M.

1990-01-01

During 1989, phase III testing of Space Station Freedom Environmental Control and Life Support Systems (ECLSS) began at Marshall Space Flight Center (MSFC) with the Simplified Integrated Test. This test, conducted at the MSFC Core Module Integration Facility (CMIF), was the first time the four baseline air revitalization subsystems were integrated together. This paper details the results and lessons learned from the phase III SIT. Future plans for testing at the MSFC CMIF are also discussed.

Review of phase III trial data on IL-23 inhibitors tildrakizumab and guselkumab for psoriasis.

PubMed

Amin, M; Darji, K; No, D J; Wu, J J

2017-10-01

The development of monoclonal antibodies targeting IL-12 and IL-23 has enhanced the therapeutic options available for psoriasis patients. Recent research suggests that IL-23 alone plays a role in the pathogenesis of psoriasis. The objective was to review the phase III clinical trial data for the anti-IL-23 agents to evaluate the safety and efficacy profile of each agent. We reviewed the results of the phase III clinical trials for the anti-IL-23 agents tildrakizumab and guselkumab. The results of phase III trials on risankizumab have not yet been reported. By week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was >60% among the most efficacious dose of each agent. The percentage of patients achieving PASI 90 at week 16 was the primary endpoint for the phase III trials for guselkumab, which was above 70%. The safety profiles of the agents were comparable, with the most commonly reported adverse events of nasopharyngitis and upper respiratory tract infections. The anti-IL-23 agents demonstrated a rapid clinical improvement that is similar or superior to the improvement seen with currently marketed IL-17 inhibitors with a favourable short-term safety profile. The results of the phase III trials support the notion that IL-23 is a potential target in psoriasis treatment. © 2017 European Academy of Dermatology and Venereology.

Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients.

PubMed

Kaneko, Masato; Tanigawa, Takahiko; Hashizume, Kensei; Kajikawa, Mariko; Tajiri, Masahiro; Mueck, Wolfgang

2013-01-01

This study was designed to confirm the appropriateness of the dose setting for a Japanese phase III study of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), which had been based on model simulation employing phase II study data. The previously developed mixed-effects pharmacokinetic/pharmacodynamic (PK-PD) model, which consisted of an oral one-compartment model parameterized in terms of clearance, volume and a first-order absorption rate, was rebuilt and optimized using the data for 597 subjects from the Japanese phase III study, J-ROCKET AF. A mixed-effects modeling technique in NONMEM was used to quantify both unexplained inter-individual variability and inter-occasion variability, which are random effect parameters. The final PK and PK-PD models were evaluated to identify influential covariates. The empirical Bayes estimates of AUC and C(max) from the final PK model were consistent with the simulated results from the Japanese phase II study. There was no clear relationship between individual estimated exposures and safety-related events, and the estimated exposure levels were consistent with the global phase III data. Therefore, it was concluded that the dose selected for the phase III study with Japanese NVAF patients by means of model simulation employing phase II study data had been appropriate from the PK-PD perspective.

Benzocaine polymorphism: pressure-temperature phase diagram involving forms II and III.

PubMed

Gana, Inès; Barrio, Maria; Do, Bernard; Tamarit, Josep-Lluís; Céolin, René; Rietveld, Ivo B

2013-11-18

Understanding the phase behavior of an active pharmaceutical ingredient in a drug formulation is required to avoid the occurrence of sudden phase changes resulting in decrease of bioavailability in a marketed product. Benzocaine is known to possess three crystalline polymorphs, but their stability hierarchy has so far not been determined. A topological method and direct calorimetric measurements under pressure have been used to construct the topological pressure-temperature diagram of the phase relationships between the solid phases II and III, the liquid, and the vapor phase. In the process, the transition temperature between solid phases III and II and its enthalpy change have been determined. Solid phase II, which has the highest melting point, is the more stable phase under ambient conditions in this phase diagram. Surprisingly, solid phase I has not been observed during the study, even though the scarce literature data on its thermal behavior appear to indicate that it might be the most stable one of the three solid phases. Copyright © 2013 Elsevier B.V. All rights reserved.

Studies on the Inhalation Toxicity of Dyes Present in Colored Smoke Munitions. Phase III, Studies: Four-Week Inhalation Exposures of Rats to Dye Aerosols.

DTIC Science & Technology

1984-09-10

0") AD STUDIES ON THE INHALATION TOXICITY CO• OF DYES PRESENT IN COLORED Ln SMOKE MUNIlIONS U FINAL REPORT FOR PHASE III STUDIES : SFOUR- ELK...3 RECIIEPIT’S CATA6.0G NUMBE.• 4. TITLE (and ,ubiltI.e) S. TYPE OF REPORT & PERIOD COygC r., Studies on the Inhalation Toxicity of Dyes Final: Phase...III Present in Colored Smoke Munitions. Final Report Fh for Phase 111 Studies : FoLr-Week Inhalation G. PERFORMING ORO. REPORT N,’,ER Exposures of Rats

Ventilatory inhomogeneity determined from multiple-breath washouts during sustained microgravity on Spacelab SLS-1.

PubMed

Prisk, G K; Guy, H J; Elliott, A R; Paiva, M; West, J B

1995-02-01

We used multiple-breath N2 washouts (MBNW) to study the inhomogeneity of ventilation in four normal humans (mean age 42.5 yr) before, during, and after 9 days of exposure to microgravity on Spacelab Life Sciences-1. Subjects performed 20-breath MBNW at tidal volumes of approximately 700 ml and 12-breath MBNW at tidal volumes of approximately 1,250 ml. Six indexes of ventilatory inhomogeneity were derived from data from 1) distribution of specific ventilation (SV) from mixed-expired and 2) end-tidal N2, 3) change of slope of N2 washout (semilog plot) with time, 4) change of slope of normalized phase III of successive breaths, 5) anatomic dead space, and 6) Bohr dead space. Significant ventilatory inhomogeneity was seen in the standing position at normal gravity (1 G). When we compared standing 1 G with microgravity, the distributions of SV became slightly narrower, but the difference was not significant. Also, there were no significant changes in the change of slope of the N2 washout, change of normalized phase III slopes, or the anatomic and Bohr dead spaces. By contrast, transition from the standing to supine position in 1 G resulted in significantly broader distributions of SV (P < 0.05) and significantly greater changes in the changes in slope of the N2 washouts (P < 0.001), indicating more ventilatory inhomogeneity in that posture. Thus these techniques can detect relatively small changes in ventilatory inhomogeneity. We conclude that the primary determinants of ventilatory inhomogeneity during tidal breathing in the upright posture are not gravitational in origin.

Ventilatory inhomogeneity determined from multiple-breath washouts during sustained microgravity on Spacelab SLS-1

NASA Technical Reports Server (NTRS)

Prisk, G. Kim; Guy, Harold J. B.; Elliott, Ann R.; Paiva, Manuel; West, John B.

1995-01-01

We used multiple-breath N2 washouts (MBNW) to study the homogeneity of ventilation in four normal humans (mean age 42.5 yr) before, during, and after 9 days of exposure to microgravity on Spacelab Life Sciences-1. Subjects performed 20-breath MBNW at tidal volumes of approximately 700 ml and 12-breath MBNW at tidal volumes of approximately 1,250 ml. Six indexes of ventilatory inhomogeneity were derived from data from (1) distribution of specific ventilation (SV) from mixed-expired and (2) end-tidal N2, (3) change of slope of N2 washout (semilog plot) with time, (4) change of slope of normalized phase III of successive breaths, (5) anatomic lead dead space, and (6) Bohr dead space. Significant ventilatory inhomogeneity was seen in the standing position at normal gravity (1 G). When we compared standing 1 G with microgravity, the distributions of SV became slightly narrower, but the difference was not significant. Also, there were no significant changes in the change of slope of the N2 washout, change of normalized phase III slopes, or the anatomic and Bohr dead spaces. By contrast, transition from the standing to supine position in 1 G resulted in significantly broader distributions of SV and significantly greater changes in the changes in slope of the N2 washouts, indicating more ventilatory inhomogeneity in that posture. Thus these techniques can detect relatively small changes in ventilatory inhomogeneity. We conclude that the primary determinants of ventilatory inhomogeneity during tidal breathing in the upright posture are not gravitational in origin.

PLCO Ovarian Phase III Validation Study — EDRN Public Portal

Cancer.gov

Our preliminary data indicate that the performance of CA 125 as a screening test for ovarian cancer can be improved upon by additional biomarkers. With completion of one additional validation step, we will be ready to test the performance of a consensus marker panel in a phase III validation study. Given the original aims of the PLCO trial, we believe that the PLCO represents an ideal longitudinal cohort offering specimens for phase III validation of ovarian cancer biomarkers.

Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2017-12-05

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Waldenström Macroglobulinemia

Preparation of cerium halide solvate complexes

DOEpatents

Vasudevan, Kalyan V; Smith, Nickolaus A; Gordon, John C; McKigney, Edward A; Muenchaussen, Ross E

2013-08-06

Crystals of a solvated cerium(III) halide solvate complex resulted from a process of forming a paste of a cerium(III) halide in an ionic liquid, adding a solvent to the paste, removing any undissolved solid, and then cooling the liquid phase. Diffusing a solvent vapor into the liquid phase also resulted in crystals of a solvated cerium(III) halide complex.

Effect of amoxicillin/clavulanate on gastrointestinal motility in children.

PubMed

Gomez, Roberto; Fernandez, Sergio; Aspirot, Ann; Punati, Jaya; Skaggs, Beth; Mousa, Hayat; Di Lorenzo, Carlo

2012-06-01

The aim of the present study was to evaluate the effect of amoxicillin/clavulanate (A/C) on gastrointestinal motility. Twenty consecutive pediatric patients referred for antroduodenal manometry received 20 mg/kg of A/C into the small bowel lumen. In 10 patients (group A), A/C was given 1 hour after and in 10 (group B), 1 hour before ingestion of a meal. Characteristics of the migrating motor complex, including presence, frequency, amplitude, and propagation of duodenal phase III and phase I duration and phase II motility index (MI), were evaluated 30 minutes before and after A/C administration. There were no statistically significant differences in age and sex between the 2 groups. Manometry studies were considered normal in 8 patients in each group. In group A, 2 patients developed duodenal phase III after receiving A/C, and no significant difference was found in the MI before and after the drug administration. In group B, 9 patients developed duodenal phase III (P <0.05 vs group A). All phase III occurred within a few minutes from the medication administration. Most duodenal phase III contractions were preceded by an antral component during fasting but never after the medication was administered in either of the 2 groups (P<0.001 vs fasting). In group B, the duration of duodenal phase I was shorter after drug administration (P<0.05). There was no significant difference in duodenal phase II MI before and after A/C administration for the 2 study groups. In children, administration of A/C directly into the small bowel before a meal induces phase III-type contractions in the duodenum, with characteristics similar to those present in the fasting state. These data suggest the possible use of A/C as a prokinetic agent. Further studies are needed to clarify its specific mechanism of action and the group of patients most likely to benefit from its use.

Neutron imaging systems utilizing lithium-containing semiconductor crystals

DOEpatents

Stowe, Ashley C.; Burger, Arnold

2017-04-25

A neutron imaging system, including: a plurality of Li-III-VI.sub.2 semiconductor crystals arranged in an array, wherein III represents a Group III element and VI represents a Group VI element; and electronics operable for detecting and a charge in each of the plurality of crystals in the presence of neutrons and for imaging the neutrons. Each of the crystals is formed by: melting the Group III element; adding the Li to the melted Group III element at a rate that allows the Li and Group III element to react, thereby providing a single phase Li-III compound; and adding the Group VI element to the single phase Li-III compound and heating. Optionally, each of the crystals is also formed by doping with a Group IV element activator.

A Roadmap for the Development of Applied Computational Psychiatry.

PubMed

Paulus, Martin P; Huys, Quentin J M; Maia, Tiago V

2016-09-01

Computational psychiatry is a burgeoning field that utilizes mathematical approaches to investigate psychiatric disorders, derive quantitative predictions, and integrate data across multiple levels of description. Computational psychiatry has already led to many new insights into the neurobehavioral mechanisms that underlie several psychiatric disorders, but its usefulness from a clinical standpoint is only now starting to be considered. Examples of computational psychiatry are highlighted, and a phase-based pipeline for the development of clinical computational-psychiatry applications is proposed, similar to the phase-based pipeline used in drug development. It is proposed that each phase has unique endpoints and deliverables, which will be important milestones to move tasks, procedures, computational models, and algorithms from the laboratory to clinical practice. Application of computational approaches should be tested on healthy volunteers in Phase I, transitioned to target populations in Phase IB and Phase IIA, and thoroughly evaluated using randomized clinical trials in Phase IIB and Phase III. Successful completion of these phases should be the basis of determining whether computational models are useful tools for prognosis, diagnosis, or treatment of psychiatric patients. A new type of infrastructure will be necessary to implement the proposed pipeline. This infrastructure should consist of groups of investigators with diverse backgrounds collaborating to make computational psychiatry relevant for the clinic.

75 FR 30385 - Defense Transportation Regulation, Part IV

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-01

... extensions will be considered due to the timelines associated with funding and programming future Phase III... extensions will be considered due to the timelines associated with funding and programming future Phase III...

Characterisation of different polymorphs of tris(8-hydroxyquinolinato)aluminium(III) using solid-state NMR and DFT calculations

PubMed Central

Goswami, Mithun; Nayak, Pabitra K; Periasamy, N; Madhu, PK

2009-01-01

Background Organic light emitting devices (OLED) are becoming important and characterisation of them, in terms of structure, charge distribution, and intermolecular interactions, is important. Tris(8-hydroxyquinolinato)-aluminium(III), known as Alq3, an organomettalic complex has become a reference material of great importance in OLED. It is important to elucidate the structural details of Alq3 in its various isomeric and solvated forms. Solid-state nuclear magnetic resonance (NMR) is a useful tool for this which can also complement the information obtained with X-ray diffraction studies. Results We report here 27Al one-dimensional (1D) and two-dimensional (2D) multiple-quantum magic-angle spinning (MQMAS) NMR studies of the meridional (α-phase) and the facial (δ-phase) isomeric forms of Alq3. Quadrupolar parameters are estimated from the 1D spectra under MAS and anisotropic slices of the 2D spectra and also calculated using DFT (density functional theory) quantum-chemical calculations. We have also studied solvated phase of Alq3 containing ethanol in its lattice. We show that both the XRD patterns and the quadrupolar parameters of the solvated phase are different from both the α-phase and the δ-phase, although the fluorescence emission shows no substantial difference between the α-phase and the solvated phase. Moreover, we have shown that after the removal of ethanol from the matrix the solvated Alq3 has similar XRD patterns and quadrupolar parameters to that of the α-phase. Conclusion The 2D MQMAS experiments have shown that all the different modifications of Alq3 have 27Al in single unique crystallographic site. The quadrupolar parameters predicted using the DFT calculation under the isodensity polarisable continuum model resemble closely the experimentally obtained values. The solvated phase of Alq3 containing ethanol has structural difference from the α-phase of Alq3 (containing meridional isomer) from the solid-state NMR studies. Solid-state NMR can hence be used as an effective complementary tool to XRD for characterisation and structural elucidation. PMID:19900275

Characterisation of different polymorphs of tris(8-hydroxyquinolinato)aluminium(III) using solid-state NMR and DFT calculations.

PubMed

Goswami, Mithun; Nayak, Pabitra K; Periasamy, N; Madhu, P K

2009-11-09

Organic light emitting devices (OLED) are becoming important and characterisation of them, in terms of structure, charge distribution, and intermolecular interactions, is important. Tris(8-hydroxyquinolinato)-aluminium(III), known as Alq3, an organomettalic complex has become a reference material of great importance in OLED. It is important to elucidate the structural details of Alq3 in its various isomeric and solvated forms. Solid-state nuclear magnetic resonance (NMR) is a useful tool for this which can also complement the information obtained with X-ray diffraction studies. We report here 27Al one-dimensional (1D) and two-dimensional (2D) multiple-quantum magic-angle spinning (MQMAS) NMR studies of the meridional (alpha-phase) and the facial (delta-phase) isomeric forms of Alq3. Quadrupolar parameters are estimated from the 1D spectra under MAS and anisotropic slices of the 2D spectra and also calculated using DFT (density functional theory) quantum-chemical calculations. We have also studied solvated phase of Alq3 containing ethanol in its lattice. We show that both the XRD patterns and the quadrupolar parameters of the solvated phase are different from both the alpha-phase and the delta-phase, although the fluorescence emission shows no substantial difference between the alpha-phase and the solvated phase. Moreover, we have shown that after the removal of ethanol from the matrix the solvated Alq3 has similar XRD patterns and quadrupolar parameters to that of the alpha-phase. The 2D MQMAS experiments have shown that all the different modifications of Alq3 have 27Al in single unique crystallographic site. The quadrupolar parameters predicted using the DFT calculation under the isodensity polarisable continuum model resemble closely the experimentally obtained values. The solvated phase of Alq3 containing ethanol has structural difference from the alpha-phase of Alq3 (containing meridional isomer) from the solid-state NMR studies. Solid-state NMR can hence be used as an effective complementary tool to XRD for characterisation and structural elucidation.

Individualized Inservice Teacher Education (Project In-Step). Evaluation Report. Phase III.

ERIC Educational Resources Information Center

Thurber, John C.

This is a report on the third phase of Project IN-STEP, which was intended to develop a viable model for individualized, multi-media in-service teacher education programs. (Phase I and II are reported in ED 033 905, and ED 042 709). The rationale for Phase III was to see if the model could be successfully transferred to an area other than teaching…

Rotator Phases of n-Heptane under High Pressure: Raman Scattering and X-ray Diffraction Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

C Ma; Q Zhou; F Li

2011-12-31

We performed high-pressure Raman scattering and angle-dispersive synchrotron X-ray diffraction measurements on n-heptane at room temperature. It has been found that n-heptane undergoes a liquid to rotator phase III (R{sub III}) transition at 1.2 GPa and then transforms into another rotator phase R{sub IV} at about 3 GPa. As the pressure reaches 7.5 GPa, a transition from an orientationally disordered R{sub IV} phase to an ordered crystalline state starts and is completed around 14.5 GPa. Our results clearly present the high-pressure phase transition sequence (liquid-R{sub III}-R{sub IV}-crystal) of n-heptane, similar to that of normal alkanes.

Phase transformation in the alumina-titania system during flash sintering experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jha, S. K.; Lebrun, J. M.; Raj, R.

2016-02-01

We show that phase transformation in the alumina–titania system, which produces aluminum-titanate, follows an unusual trajectory during flash sintering. The experiments begin with mixed powders of alumina–titania and end in dense microstructures that are transformed into aluminum-titanate. The sintering and the phase transformation are separated in time, with the sintering occurs during Stage II, and phase transformation during Stage III of the flash sintering experiment. Stage III is the steady-state condition of flash activated state that is established under current control, while Stage II is the period of transition from voltage to current control. The extent of phase transformation increasesmore » with the current density and the hold time in Stage III.« less

Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

PubMed Central

Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San

2016-01-01

Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177

Effect of delayed-release dimethyl fumarate on no evidence of disease activity in relapsing-remitting multiple sclerosis: integrated analysis of the phase III DEFINE and CONFIRM studies.

PubMed

Havrdova, E; Giovannoni, G; Gold, R; Fox, R J; Kappos, L; Phillips, J Theodore; Okwuokenye, M; Marantz, J L

2017-05-01

Significant effects on clinical/neuroradiological disease activity have been reported in patients with relapsing-remitting multiple sclerosis treated with delayed-release dimethyl fumarate (DMF) in phase III DEFINE/CONFIRM trials. We conducted a post hoc analysis of integrated data from DEFINE/CONFIRM to evaluate the effect of DMF on achieving no evidence of disease activity (NEDA) in patients with relapsing-remitting multiple sclerosis. The analysis included patients randomized to DMF 240 mg twice daily, placebo or glatiramer acetate (CONFIRM only) for ≤2 years. A time-to-event method was used to estimate the percentage of patients achieving NEDA. Clinical NEDA (no relapses/no 12-week confirmed disability progression) was analysed in the intention-to-treat (ITT) population. Neuroradiological (no new/newly enlarging T2 hyperintense lesions/no gadolinium-enhancing lesions) and overall NEDA (clinical and neuroradiological NEDA) were analysed in the magnetic resonance imaging (MRI) cohort. The ITT and MRI populations comprised 1540 and 692 patients, respectively. The percentage of patients with clinical NEDA (ITT population) and neuroradiological NEDA (MRI cohort) was higher with DMF versus placebo over 2 years [clinical NEDA: 38.9% relative reduction; hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.52-0.72; P < 0.0001; neuroradiological NEDA: 40.0% relative reduction; HR, 0.60; 95% CI, 0.49-0.73; P < 0.0001]. The percentage of patients achieving overall NEDA (MRI cohort) was also higher with DMF (26%) versus placebo (12%) over 2 years, with a relative risk reduction of 42.7% (HR, 0.57; 95% CI, 0.48-0.69; P < 0.0001). A significantly higher percentage of patients treated with DMF achieved NEDA status over 2 years compared with placebo. © 2017 Biogen. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Imprinted magnetic graphene oxide for the mini-solid phase extraction of Eu (III) from coal mine area

NASA Astrophysics Data System (ADS)

Patra, Santanu; Roy, Ekta; Madhuri, Rashmi; Sharma, Prashant K.

2017-05-01

The present work represents the preparation of imprinted magnetic reduced graphene oxide and applied it for the selective removal of Eu (III) from local coal mines area. A simple solid phase extraction method was used for this purpose. The material shows a very high adsorption as well as removal efficiency towards Eu (III), which suggest that the material have potential to be used in future for their real time applications in removal of Eu (III) from complex matrices.

Job Aids: Descriptive Authoring Flowcharts for Phase III--DEVELOP of the Instructional Systems Development Model.

ERIC Educational Resources Information Center

Schulz, Russel E.; Farrell, Jean R.

This resource guide for the use of job aids ("how-to-do-it" guidance) for activities identified in the third phase of the Instructional Systems Development Model (ISD) contains an introduction to the use of job aids, as well as descriptive authoring flowcharts for Blocks III.1 through III.5. The introduction includes definitions;…

Polarized neutron scattering study of the multiple order parameter system NdB4

NASA Astrophysics Data System (ADS)

Metoki, N.; Yamauchi, H.; Matsuda, M.; Fernandez-Baca, J. A.; Watanuki, R.; Hagihala, M.

2018-05-01

Neutron polarization analysis has been carried out in order to clarify the magnetic structures of multiple order parameter f -electron system NdB4. We confirmed the noncollinear "all-in all-out" structure (Γ4) of the in-plane moment, which is in good agreement with our previous neutron powder diffraction study. We found that the magnetic moment along the c -axis mc showed diagonally antiferromagnetic structure (Γ10), inconsistent with previously reported "vortex" structure (Γ2). The microscopic mixture of these two structures with q⃗0=(0 ,0 ,0 ) appears in phase II and remains stable in phases III and IV, where an incommensurate modulation coexists. The unusual magnetic ordering is phenomenologically understood via Landau theory with the primary order parameter Γ4 coupled with higher-order secondary order parameter Γ10. The magnetic moments were estimated to be 1.8 ±0.2 and 0.2 ±0.05 μB at T =7.5 K for Γ4 and Γ10, respectively. We also found a long-period incommensurate modulation of the q⃗1=(0 ,0 ,1 /2 ) antiferromagnetic structure of mc with the propagation q⃗s 1=(0.14 ,0.14 ,0.1 ) and q⃗s 2=(0.2 ,0 ,0.1 ) in phase III and IV, respectively. The amplitude of sinusoidal modulation was about mc=1.0 ±0.2 μB at T =1.5 K. The local (0 ,0 ,1 /2 ) structure consists of in-plane ferromagnetic and out-of-plane antiferromagnetic coupling of mc, opposite to the coexisting Γ10. The mc of Γ10 is significantly enhanced up to 0.6 μB at T =1.5 K, which is accompanied by the incommensurate modulations. The Landau phenomenological approach indicates that the higher-order magnetic and/or multipole interactions based on the pseudoquartet f -electron state play important roles.

Increase of poorly proliferated p63+ /Ki67+ basal cells forming multiple layers in the aberrant remodeled epithelium in nasal polyps.

PubMed

Zhao, L; Li, Y Y; Li, C W; Chao, S S; Liu, J; Nam, H N; Dung, N T N; Shi, L; Wang, D Y

2017-06-01

Aberrant epithelial remodeling with the ectopic expression of p63 (basal cell markers) is an important pathologic phenomenon seen in chronically inflamed airway epithelium such as in nasal polyps (NPs). Biopsies were obtained from 55 NP patients and 18 healthy controls (inferior turbinate). Among NP patients, 15 were treated with oral and nasal steroids, so that two sets of NP biopsies were taken before and after the treatments. p63, Ki67, type IV β-tubulin, and cell cycle markers were investigated in these specimens. The number of p63 + cells is significantly higher in both hyperplastic (1.53-fold, P < 0.0001) and squamous metaplastic (2.02-fold, P < 0.0001) epithelium from NPs than from healthy controls. There are three types of proliferative basal cells (p63 + /Ki67 + ) which are in different phases of the cell cycle, such as G1 phase (type I cells), S to G2 phase (type II cells), and mitosis (type III cells). Of importance, some type I cells may arrest after proliferation although they may still be p63 + /Ki67 + . In healthy epithelium, the ratio of the type I and II cells is almost 50:50. However, less type II cells are found in hyperplastic epithelium (34.85%, P = 0.012) and in squamous metaplastic epithelium (30.77%, P = 0.02) together with the presence of type III cells (3.45%, P = 0.01). These findings were not changed after steroid treatments. An increase of poorly proliferated basal cells forming multiple layers, which may stain for basal cell markers but does not form a proper epidermal barrier, is an important histopathologic phenomenon in aberrant remodeled epithelium of NPs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Development and testing of responder : phase III.

DOT National Transportation Integrated Search

2017-06-28

This report documents the research project Development and Testing of Responder Phase III. Under previous research, a Responder system has been developed to provide relevant and timely information to first responders, allow responders to provid...

Phase III Early Restoration Meeting | NOAA Gulf Spill Restoration

Science.gov Websites

Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News Publications Press Releases Story programmatic approach to early restoration planning for Phase III and future early restoration plans. Open

Phase III Early Restoration Meeting - Corpus Christi, TX | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News programmatic approach to early restoration planning for Phase III and future early restoration plans. Open

Phase III Early Restoration Meeting - Pensacola, FL (rescheduled) | NOAA

Science.gov Websites

Restoration Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News programmatic approach to early restoration planning for Phase III and future early restoration plans. Open

Motivation and participation in a phase III cardiac rehabilitation programme: an application of the health action process approach.

PubMed

Dohnke, Birte; Nowossadeck, Enno; Müller-Fahrnow, Werner

2010-10-01

This longitudinal study extends the previous research on low participation rates and high dropout rates in phase III cardiac rehabilitation (CR) exercise programmes. It examines the correlates of motivation and participation 6 months after inpatient phase II CR (T1) and the predictors of dropout 6 months later (T2) using the health action process approach (HAPA). Risk perception, outcome expectancies, self-efficacy, intention (at T1), and participation (at T1 and T2) in relation to phase III CR programmes was assessed in 456 patients. Based on intention and participation at T1, patients were classified as nonintenders (56%), intenders (13%), or actors (31%). Group differences were confirmed in outcome expectancies and self-efficacy. By T2, 21% of T1 actors had dropped out. Dropouts and maintainers differed in intention and self-efficacy (at T1). Results are in line with the HAPA and suggest a perspective for tailoring motivational counselling to improve participation in phase III CR programmes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, T.; Griffin, A. M.; Gorski, C. A.

Dissimilatory microbial reduction of solid-phase Fe(III)-oxides and Fe(III)-bearing phyllosilicates (Fe(III)-phyllosilicates) is an important process in anoxic soils, sediments, and subsurface materials. Although various studies have documented the relative extent of microbial reduction of single-phase Fe(III)-oxides and Fe(III)-phyllosilicates, detailed information is not available on interaction between these two processes in situations where both phases are available for microbial reduction. The goal of this research was to use the model dissimilatory iron-reducing bacterium (DIRB) Geobacter sulfurreducens to study Fe(III)-oxide vs. Fe(III)-phyllosilicate reduction in a range of subsurface materials and Fe(III)-oxide stripped versions of the materials. Low temperature (12K) Mossbauer spectroscopy was usedmore » to infer changes in the relative abundances of Fe(III)-oxide, Fe(III)-phyllosilicate, and phyllosilicate-associated Fe(II) (Fe(II)-phyllosilicate). A Fe partitioning model was employed to analyze the fate of Fe(II) and assess the potential for abiotic Fe(II)-catalyzed reduction of Fe(III)-phyllosilicates. The results showed that in most cases Fe(III)- oxide utilization dominated (70-100 %) bulk Fe(III) reduction activity, and that electron transfer from oxide-derived Fe(II) played only a minor role (ca. 10-20 %) in Fe partitioning. In addition, the extent of Fe(III)-oxide reduction was positively correlated to surface area-normalized cation exchange capacity and the phyllosilicate-Fe(III)/total Fe(III) ratio, which suggests that the phyllosilicates in the natural sediments promoted Fe(III)-oxide reduction by binding of oxide-derived Fe(II), thereby enhancing Fe(III)-oxide reduction by reducing or delaying the inhibitory effect that Fe(II) accumulation on oxide and DIRB cell surfaces has on Fe(III)-oxide reduction. In general our results suggest that although Fe(III)-oxide reduction is likely to dominate bulk Fe(III) reduction in most subsurface sediments, Fe(II) binding by phyllosilicates is likely to play a key role in controlling the long-term kinetics of Fe(III)-oxide reduction.« less

A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.

PubMed

Biran, Noa; Rowley, Scott D; Vesole, David H; Zhang, Shijia; Donato, Michele L; Richter, Joshua; Skarbnik, Alan P; Pecora, Andrew; Siegel, David S

2016-12-01

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m 2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m 2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Installation Restoration Program. Phase II--Confirmation/Quantification. Stage 1.

DTIC Science & Technology

1985-03-01

four phases. Phase I, Initial Assessment/ Records Search, is designed to identify possible hazardous waste contami- nated sites and potential...7 71 -. - - IL’ -, 1% 33 AihlIII Is 33 n~iL t iiC UII! ii CL C LU 1-3, Phase II, Confirmation and Quantification, is designed to confirm the...additional monitoring data upon which design of mitigative actions are based. In Phase III, Technology Base Development, appropriate technology is selected and

Recent developments in electroabsorption modulators at Acreo Swedish ICT

NASA Astrophysics Data System (ADS)

Wang, Qin; Zhang, Andy Z.; Almqvist, Susanne; Junique, Stephane; Noharet, Bertrand; Platt, Duncan; Salter, Michael; Andersson, Jan Y.

2015-03-01

Three types of electroabsorption modulators (EAMs) based on III-V semiconductor multiple quantum wells (MQW) are presented in this work. One is a novel monolithic integration traveling-wave EAM for an analog optical transmitter/transceiver to achieve integrated photonic mm-wave functions for broadband connectivity. Another one is composed of an integrated EAM 1D array in a photonic beam-former as a Ku-band phased array antenna for seamless aeronautical networking through integration of data links, radios, and antennas. The third one addresses the use of MQW EAMs in free space optical links through biological tissue for transcutaneous communication.

Electronic monitoring and voice prompts improve hand hygiene and decrease nosocomial infections in an intermediate care unit.

PubMed

Swoboda, Sandra M; Earsing, Karen; Strauss, Kevin; Lane, Stephen; Lipsett, Pamela A

2004-02-01

To determine whether electronic monitoring of hand hygiene and voice prompts can improve hand hygiene and decrease nosocomial infection rates in a surgical intermediate care unit. Three-phase quasi-experimental design. Phase I was electronic monitoring and direct observation; phase II was electronic monitoring and computerized voice prompts for failure to perform hand hygiene on room exit; and phase III was electronic monitoring only. Nine-room, 14-bed intermediate care unit in a university, tertiary-care institution. All patient rooms, utility room, and staff lavatory were monitored electronically. All healthcare personnel including physicians, nurses, nursing support personnel, ancillary staff, all visitors and family members, and any other personnel interacting with patients on the intermediate care unit. All patients with an intermediate care unit length of stay >48 hrs were followed for nosocomial infection. Electronic monitoring during all phases, computerized voice prompts during phase II only. We evaluated a total of 283,488 electronically monitored entries into a patient room with 251,526 exits for 420 days (10,080 hrs and 3,549 patient days). Compared with phase I, hand hygiene compliance in patient rooms improved 37% during phase II (odds ratio, 1.38; 95% confidence interval, 1.04-1.83) and 41% in phase III (odds ratio, 1.41; 95% confidence interval, 1.07-1.84). When adjusting for patient admissions during each phase, point estimates of nosocomial infections decreased by 22% during phase II and 48% during phase III; when adjusting for patient days, the number of infections decreased by 10% during phase II and 40% during phase III. Although the overall rate of nosocomial infections significantly decreased when combining phases II and III, the association between nosocomial infection and individual phase was not significant. Electronic monitoring provided effective ongoing feedback about hand hygiene compliance. During both the voice prompt phase and post-intervention phase, hand hygiene compliance and nosocomial infection rates improved suggesting that ongoing monitoring and feedback had both a short-term and, perhaps, a longer-term effect.

Heat capacities of quasi-two-dimensional hetero-spin honeycomb magnets {NBu4[CuIICrIII(ox)3]}n and {PPh4[MnIICrIII(ox)3]}n (Bu=n-butyl, Ph=phenyl, H2ox=oxalic acid): High-temperature series expansion analysis

NASA Astrophysics Data System (ADS)

Hashiguchi, Takao; Miyazaki, Yuji; Asano, Kaori; Nakano, Motohiro; Sorai, Michio; Tamaki, Hiroko; Matsumoto, Naohide; Ōkawa, Hisashi

2003-10-01

Heat capacities of two metal-assembled complexes {NBu4[CuIICrIII(ox)3]}n and {PPh4[MnIICrIII(ox)3]}n (Bu=n-butyl, Ph=phenyl, H2ox=oxalic acid) were measured by adiabatic calorimetry in the 0.5-300 K temperature range. A ferromagnetic phase transition was detected at Tc=6.98 K for {NBu4[CuCr(ox)3]}n and Tc=5.59 K for {PPh4[MnCr(ox)3]}n, above which a remarkable heat capacity tail suggesting the short-range order effects was observed. Furthermore, a lambda-type heat-capacity anomaly due to a structural phase transition was found at Ttrs=226.9 K for {NBu4[CuCr(ox)3]}n and at Ttrs=71.3 K for {PPh4[MnCr(ox)3]}n. The observed entropy gains due to the magnetic phase transitions are very close to the theoretical values, R ln(2×4) for {NBu4[CuCr(ox)3]}n and R ln(6×4) for {PPh4[MnCr(ox)3]}n, expected from the spin multiplicities (CuII, s=1/2; MnII, s=5/2; CrIII, s=3/2). Since this series of metal oxalato assemblies can crystallize in either 2D honeycomb or 3D helical hetero-spin lattices, the theoretical magnetic heat capacities for both lattices were calculated by the high-temperature series expansion up to seventh cumulant to compare with their experimental magnetic heat capacities. The magnetic heat capacities above Tc were reproduced well by the theoretical ones for the 2D honeycomb lattice rather than the 3D helical lattice. The intralayer exchange interaction was estimated to be J/kB=5.0 K for {NBu4[CuCr(ox)3]}n and J/kB=0.95 K for {PPh4[MnCr(ox)3]}n. The analyses based on spin wave theory revealed that both compounds bring about dimensional crossovers into 3D ferromagnetic orders below Tc through the weak interlayer interactions.

The Compact Environmental Anomaly Sensor (CEASE) III

NASA Astrophysics Data System (ADS)

Roddy, P.; Hilmer, R. V.; Ballenthin, J.; Lindstrom, C. D.; Barton, D. A.; Ignazio, J. M.; Coombs, J. M.; Johnston, W. R.; Wheelock, A. T.; Quigley, S.

2016-12-01

The Air Force Research Laboratory's Energetic Charged Particle (ECP) sensor project is a comprehensive effort to measure the charged particle environment that causes satellite anomalies. The project includes the Compact Environmental Anomaly Sensor (CEASE) III, building on the flight heritage of prior CEASE designs. CEASE III consists of multiple sensor modules. High energy particles are observed using independent unique silicon detector stacks. In addition CEASE III includes an electrostatic analyzer (ESA) assembly which uses charge multiplication for particle detection. The sensors cover a wide range of proton and electron energies that contribute to satellite anomalies.

Raman spectroscopic study of calcite III to aragonite transformation under high pressure and high temperature

NASA Astrophysics Data System (ADS)

Liu, Chuanjiang; Zheng, Haifei; Wang, Duojun

2017-10-01

In our study, a series of Raman experiments on the phase transition of calcite at high pressure and high temperature were investigated using a hydrothermal diamond anvil cell and Raman spectroscopy technique. It was found that calcite I transformed to calcite II and calcite III at pressures of 1.62 and 2.12 GPa and room temperature. With increasing temperature, the phase transition of calcite III to aragonite occurred. Aragonite was retained upon slowly cooling of the system, indicating that the transition of calcite III to aragonite was irreversible. Based on the available data, the phase boundary between calcite III and aragonite was determined by the following relation: P(GPa) = 0.013 × T(°C) + 1.22 (100°C ≤ T ≤ 170°C). It showed that the transition pressure linearly rose with increasing temperature. A better understanding of the stability of calcite III and aragonite is of great importance to further explore the thermodynamic behavior of carbonates and carbon cycling in the mantle.

Trends in heteroepitaxy of III-Vs on silicon for photonic and photovoltaic applications

NASA Astrophysics Data System (ADS)

Lourdudoss, Sebastian; Junesand, Carl; Kataria, Himanshu; Metaferia, Wondwosen; Omanakuttan, Giriprasanth; Sun, Yan-Ting; Wang, Zhechao; Olsson, Fredrik

2017-02-01

We present and compare the existing methods of heteroepitaxy of III-Vs on silicon and their trends. We focus on the epitaxial lateral overgrowth (ELOG) method as a means of achieving good quality III-Vs on silicon. Initially conducted primarily by near-equilibrium epitaxial methods such as liquid phase epitaxy and hydride vapour phase epitaxy, nowadays ELOG is being carried out even by non-equilibrium methods such as metal organic vapour phase epitaxy. In the ELOG method, the intermediate defective seed and the mask layers still exist between the laterally grown purer III-V layer and silicon. In a modified ELOG method called corrugated epitaxial lateral overgrowth (CELOG) method, it is possible to obtain direct interface between the III-V layer and silicon. In this presentation we exemplify some recent results obtained by these techniques. We assess the potentials of these methods along with the other existing methods for realizing truly monolithic photonic integration on silicon and III-V/Si heterojunction solar cells.

Phase III Early Restoration Meeting - Lake Charles, LA | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News early restoration planning for Phase III and future early restoration plans. Open House: 5:30pm Public

Extraction equilibrium of indium(III) from nitric acid solutions by di(2-ethylhexyl)phosphoric acid dissolved in kerosene.

PubMed

Tsai, Hung-Sheng; Tsai, Teh-Hua

2012-01-04

The extraction equilibrium of indium(III) from a nitric acid solution using di(2-ethylhexyl) phosphoric acid (D2EHPA) as an acidic extractant of organophosphorus compounds dissolved in kerosene was studied. By graphical and numerical analysis, the compositions of indium-D2EHPA complexes in organic phase and stoichiometry of the extraction reaction were examined. Nitric acid solutions with various indium concentrations at 25 °C were used to obtain the equilibrium constant of InR₃ in the organic phase. The experimental results showed that the extraction distribution ratios of indium(III) between the organic phase and the aqueous solution increased when either the pH value of the aqueous solution and/or the concentration of the organic phase extractant increased. Finally, the recovery efficiency of indium(III) in nitric acid was measured.

Influence of Al(III) on biofilm and its extracellular polymeric substances in sequencing batch biofilm reactors.

PubMed

Hu, Xuewei; Yang, Lei; Lai, Xinke; Yao, Qi; Chen, Kai

2017-10-03

This paper presented the influence of Al(III) on biodegradability, micromorphology, composition and functional groups characteristics of the biofilm extracellular polymeric substances (EPS) during different growth phases. The sequencing batch biofilm reactors were developed to cultivate biofilms under different Al(III) dosages. The results elucidated that Al(III) affected biofilm development adversely at the beginning of biofilm growth, but promoted the biofilm mass and improved the biofilm activity with the growth of the biofilm. The micromorphological observation indicated that Al(III) led to a reduction of the filaments and promotion of the EPS secretion in growth phases of the biofilm, also Al(III) could promote microorganisms to form larger colonies for mature biofilm. Then, the analysis of EPS contents and components suggested that Al(III) could increase the protein (PN) of tightly bound EPS (TB-EPS) which alleviated the metal toxicity inhibition on the biofilm during the initial phases of biofilm growth. The biofilm could gradually adapt to the inhibition caused by Al(III) at the biofilm maturation moment. Finally, through the Fourier transform infrared spectroscopy, it was found that Al(III) was beneficial for the proliferation and secretion of TB-EPS functional groups, especially the functional groups of protein and polysaccharides.

40 CFR 63.163 - Standards: Pumps in light liquid service.

Code of Federal Regulations, 2013 CFR

2013-07-01

... later than 1 year after the compliance date; and (C) Phase III, beginning no later than 21/2 years after... requirements; and (B) Beginning no later than 1 year after initial start-up, comply with the Phase III... parts per million or greater. (ii) For Phase II, an instrument reading of 5,000 parts per million or...

40 CFR 63.163 - Standards: Pumps in light liquid service.

Code of Federal Regulations, 2012 CFR

2012-07-01

... later than 1 year after the compliance date; and (C) Phase III, beginning no later than 21/2 years after... requirements; and (B) Beginning no later than 1 year after initial start-up, comply with the Phase III... parts per million or greater. (ii) For Phase II, an instrument reading of 5,000 parts per million or...

40 CFR 63.163 - Standards: Pumps in light liquid service.

Code of Federal Regulations, 2014 CFR

2014-07-01

... later than 1 year after the compliance date; and (C) Phase III, beginning no later than 21/2 years after... requirements; and (B) Beginning no later than 1 year after initial start-up, comply with the Phase III... parts per million or greater. (ii) For Phase II, an instrument reading of 5,000 parts per million or...

Phase II and III Clinical Studies of Diphtheria-Tetanus-Acellular Pertussis Vaccine Containing Inactivated Polio Vaccine Derived from Sabin Strains (DTaP-sIPV).

PubMed

Okada, Kenji; Miyazaki, Chiaki; Kino, Yoichiro; Ozaki, Takao; Hirose, Mizuo; Ueda, Kohji

2013-07-15

Phase II and III clinical studies were conducted to evaluate immunogenicity and safety of a novel DTaP-IPV vaccine consisting of Sabin inactivated poliovirus vaccine (sIPV) and diphtheria-tetanus-acellular pertussis vaccine (DTaP). A Phase II study was conducted in 104 healthy infants using Formulation H of the DTaP-sIPV vaccine containing high-dose sIPV (3, 100, and 100 D-antigen units for types 1, 2, and 3, respectively), and Formulations M and L, containing half and one-fourth of the sIPV in Formulation H, respectively. Each formulation was administered 3 times for primary immunization and once for booster immunization. A Phase III study was conducted in 342 healthy infants who received either Formulation M + oral polio vaccine (OPV) placebo or DTaP + OPV. The OPV or OPV placebo was orally administered twice between primary and booster immunizations. Formulation M was selected as the optimum dose. In the Phase III study, the seropositive rate was 100% for all Sabin strains after primary immunization, and the neutralizing antibody titer after booster immunization was higher than in the control group (DTaP + OPV). All adverse reactions were clinically acceptable. DTaP-sIPV was shown to be a safe and immunogenic vaccine. JapicCTI-121902 for Phase II study, JapicCTI-101075 for Phase III study (http://www.clinicaltrials.jp/user/cte_main.jsp).

Structures and phase transitions in a new ferroelectric -- pyridinium chlorochromate -- studied by X-ray diffraction, DSC and dielectric methods.

PubMed

Małuszyńska, Hanna; Czarnecki, Piotr; Czarnecka, Anna; Pająk, Zdzisław

2012-04-01

Pyridinium chlorochromate, [C(5)H(5)NH](+)[ClCrO(3)](-) (hereafter referred to as PyClCrO(3)), was studied by X-ray diffraction, differential scanning calorimetry (DSC) and dielectric methods. Studies reveal three reversible phase transitions at 346, 316 and 170 K with the following phase sequence: R ̅3m (I) → R3m (II) → Cm (III) → Cc (IV), c' = 2c. PyClCrO(3) is the first pyridinium salt in which all four phases have been successfully characterized by a single-crystal X-ray diffraction method. Structural results together with dielectric and calorimetric studies allow the classification of the two intermediate phases (II) and (III) as ferroelectric with the Curie point at 346 K, and the lowest phase (IV) as most probably ferroelectric. The ferroelectric hysteresis loop was observed only in phase (III). The high ionic conductivity hindered its observation in phase (II).

Effect of weak magnetic field on arsenate and arsenite removal from water by zerovalent iron: an XAFS investigation.

PubMed

Sun, Yuankui; Guan, Xiaohong; Wang, Jianmin; Meng, Xiaoguang; Xu, Chunhua; Zhou, Gongming

2014-06-17

In this study, a weak magnetic field (WMF), superimposed with a permanent magnet, was utilized to improve ZVI corrosion and thereby enhance As(V)/As(III) removal by ZVI at pHini 3.0-9.0. The experiment with real arsenic-bearing groundwater revealed that WMF could greatly improve arsenic removal by ZVI even in the presence of various cations and anions. The WMF-induced improvement in As(V)/As(III) removal by ZVI should be primarily associated with accelerated ZVI corrosion, as evidenced by the pH variation, Fe(2+) release, and the formation of corrosion products as characterized with X-ray absorption fine structure spectroscopy. The arsenic species analysis in solution/solid phases at pHini 3.0 revealed that As(III) oxidation to As(V) in aqueous phase preceded its subsequent sequestration by the newly formed iron (hydr)oxides. However, both As(V) adsorption following As(III) oxidation to As(V) in solution and As(III) adsorption preceding its conversion to As(V) in solid phase were observed at pHini 5.0-9.0. The application of WMF accelerated the transformation of As(III) to As(V) in both aqueous and solid phases at pHini 5.0-9.0 and enhanced the oxidation of As(III) to As(V) in solution at pHini 3.0.

The Systems Approach to Functional Job Analysis. Task Analysis of the Physician's Assistant: Volume II--Curriculum and Phase I Basic Core Courses and Volume III--Phases II and III--Clinical Clerkships and Assignments.

ERIC Educational Resources Information Center

Wake Forest Univ., Winston Salem, NC. Bowman Gray School of Medicine.

This publication contains a curriculum developed through functional job analyses for a 24-month physician's assistant training program. Phase 1 of the 3-phase program is a 6-month basic course program in clinical and bioscience principles and is required of all students regardless of their specialty interest. Phase 2 is a 6 to 10 month period of…

[Monoclonal antibodies for the treatment of multiple sclerosis].

PubMed

Sánchez-Seco, Victoria Galán; Casanova Peño, Ignacio; Arroyo González, Rafael

2014-12-01

Until the mid 1990s, with the appearance of interferon beta and glatiramer acetate, there was no treatment for multiple sclerosis (MS). However, due to their moderate therapeutic potential in some patients, a broad search was continued to find new and more effective treatment strategies, largely concentrated on monoclonal antibodies (MOAB). Natalizumab, the first MOAB for the treatment of MS, was approved at the end of 2004, representing a major advance in the field of neuroimmunology. Today, there is broad experience with natalizumab and other MOAB (alemtuzumab, daclizumab, rituximab, ocrelizumab, ofatumumab and anti-lingo-1) that are pending commercialization or are under phase II or III of development with promising results. The present review analyzes the efficacy and safety results of all these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Chattanooga SmartBus Project : phase III evaluation report

DOT National Transportation Integrated Search

2009-12-01

This report presents the results of Phase III of the national evaluation of the Chattanooga Area Regional Transportation Authoritys (CARTA) SmartBus Project. The SmartBus Project is a comprehensive transit ITS program for the city of Chattanooga, ...

Phase III Early Restoration Meeting - Galveston, TX | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News planning for Phase III and future early restoration plans. Open House: 6:00pm Public Meeting: 6:30pm

Phase III Early Restoration Meeting - Port Arthur, TX | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News planning for Phase III and future early restoration plans. Open House: 6:00pm Public Meeting: 6:30pm

Phase III Early Restoration Meeting - Panama City, FL | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News planning for Phase III and future early restoration plans. Open House: 6:00pm Public Meeting: 6:30pm

Type III Neuregulin 1 Is Required for Multiple Forms of Excitatory Synaptic Plasticity of Mouse Cortico-Amygdala Circuits

PubMed Central

Emmetsberger, Jaime; Talmage, David A.; Role, Lorna W.

2013-01-01

The amygdala plays an important role in the formation and storage of memories associated with emotional events. The cortical glutamatergic inputs onto pyramidal neurons in the basolateral nucleus of the amygdala (BLA) contribute to this process. As the interaction between neuregulin 1 (Nrg1) and its ErbB receptors has been implicated in the pathological mechanisms of schizophrenia, loss of Nrg1 may disrupt cortical–amygdala neural circuits, resulting in altered processing of salient memories. Here we show that Nrg1 is critical in multiple forms of plasticity of cortical projections to pyramidal neurons of the BLA. The miniature EPSCs in Nrg1 heterozygous animals have a faster time constant of decay and evoked synaptic currents have a smaller NMDA/AMPA ratio than those recorded in wild-type (WT) littermates. Both high-frequency electrical stimulation of cortical inputs and θ burst stimulation combined with nicotine exposure results in long-lasting potentiation in WT animals. However, the same manipulations have little to no effect on glutamatergic synaptic plasticity in the BLA from Nrg1 heterozygous mice. Comparison of WT, Nrg1 heterozygous animals and α7 nicotinic receptor heterozygous mice reveals that the sustained phase of potentiation of glutamatergic transmission after θ burst stimulation with or without nicotine only occurs in the WT mice. Together, these findings support the idea that type III Nrg1 is essential to multiple aspects of the modulation of excitatory plasticity at cortical–BLA synapses. PMID:23739962

Effective properties of a fly ash geopolymer: Synergistic application of X-ray synchrotron tomography, nanoindentation, and homogenization models

DOE PAGES

Das, Sumanta; Yang, Pu; Singh, Sudhanshu S.; ...

2015-09-02

Microstructural and micromechanical investigation of a fly ash-based geopolymer using: (i) synchrotron x-ray tomography (XRT) to determine the volume fraction and tortuosity of pores that are influential in fluid transport, (ii) mercury intrusion porosimetry (MIP) to capture the volume fraction of smaller pores, (iii) scanning electron microscopy (SEM) combined with multi-label thresholding to identify and characterize the solid phases in the microstructure, and (iv) nanoindentation to determine the component phase elastic properties using statistical deconvolution, is reported in this paper. The phase volume fractions and elastic properties are used in multi-step mean field homogenization (Mori- Tanaka and double inclusion) modelsmore » to determine the homogenized macroscale elastic modulus of the composite. The homogenized elastic moduli are in good agreement with the flexural elastic modulus determined on macroscale paste beams. As a result, the combined use of microstructural and micromechanical characterization tools at multiple scales provides valuable information towards the material design of fly ash geopolymers.« less

Palbociclib: A new hope in the treatment of breast cancer.

PubMed

Palanisamy, R Priyadharsini

2016-01-01

Breast cancer being one of the common cancers has high morbidity and mortality. Despite the conventional treatment, the burden of the disease increases year after year. There is a need for newer drugs that target the different mechanisms in the pathogenesis. The interaction of cyclins with cyclin dependent kinases (CDKs) plays a major role in the abnormal cell cycle in cancer and it is considered to be an important target. Palbociclib is a CDK inhibitor currently approved for the treatment of breast cancer. The preclinical studies with breast cancer lines were sensitive to palbociclib and the clinical trials phase I, phase II (PALOMA 1), and phase III (PALOMA 2, 3, PENTELOPE, PEARL) showed that the drug was efficacious when combined other conventional drugs for breast cancer. Palbociclib was also been tested in various other germ cell tumors, melanoma, multiple myeloma, glioblastoma multiforme etc., The major adverse effect of the drug includes hematological toxicity mainly neutropenia, gastrointestinal adverse effects.

North Carolina "Sealed Corridor" Phase I, II, and III Assessment

DOT National Transportation Integrated Search

2009-10-01

The Federal Railroad Administration (FRA) tasked the John A. Volpe National Transportation Systems Center to document the further success of the North Carolina DOT "Sealed Corridor" project through Phases I, II, and III. The Sealed Corridor is the se...

Phase III gross solids removal devices pilot study, 2002-2005.

DOT National Transportation Integrated Search

2005-12-01

The objective of the Phase III Gross Solids Removal Devices (GSRDs) Pilot study was to : evaluate the performance of non-proprietary devices that can capture gross solids and that can be : incorporated into existing highway drainage systems or implem...

Improvement of conspicuity of trailblazing signs, Phase III : evaluation of fluorescent colors.

DOT National Transportation Integrated Search

2001-01-01

This report represents a Phase III effort to design and evaluate a new sign design for incident route trailblazing. The colors evaluated were fluorescent coral, fluorescent purple, fluorescent yellow-green, and non-fluorescent purple. The results ind...

Clinical Investigation Program Report, RCS MED-300 (R-1).

DTIC Science & Technology

1985-10-31

Patients with Locally Advanced Gastric Adenocarcinoma, Phase III. (C) 63 1982 SWOG 8006, Preoperative Reductive Chemotherapy for Stage III or IV Operable...Mesothelioma Localized to One Hemithorax, Phase III. (C) 81 1984 SWOG 8104, Treatment of Advanced Seminoma (Stage cII (4) + clII) with Combined...of Locally or Regionally Recurrent but Surgically Resectable Breast Cancer. (C) 99 1984 SWOG 8300, Treatment of Limited Non-Small Cell Lung Cancer

Growth-differentiation factor-15, endoglin and N-terminal pro-brain natriuretic peptide induction in athletes participating in an ultramarathon foot race.

PubMed

Tchou, Isabelle; Margeli, Alexandra; Tsironi, Maria; Skenderi, Katerina; Barnet, Marc; Kanaka-Gantenbein, Christina; Papassotiriou, Ioannis; Beris, Photis

2009-09-01

We investigated the actions of growth-differentiation factor (GDF)-15, endoglin and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in 15 male athletes who participated in the ultradistance foot race of the 246 km 'Sparthathlon'. Measurements were performed before (phase I), at the end of the race (phase II) and 48 h post-race (phase III). GDF-15 and endoglin serum concentrations were determined with enzyme-linked immunosorbent assay and NT-pro-BNP plasma levels by electrochemiluminescence. GDF-15 levels were increased from phase I (563.9 +/- 57.1 pg ml(-1)) to phase II (2311.1 +/- 462.3 pg ml(-1)) and decreased at phase III (862.0 +/- 158.0 pg ml(-1)) (p < 0.0002). NT-pro-BNP levels followed a similar pattern to that of GDF-15 from 38.1 +/- 4.8 pg ml(-1) at phase I to 1280.6 +/- 259.0 pg ml(-1) at phase II and 89.8 +/- 13.6 pg ml(-1) at phase III (p < 0.0001) and at the same time points, endoglin levels were 4.7 +/- 0.2 ng ml(-1) at phase I, 5.8 +/- 0.2 ng ml(-1) at phase II and 4.3 +/- 0.2 ng ml(-1) at phase III (p < 0.002). These findings indicate that circulating GDF-15, endoglin and NT-pro-BNP levels reflect a transient endothelial dysfunction in these athletes who participated in a foot race consisting of continuous, prolonged and brisk exercise.

Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease.

PubMed

Germain, Dominique P; Waldek, Stephen; Banikazemi, Maryam; Bushinsky, David A; Charrow, Joel; Desnick, Robert J; Lee, Philip; Loew, Thomas; Vedder, Anouk C; Abichandani, Rekha; Wilcox, William R; Guffon, Nathalie

2007-05-01

Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

Development of an EORTC quality of life phase III module measuring cancer-related fatigue (EORTC QLQ-FA13).

PubMed

Weis, Joachim; Arraras, Juan Ignacio; Conroy, Thierry; Efficace, Fabio; Fleissner, Claudia; Görög, Attila; Hammerlid, Eva; Holzner, Bernhard; Jones, Louise; Lanceley, Anne; Singer, Susanne; Wirtz, Markus; Flechtner, Henning; Bottomley, Andrew

2013-05-01

European Organisation for Research and Treatment of Cancer (EORTC) has developed a new multidimensional instrument measuring cancer-related fatigue that can be used in conjunction with the quality of life core questionnaire, EORTC QLQ-C30. The paper focuses on the development of the phase III module, collaborating with seven European countries, including a patient sample of 318 patients. The methodology followed the EORTC guidelines for developing phase III modules. Patients were assessed by questionnaires (EORTC QLQ-C30 with the EORTC Fatigue Module FA15) followed by an interview, asking for their opinions on the difficulty in understanding, on annoyance and on intrusiveness. The phase II FA15 was revised on the basis of qualitative analyses (comments of the patients), quantitative results (descriptive statistics) as well as the multi-item response theory analyses. The three dimensions (physical, emotional and cognitive) of the scale could be confirmed. As a result, EORTC QLQ-FA13 is now available as a valid phase III module measuring cancer-related fatigue in clinical trials and will be psychometrically improved in the upcoming phase IV. Copyright © 2012 John Wiley & Sons, Ltd.

Investigation of the Acoustics of Plucked String Tones Based on the Analysis of Their Time-Varying Spectra.

NASA Astrophysics Data System (ADS)

Chen, Kwok-Ping John

This research investigates two aspects of the time-varying vibration patterns of plucked string tones of classical guitar, Chinese pipa and Chinese ch'in. First, the assumption that horizontal and vertical frequencies and decay rates may be different is used as a basis for classifying the partial amplitude envelopes into four types. It is found that the partial envelopes of the tones produced by the three instruments, using the finger tip excitation method, on a single undamped string, can be described in terms of these four types. The results show that ch'in tones contain Type III, and IV, guitar tones contain Type I, II and III, and pipa tones contain all four types with a higher percentage of Type III and IV. Second, the theories of "missing modes" (Young, 1800), (Benade, 1976) and delayed generation of these modes (Fletcher, 1984), (Hall, 1987) are re-examined experimentally. The edge of a conventional guitar pick is used to excite a single undamped string on a classical guitar at nodal position N which is L/N from the bridge. As a result, it is a consistent feature that any mode whose index n is a multiple of N is attenuated during the attack phase but subsequently rises with a more gradual attack to reach a significant peak amplitude, except for the first multiple of locations L/3 to L/7. This amplitude envelope pattern, Type V, which is only applicable when the pick-edge excitation method is used, is distinct from the other four types mentioned above.

Early response to therapy and survival in multiple myeloma.

PubMed

Schaar, C G; Kluin-Nelemans, J C; le Cessie, S; Franck, P F H; te Marvelde, M C; Wijermans, P W

2004-04-01

Whether the response to chemotherapy is a prognosticator in multiple myeloma (MM) is still not known. Therefore, the relationship between survival and the rate of monoclonal protein (M-protein) decrement during the first cycles of therapy was prospectively assessed in 262 patients with newly diagnosed MM that were included in a phase III trial (HOVON-16). M-proteins were collected monthly during melphalan-prednisone therapy (MP: melphalan 0.25 mg/kg, prednisone 1.0 mg/kg orally for 5 d every 4 weeks). Patients with light chain disease (n = 18), immunoglobulin M (IgM)-MM (n = 1) and no immunotyping (n = 1) were excluded. Of the 242 patients studied, 75% had IgG M-protein and 25% IgA; MM stages: I: 1%, II: 35% and III: 64%. The median M-protein decrease after the first cycle of MP was 21% for IgG and 27% for IgA, and declined to < 5% after four cycles. An obvious survival advantage was seen for patients who had an M-protein decrease of at least 30% after the first MP cycle, which became significant when an M-protein decrease of 40% or more was reached. As established prognostic parameters (Salmon & Durie stage, serum creatinine, and haemoglobin) also remained prognostically significant, we concluded that early response to MP predicts for survival in MM.

Extravasation of liposomal daunorubicin in patients with AIDS-associated Kaposi's sarcoma: a report of four cases.

PubMed

Cabriales, S; Bresnahan, J; Testa, D; Espina, B M; Scadden, D T; Ross, M; Gill, P S

1998-01-01

To report on four patients with AIDS-related Kaposi's sarcoma who were treated with liposomal daunorubicin (DaunoXome, NeXstar Pharmaceuticals, Inc., San Dimas, CA) as part of phase I/II and phase III clinical trials and who experienced extravasation during IV infusion. All patients were treated with ice as an immediate intervention. In addition, two patients received treatment with multiple subcutaneous injections of steroids. Two patients experienced erythema, swelling, and pain after the extravasation. Two patients who were treated aggressively reported erythema and swelling without pain. Three patients observed changes in the texture of their skin that was accompanied by decreased sensation, which developed after 8-16 weeks. These changes completely resolved in all patients receiving intervention after six months. None of the patients suffered tissue necrosis. Extravasation with liposomal daunorubicin is notable for the absence of tissue necrosis that typically is observed with anthracyclines. Long-term effects were limited to skin discoloration and decreased sensation, both of which resolved in all patients. The lack of observed skin necrosis with daunorubicin suggests a treatment advantage with a reduction in the required aggressive extravasation procedures for free anthracyclines as well as increased safety for the patient. Additional data is needed to confirm these observations.

Telotristat ethyl: proof of principle and the first oral agent in the management of well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea.

PubMed

Masab, Muhammad; Saif, Muhammad Wasif

2017-12-01

Metastatic neuroendocrine tumors (NETs) are associated with carcinoid syndrome that is typically characterized by diarrhea, cutaneous flushing and bronchospasm. Treatment with somatostatin analogues (SSA) improves the symptom burden but a significant proportion of patients stop responding to SSA therapy eventually. Novel agents with the potential to effectively control the symptoms are urgently needed. This article reviews an in-depth analysis of the phase I-III clinical trials determining the clinical rationale for the use of tryptophan hydroxylase inhibitor, telotristat ethyl in patients with well-differentiated metastatic NETs and uncontrolled carcinoid syndrome. Telotristat ethyl has already been approved for the treatment of inadequately controlled carcinoid syndrome symptoms in metastatic NET patients on SSA therapy. Results from multiple phase I-III clinical studies of telotristat ethyl therapy have reported a significant decrease in the daily bowel movement frequency, increase in quality of life and the subsequent decrease in annual health costs related to carcinoid syndrome symptoms in NET patients. The associated decrease in urinary 5-hydroxyindoleacetic acid (u5-HIAA) provides evidence that telotristat ethyl effectively decreases serotonin production, and therefore, offers a rationale to investigate this agent to mitigate serotonin-mediated complications in this patient population, especially cardiac valvular disease or mesenteric fibrosis.

Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer.

PubMed

Mahner, Sven; Woelber, Linn; Mueller, Volkmar; Witzel, Isabell; Prieske, Katharina; Grimm, Donata; Keller-V Amsberg, Gunhild; Trillsch, Fabian

2015-01-01

In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated.

Validation of measurements of ventilation-to-perfusion ratio inequality in the lung from expired gas

NASA Technical Reports Server (NTRS)

Prisk, G. Kim; Guy, Harold J B.; West, John B.; Reed, James W.

2003-01-01

The analysis of the gas in a single expirate has long been used to estimate the degree of ventilation-perfusion (Va/Q) inequality in the lung. To further validate this estimate, we examined three measures of Va/Q inhomogeneity calculated from a single full exhalation in nine anesthetized mongrel dogs under control conditions and after exposure to aerosolized methacholine. These measurements were then compared with arterial blood gases and with measurements of Va/Q inhomogeneity obtained using the multiple inert gas elimination technique. The slope of the instantaneous respiratory exchange ratio (R slope) vs. expired volume was poorly correlated with independent measures, probably because of the curvilinear nature of the relationship due to continuing gas exchange. When R was converted to the intrabreath Va/Q (iV/Q), the best index was the slope of iV/Q vs. volume over phase III (iV/Q slope). This was strongly correlated with independent measures, especially those relating to inhomogeneity of perfusion. The correlations for iV/Q slope and R slope considerably improved when only the first half of phase III was considered. We conclude that a useful noninvasive measurement of Va/Q inhomogeneity can be derived from the intrabreath respiratory exchange ratio.

40 CFR 86.109-94 - Exhaust gas sampling system; Otto-cycle vehicles not requiring particulate emission measurements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... detection for the HPLC analyzer. Sampling systems for all phases shall be identical. (iii) The methanol and... detection for the HPLC analyzer. Sampling systems for all phases shall be identical. (iii) The methanol and...

40 CFR 86.109-94 - Exhaust gas sampling system; Otto-cycle vehicles not requiring particulate emission measurements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... detection for the HPLC analyzer. Sampling systems for all phases shall be identical. (iii) The methanol and... detection for the HPLC analyzer. Sampling systems for all phases shall be identical. (iii) The methanol and...

40 CFR 86.109-94 - Exhaust gas sampling system; Otto-cycle vehicles not requiring particulate emission measurements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... detection for the HPLC analyzer. Sampling systems for all phases shall be identical. (iii) The methanol and... detection for the HPLC analyzer. Sampling systems for all phases shall be identical. (iii) The methanol and...

Balancing the benefits and risks of disease-modifying therapy in patients with multiple sclerosis.

PubMed

Sørensen, Per Soelberg

2011-12-01

Balancing efficacy versus burden of therapy is essential for the choice of disease-modifying therapy in every MS patient. The first-line therapies, interferon-? and glatiramer acetate, have well-established efficacy and present no major safety concerns. Certain second-line therapies, such as natalizumab, offer potentially greater efficacy, but are associated with an increased level of risk. Over the last year, the first two oral treatments of relapsing-remitting multiple sclerosis, cladribine and fingolimod, have been marketed in certain countries, although cladribine was subsequently withdrawn. In the Phase III clinical development programme, both drugs appeared effective and reasonably safe. However, there were cases of serious adverse events (malignancies and fatal infections) whose relationship with treatment was unclear. Specific postmarketing studies will be necessary to assess the risks of these new oral therapies. Indeed, both natalizumab and mitoxantrone are known today to be associated with rare adverse drug reactions (progressive multifocal leukoencephalopathy for natalizumab and treatment-related leukaemia for mitoxantrone), which were not identified before the treatments were approved. The use of therapies carrying potential serious risks is justified in patients who cannot be treated effectively with safe first-line therapies, but probably not in the average relapsing-remitting multiple sclerosis or clinical isolated syndrome patient. Pivotal Phase III clinical trials, on which basis drug approval is generally granted, are designed to demonstrate clinical efficacy and reveal frequently occurring adverse effects of a new drug. However, post-approval trials with extensive patient exposure are needed to generate knowledge of more patient-specific clinical effectiveness and long-term safety, in particular with respect to rare adverse reactions. Other post-approval measures, such as risk management programmes, pharmacovigilance studies, or phased launch of the drug, may be useful to ensure that risks associated with new treatments are identified and minimised. The final evaluation of the benefits to risks balance of a drug should be made in every patient by weighing benefits in disease activity and progression, quality of life and health economy against both commonly occurring mild side-effects and rare potentially life-threatening adverse drug effects. This decision should be shared between the physician and patient, who may not share the same perceptions of acceptable risk. Copyright © 2011 Elsevier B.V. All rights reserved.

Benzyl and Methyl Fatty Hydroxamic Acids Based on Palm Kernel Oil as Chelating Agent for Liquid-Liquid Iron(III) Extraction

PubMed Central

Haron, Md Jelas; Jahangirian, Hossein; Silong, Sidik; Yusof, Nor Azah; Kassim, Anuar; Rafiee-Moghaddam, Roshanak; Mahdavi, Behnam; Peyda, Mazyar; Abdollahi, Yadollah; Amin, Jamileh

2012-01-01

Liquid-liquid iron(III) extraction was investigated using benzyl fatty hydroxamic acids (BFHAs) and methyl fatty hydroxamic acids (MFHAs) as chelating agents through the formation of iron(III) methyl fatty hydroxamate (Fe-MFHs) or iron(III) benzyl fatty hydroxamate (Fe-BFHs) in the organic phase. The results obtained under optimized conditions, showed that the chelating agents in hexane extract iron(III) at pH 1.9 were realized effectively with a high percentage of extraction (97.2% and 98.1% for MFHAs and BFHAs, respectively). The presence of a large amount of Mg(II), Ni(II), Al(III), Mn(II) and Co(II) ions did affect the iron(III) extraction. Finally stripping studies for recovering iron(III) from organic phase (Fe-MFHs or Fe-BFHs dissolved in hexane) were carried out at various concentrations of HCl, HNO3 and H2SO4. The results showed that the desired acid for recovery of iron(III) was 5 M HCl and quantitative recovery of iron(III) was achieved from Fe(III)-MFHs and Fe(III)-BFHs solutions in hexane containing 5 mg/L of Fe(III). PMID:22408444

Secukinumab in the Treatment of Psoriasis and Psoriatic Arthritis: A Review of the Literature.

PubMed

Abrouk, M; Gandy, J; Nakamura, M; Lee, K; Brodsky, M; Singh, R; Zhu, H; Farahnik, B; Bhutani, T; Koo, J

2017-07-01

While there are several commercially available treatment options for psoriasis and psoriatic arthritis, there remains a large number of individuals who are refractory to current modalities. In the recent past, there has been increasing evidence that interleukin (IL)-17 plays a vital role in the pathophysiology of psoriasis. Preclinical, phase II, and phase III studies of secukinumab (Cosentyx®) targeting IL-17 and its receptor have thus far proved to be promising. We reviewed the results of phase II and phase III clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only published studies were considered in the present review. We also performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumab OR AIN457) AND (psoriasis OR psoriatic arthritis). In our review of the literature, seven phase III and five phase II clinical trials, as well as open-label extension studies with unpublished findings were found. Results from phase III clinical trials indicated secukinumab to be efficacious and safe for the treatment of psoriasis and psoriatic arthritis according to Psoriasis Area and Severity Index (PASI) and American College of Rheumatology (ACR) scores. The safety profile of this agent was similar across all studies, with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction. Secukinumab demonstrates rapid and robust clinical improvement accompanied by a favorable short- term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis and psoriatic arthritis treatment. Additional extension studies of lower level evidence are needed to further understand the safety profile of the drug.

Design of a phase III multicenter trial to evaluate the efficacy of the RTS,S/AS01 malaria vaccine in children across diverse transmission settings in Africa

PubMed Central

2011-01-01

Background GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative are working in partnership to develop a malaria vaccine to protect infants and children living in malaria endemic regions of sub-Saharan Africa, which can be delivered through the Expanded Programme on Immunization. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and shown to have a favourable safety profile and to be well-tolerated in both adults and children. This paper details the design of the phase III multicentre efficacy trial of the RTS,S/AS01 malaria vaccine candidate, which is pivotal for licensure and policy decision-making. Methods The phase III trial is a randomized, controlled, multicentre, participant- and observer-blind study on-going in 11 centres associated with different malaria transmission settings in seven countries in sub-Saharan Africa. A minimum of 6,000 children in each of two age categories (6-12 weeks, 5-17 months) have been enrolled. Children were randomized 1:1:1 to one of three study groups: (1) primary vaccination with RTS,S/AS01 and booster dose of RTS,S/AS01; (2) primary vaccination with RTS,S/AS01 and a control vaccine at time of booster; (3) primary vaccination with control vaccine and a control vaccine at time of booster. Primary vaccination comprises three doses at monthly intervals; the booster dose is administered at 18 months post-primary course. Subjects will be followed to study month 32. The co-primary objectives are the evaluation of efficacy over one year post-dose 3 against clinical malaria when primary immunization is delivered at: (1) 6-12 weeks of age, with co-administration of DTPwHepB/Hib antigens and OPV; (2) 5-17 months of age. Secondary objectives include evaluation of vaccine efficacy against severe malaria, anaemia, malaria hospitalization, fatal malaria, all-cause mortality and other serious illnesses including sepsis and pneumonia. Efficacy of the vaccine against clinical malaria under different transmission settings, the evolution of efficacy over time and the potential benefit of a booster will be evaluated. In addition, the effect of RTS,S/AS01 vaccination on growth, and the safety and immunogenicity in HIV-infected and malnourished children will be assessed. Safety of the primary course of immunization and the booster dose will be documented in both age categories. Conclusions This pivotal phase III study of the RTS,S/AS01 candidate malaria vaccine in African children was designed and implemented by the Clinical Trials Partnership Committee. The study will provide efficacy and safety data to fulfil regulatory requirements, together with data on a broad range of endpoints that will facilitate the evaluation of the public health impact of the vaccine and will aid policy and implementation decisions. Trial registration Clinicaltrials.gov NCT00866619 PMID:21816029

Remedial Action Report for Operable Units 6-05 and 10-04, Phase III

DOE Office of Scientific and Technical Information (OSTI.GOV)

R. P. Wells

2007-08-15

This Phase III remedial action report addresses the remediation of lead-contaminated soils found at the Security Training Facility STF-02 Gun Range at the Idaho National Laboratory Site. Phase I, consisting of developing and implementing institutional controls at Operble Unit 10-04 sites and developing and implementing Idaho National Laboratory Site-wide plans for both institutional controls and ecological monitoring, was addressed in a previous report. Phase II will remediate sites contaminated with trinitrotoluene and Royal Demolition Explosive. Phase IV will remediate hazards from unexploded ordnance.

New Round of Studies Begin in Phase 0/I/II Cancer Prevention Clinical Trials Program | Division of Cancer Prevention

Cancer.gov

The NCI Division of Cancer Prevention’s Phase 0/I/II Cancer Prevention Clinical Trials Program, also known as the Consortia for Early Phase Prevention Trials, is beginning a new round of studies in the effort toward systematic early clinical development of promising preventive agents for people at increased risk of developing cancer. |

Fludarabine and Total-Body Irradiation Followed By Donor Stem Cell Transplant and Cyclosporine and Mycophenolate Mofetil in Treating HIV-Positive Patients With or Without Cancer

ClinicalTrials.gov

2017-04-17

Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Aggressive NK-cell Leukemia; AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; AIDS-related Small Noncleaved Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV Infection; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Central Nervous System Lymphoma; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Hodgkin Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Growth of wide-bandgap nitride semiconductors by MBE

NASA Astrophysics Data System (ADS)

Moustakas, T. D.

2002-08-01

This paper reviews progress in the heteroepitaxial growth of Ill-Nitride semiconductors. The growth of wurtzite and zinc-blende allotropic forms of GaN on various substrates with hexagonal and cubic symmetry respectively were discussed. In particular we addressed the growth on the various faces of sapphire, 6H-SiC and (001) Si. It has been shown that the kinetics of growth by plasma-MBE or ammonia-MBE are different. Specifically, in plasma-assisted MBE smooth films are obtained under group-III rich conditions of growth. On the other hand in ammonia-MBE smooth films are obtained under nitrogen rich conditions of growth. High quality films were obtained on 6H-SiC without the employment of any buffer. The various nucleation steps used to improve the two dimensional growth as well as to control the film polarity were discussed. The n- and p-doping of GaN were addressed. The concept of increasing the solubility of Mg in GaN by simultaneously bombarding the surface of the growing film with a flux of electrons (co-doping GaN with Mg and electrons) was discussed. The influence of the strength of Al-N, Ga-N and In-N bonds on the kinetics of growth of nitride alloys was pointed out. Specifically, it was shown that in both the nitrogen-rich and group-III rich growth regimes, the incorporation probability of aluminum is unity for the investigated temperature range of 750-800° C. On the other hand the incorporation probability of gallium is constant but less than unity only in the nitrogen-rich regime of growth. In the group-III regime the incorporation probability of gallium decreases monotonically with the total group-III flux, due to the competition with aluminum for the available active nitrogen. Alloy phenomena such as phase separation and atomic ordering and the influence of these phenomena to the optical properties were addressed. InGaN alloys are thermodynamically unstable against phase separation. At compositions above 30% they tend to undergo partial phase separation. Furthermore, InGaN alloys were found to undergo 1x1 monolayer cation ordering. AlGaN alloys do not show evidence of phase separation but they were found to undergo multiple type of superlattice ordering. Under nitrogen-rich growth conditions they show one monolayer periodicity, while under group-III rich growth it was found that the structure is a superposition of a seven monolayer and twelve monolayer superlattices. Finally, the growth of heterostructures and MQWs and the use of the MBE method for the fabrication of optical, electronic and electromechanical devices were discussed.

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group.

PubMed

Lübbert, Michael; Suciu, Stefan; Hagemeijer, Anne; Rüter, Björn; Platzbecker, Uwe; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; Germing, Ulrich; Salih, Helmut R; Muus, Petra; Pflüger, Karl-Heinz; Schaefer, Hans-Eckart; Bogatyreva, Lioudmila; Aul, Carlo; de Witte, Theo; Ganser, Arnold; Becker, Heiko; Huls, Gerwin; van der Helm, Lieke; Vellenga, Edo; Baron, Frédéric; Marie, Jean-Pierre; Wijermans, Pierre W

2016-01-01

In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.

How Data Packages Lacking Phase III Pivotal Trial Data Can Support Regulatory Approval and Reimbursement for Oncologics in Australia.

PubMed

Macaulay, Richard; Siddiqui, Mohammad Kashif; Stoddart, Samuel

2015-05-01

Oncology drugs lacking supportive phase III trial data have achieved Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory approval and even European reimbursement approval where no therapeutic alternative exists and early-stage data indicate dramatic clinical benefits. This research aimed to compare under what circumstances oncologics can obtain both regulatory and reimbursement approval in Australia on this basis. Therapeutic Goods Administration (TGA) Australian Public Assessment Reports, EMA, FDA, and Pharmaceutical Benefits Advisory Committee (PBAC) Public Summary Documents were extracted for any oncologic indication appraised in Australia on a pivotal trial package lacking phase III data, excluding pediatric indications and new formulations. Australian Public Assessment Reports were available for six TGA-appraised oncologics across seven indications on such a data package: five of seven approved, one of seven restricted, and one of seven rejected. The EMA and the FDA issued recommendations on these indications an average of 1 and 2 years earlier, respectively. The PBAC appraised six oncologics across 10 indications on such a data package, with four (nilotinib, dasatinib, imatinib, and brentuximab vedotin) approved and two rejected (cetuximab and bevacizumab). Seven of the eight approved indications required multiple submissions, with inadequate clinical data frequently cited as key. Six of the eight PBAC-approved indications included economic modeling on a cost-benefit approach. The TGA will approve oncologics that offer potentially substantial clinical benefits on the basis of an indirect comparison of single-arm trials but at a delay versus the EMA and the FDA. The PBAC reimbursement approval also requires more rigorous supportive clinical data and acceptable cost-effectiveness as demonstrated on a cost-benefit or cost-quality-adjusted life-year metric. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Practice versus knowledge when it comes to pressure ulcer prevention.

PubMed

Provo, B; Piacentine, L; Dean-Baar, S

1997-09-01

This study was completed to determine the current knowledge and documentation patterns of nursing staff in the prevention of pressure ulcers and to identify the prevalence of pressure ulcers. This pre-post intervention study was carried out in three phases. In phase 1, 67 nursing staff members completed a modified version of Bostrom's Patient Skin Integrity Survey. A Braden Scale score, the presence of actual skin breakdown, and the presence of nursing documentation were collected for each patient (n = 43). Phase II consisted of a 20-minute educational session to all staff. In phase III, 51 nursing staff completed a second questionnaire similar to that completed in phase I. Patient data (n = 49) were again collected using the same procedure as phase I. Twenty-seven staff members completed questionnaires in both phase I and phase III of the study. No statistically significant differences were found in the knowledge of the staff before or after the educational session. The number of patients with a documented plan of care showed a statistically significant difference from phase I to phase III. The number of patients with pressure ulcers or at risk for pressure ulcer development (determined by a Braden Scale score of 16 or less) did not differ statistically from phase I to phase III. Knowledge about pressure ulcers in this sample of staff nurses was for the most part current and consistent with the recommendations in the Agency for Health Care Policy and Research guideline. Documentation of pressure ulcer prevention and treatment improved after the educational session. Although a significant change was noted in documentation, it is unclear whether it reflected an actual change in practice.

Development of a central data warehouse for statewide ITS and transportation data in Florida phase III : final report.

DOT National Transportation Integrated Search

2009-12-15

This report documents Phase III of the development and operation of a prototype for the Statewide Transportation : Engineering Warehouse for Archived Regional Data (STEWARD). It reflects the progress on the development and : operation of STEWARD sinc...

Application of Δ- and λ-isomerism of octahedral metal complexes for inducing chiral nematic phases.

PubMed

Sato, Hisako; Yamagishi, Akihiko

2009-11-20

The Delta- and Lambda-isomerism of octahedral metal complexes is employed as a source of chirality for inducing chiral nematic phases. By applying a wide range of chiral metal complexes as a dopant, it has been found that tris(beta-diketonato)metal(III) complexes exhibit an extremely high value of helical twisting power. The mechanism of induction of the chiral nematic phase is postulated on the basis of a surface chirality model. The strategy for designing an efficient dopant is described, together with the results using a number of examples of Co(III), Cr(III) and Ru(III) complexes with C(2) symmetry. The development of photo-responsive dopants to achieve the photo-induced structural change of liquid crystal by use of photo-isomerization of chiral metal complexes is also described.

Application of Δ- and Λ-Isomerism of Octahedral Metal Complexes for Inducing Chiral Nematic Phases

PubMed Central

Sato, Hisako; Yamagishi, Akihiko

2009-01-01

The Δ- and Λ-isomerism of octahedral metal complexes is employed as a source of chirality for inducing chiral nematic phases. By applying a wide range of chiral metal complexes as a dopant, it has been found that tris(β-diketonato)metal(III) complexes exhibit an extremely high value of helical twisting power. The mechanism of induction of the chiral nematic phase is postulated on the basis of a surface chirality model. The strategy for designing an efficient dopant is described, together with the results using a number of examples of Co(III), Cr(III) and Ru(III) complexes with C2 symmetry. The development of photo-responsive dopants to achieve the photo-induced structural change of liquid crystal by use of photo-isomerization of chiral metal complexes is also described. PMID:20057959

Zwitterion-functionalized polymer microspheres as a sorbent for solid phase extraction of trace levels of V(V), Cr(III), As(III), Sn(IV), Sb(III) and Hg(II) prior to their determination by ICP-MS.

PubMed

Jia, Xiaoyu; Gong, Dirong; Zhao, Junyi; Ren, Hongyun; Wang, Jiani; Zhang, Xian

2018-03-19

This paper describes the preparation of zwitterion-functionalized polymer microspheres (ZPMs) and their application to simultaneous enrichment of V(V), Cr(III), As(III), Sn(IV), Sb(III) and Hg(II) from environmental water samples. The ZPMs were prepared by emulsion copolymerization of ethyl methacrylate, 2-diethylaminoethyl methacrylate and triethylene glycol dimethyl acrylate followed by modification with 1,3-propanesultone. The components were analyzed by elemental analyses as well as Fourier transform infrared spectroscopy, and the structures were characterized by scanning electron microscopy and transmission electron microscopy. The ZPMs were packed into a mini-column for on-line solid-phase extraction (SPE) of the above metal ions. Following extraction with 40 mM NH 4 NO 3 and 0.5 M HNO 3 solution, the ions were quantified by ICP-MS. Under the optimized conditions, the enrichment factors (from a 40 mL sample) are up to 60 for the ions V(V), As(III), Sb(III) and Hg(II), and 55 for Cr(III) and Sn(IV). The detection limits are 1.2, 3.4, 1.0, 3.7, 2.1 and 1.6 ng L -1 for V(V), Cr(III), As(III), Sn(IV), Sb(III) and Hg(II), respectively, and the relative standard deviations (RSDs) are below 5.2%. The feasibility and accuracy of the method were validated by successfully analyzing six certified reference materials as well as lake, well and river waters. Graphical abstract Zwitterion-functionalized polymer microspheres (ZPMs) were prepared and packed into a mini-column for on-line solid-phase extraction (SPE) via pump 1. Then V(V), Cr(III), As(III), Sn(IV), Sb(III) and Hg(II) ions in environmental waters were eluted and submitted to ICP-MS via pump 2.

Disease activity return after natalizumab cessation in multiple sclerosis.

PubMed

Rasenack, Maria; Derfuss, Tobias

2016-05-01

Natalizumab (NAT) was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis. Its considerable and sustained efficacy has been demonstrated in two phase III studies. However, there are several reasons why its use is limited in clinical practice. The main argument for stopping use of the drug is the risk of the rare but serious progressive multifocal leukencephalopathy. Other reasons are neutralizing antibodies and pregnancy. There is compelling evidence from some clinical trials and many case series that disease activity returns upon suspension or cessation of NAT. Several therapeutic strategies that have been tested to prevent or reduce the recurrence of disease activity will be reviewed in this article. Considering these data, it is evident that the decision to stop NAT treatment has different implications and consequences. A subsequent therapy after cessation of NAT is needed to reduce the risk of disease recurrence.

Single-Dose Oritavancin Treatment of Acute Bacterial Skin and Skin Structure Infections: SOLO Trial Efficacy by Eron Severity and Management Setting.

PubMed

Deck, Daniel H; Jordan, Jennifer M; Holland, Thomas L; Fan, Weihong; Wikler, Matthew A; Sulham, Katherine A; Ralph Corey, G

2016-09-01

Introduction of new antibiotics enabling single-dose administration, such as oritavancin may significantly impact site of care decisions for patients with acute bacterial skin and skin structure infections (ABSSSI). This analysis compared the efficacy of single-dose oritavancin with multiple-dose vancomycin in patients categorized according to disease severity via modified Eron classification and management setting. SOLO I and II were phase 3 studies evaluating single-dose oritavancin versus 7-10 days of vancomycin for treatment of ABSSSI. Patient characteristics were collected at baseline and retrospectively analyzed. Study protocols were amended, allowing outpatient management at the discretion of investigators. In this post hoc analysis, patients were categorized according to a modified Eron severity classification and management setting (outpatient vs. inpatient) and the efficacy compared. Overall, 1910 patients in the SOLO trials were categorized into Class I (520, 26.5%), II (790, 40.3%), and III (600, 30.6%). Of the 767 patients (40%) in the SOLO trials who were managed entirely in the outpatient setting 40.3% were categorized as Class II and 30.6% were Class III. Clinical efficacy was similar between oritavancin and vancomycin treatment groups, regardless of severity classification and across inpatient and outpatient settings. Class III patients had lower response rates (oritavancin 73.3%, vancomycin 76.6%) at early clinical evaluation when compared to patients in Class I (82.6%) or II (86.1%); however, clinical cure rates at the post-therapy evaluation were similar for Class III patients (oritavancin 79.8%, vancomycin 79.9%) when compared to Class I and II patients (79.1-85.7%). Single-dose oritavancin therapy results in efficacy comparable to multiple-dose vancomycin in patients categorized according to modified Eron disease severity classification regardless of whether management occurred in the inpatient or outpatient setting. The Medicines Company, Parsippany, NJ, USA. ClinicalTrials.gov identifiers, NCT01252719 (SOLO I) and NCT01252732 (SOLO II).

Magnetic antenna excitation of whistler modes. III. Group and phase velocities of wave packets

NASA Astrophysics Data System (ADS)

Urrutia, J. M.; Stenzel, R. L.

2015-07-01

The properties of whistler modes excited by single and multiple magnetic loop antennas have been investigated in a large laboratory plasma. A single loop excites a wavepacket, but an array of loops across the ambient magnetic field B0 excites approximate plane whistler modes. The single loop data are measured. The array patterns are obtained by linear superposition of experimental data shifted in space and time, which is valid in a uniform plasma and magnetic field for small amplitude waves. Phasing the array changes the angle of wave propagation. The antennas are excited by an rf tone burst whose propagating envelope and oscillations yield group and phase velocities. A single loop antenna with dipole moment across B0 excites wave packets whose topology resembles m = 1 helicon modes, but without radial boundaries. The phase surfaces are conical with propagation characteristics of Gendrin modes. The cones form near the antenna with comparable parallel and perpendicular phase velocities. A physical model for the wave excitation is given. When a wave burst is applied to a phased antenna array, the wave front propagates both along the array and into the plasma forming a "whistler wing" at the front. These laboratory observations may be relevant for excitation and detection of whistler modes in space plasmas.

Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose–toxicity and dose–efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID:24470329

Hexafluorobenzene under Extreme Conditions.

PubMed

Pravica, Michael; Sneed, Daniel; Wang, Yonggang; Smith, Quinlan; White, Melanie

2016-03-17

We report the results from three high pressure experiments on hexafluorobenzene (C6F6). In the first experiment, Raman spectra were recorded up to 34.4 GPa. A phase transition from I → II was observed near 2 GPa. Near 8.8 GPa, a phase transition to an unreported phase (III) commenced. Above 20.6 GPa, yet another phase was observed (IV). Pressure cycling was employed to determine that, below 25.6 GPa, all pressure-induced alterations were reversible. However, at pressures above 20 GPa, dramatic spectral changes and broadening were observed at 25.6 and 34.4 GPa. The sample irreversibly changed into a soft solid with waxlike consistency when pressure was reduced to ambient and was recoverable. In the second experiment, IR spectra were collected up to 14.6 GPa. The phase transition (II → III) near 8.8 GPa was confirmed. An angular dispersive X-ray diffraction experiment was conducted to 25.6 GPa. Phase transitions above 1.4 GPa (I → II), above 5.5 GPa (II → III), above 10 GPa (III → IV), and above 15.5 GPa (IV → V) were observed. Near 25.6 GPa, long-range crystalline order was lost as the X-ray diffraction spectrum presented evidence of an amorphous solid.

Changes of Polyphenolic Substances in the Anatomical Parts of Buckwheat (Fagopyrum esculentum Moench.) during Its Growth Phases

PubMed Central

Bystricka, Judita; Musilova, Janette; Tomas, Jan; Vollmannova, Alena; Lachman, Jaromir; Kavalcova, Petra

2014-01-01

In this study the changes of total polyphenolics in different anatomical parts (stems, leaves, flowers and seeds) of common buckwheat (Fagopyrum esculentum Moench.) during vegetation period were analysed. The content of total polyphenolics was evaluated in growth phase I (formation of buds), phase II (at the beginning of flowering), phase III (full blossoming) and phase IV (full ripeness). In all growth phases (GP) the stems and leaves were evaluated and statistically significant differences in polyphenolics content between the two parts were confirmed. Statistically significant differences (p < 0.01) in polyphenolics content (in GP II and III) between stems and leaves; and between stems and flowers were found. In flowers an average of 13.8 times higher and in leaves 6 times higher concentration of polyphenolics in comparison with stems was measured. In GP III the content of polyphenolics in common buckwheat was following: flowers > leaves > achene > stems. In flowers an average of 11.9 times higher, in leaves 8.3 times higher and in achenes 5.9 times higher contents of polyphenolics compared with stems were found. In GP III and IV (leaves, achenes, stems) the leaves contained in average 20 times higher and achenes 5.6 times higher polyphenolics than stems. PMID:28234337

Renaissance of antibiotics against difficult infections: Focus on oritavancin and new ketolides and quinolones.

PubMed

Van Bambeke, Françoise

2014-11-01

Lipoglycopeptide, ketolide, and quinolone antibiotics are currently in clinical development, with specific advantages over available molecules within their respective classes. The lipoglycopeptide oritavancin is bactericidal against MRSA, vancomycin-resistant enterococci, and multiresistant Streptococcus pneumoniae, and proved effective and safe for the treatment of acute bacterial skin and skin structure infection (ABSSSI) upon administration of a single 1200 mg dose (two completed phase III trials). The ketolide solithromycin (two phase III studies recruiting for community-acquired pneumonia) shows a profile of activity similar to that of telithromycin, but in vitro data suggest a lower risk of hepatotoxicity, visual disturbance, and aggravation of myasthenia gravis due to reduced affinity for nicotinic receptors. Among quinolones, finafloxacin and delafloxacin share the unique property of an improved activity in acidic environments (found in many infection sites). Finafloxacin (phase II completed; activity profile similar to that of ciprofloxacin) is evaluated for complicated urinary tract and Helicobacter pylori infections. The other quinolones (directed towards Gram-positive pathogens) show improved activity on MRSA and multiresistant S. pneumoniae compared to current molecules. They are in clinical evaluation for ABSSSI (avarofloxacin (phase II completed), nemonoxacin and delafloxacin (ongoing phase III)), respiratory tract infections (zabofloxacin and nemonoxacin (ongoing phase III)), or gonorrhea (delafloxacin).

Uranium(III)-carbon multiple bonding supported by arene δ-bonding in mixed-valence hexauranium nanometre-scale rings.

PubMed

Wooles, Ashley J; Mills, David P; Tuna, Floriana; McInnes, Eric J L; Law, Gareth T W; Fuller, Adam J; Kremer, Felipe; Ridgway, Mark; Lewis, William; Gagliardi, Laura; Vlaisavljevich, Bess; Liddle, Stephen T

2018-05-29

Despite the fact that non-aqueous uranium chemistry is over 60 years old, most polarised-covalent uranium-element multiple bonds involve formal uranium oxidation states IV, V, and VI. The paucity of uranium(III) congeners is because, in common with metal-ligand multiple bonding generally, such linkages involve strongly donating, charge-loaded ligands that bind best to electron-poor metals and inherently promote disproportionation of uranium(III). Here, we report the synthesis of hexauranium-methanediide nanometre-scale rings. Combined experimental and computational studies suggest overall the presence of formal uranium(III) and (IV) ions, though electron delocalisation in this Kramers system cannot be definitively ruled out, and the resulting polarised-covalent U = C bonds are supported by iodide and δ-bonded arene bridges. The arenes provide reservoirs that accommodate charge, thus avoiding inter-electronic repulsion that would destabilise these low oxidation state metal-ligand multiple bonds. Using arenes as electronic buffers could constitute a general synthetic strategy by which to stabilise otherwise inherently unstable metal-ligand linkages.

75 FR 14575 - Voting Equipment Evaluations Phase III

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-26

..., Human Performance-Based Standards and Usability Testing. NIST Phase III research is designed to: (1... vendor equipment will not be released. Comparative information may be released in a blind manner... electronic poll book systems as well as software used for ballot design and creation. Dated: March 23, 2010...

78 FR 18325 - Defense Transportation Regulation, Part IV

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-26

... received in connection with the Defense Personal Property Program (DP3) Phase III Direct Procurement Method... at http://www.transcom.mil/dtr/part-iv/phaseiii.cfm (DPM SECTION). All identified changes will be... Defense Personal Property System (DPS) Phase III programming projected for FY17. FOR FURTHER INFORMATION...

76 FR 36095 - Defense Transportation Regulation, Part IV

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-21

... with the Defense Personal Property Program (DP3) Phase III Domestic Small Shipments (dS2) and... Regulation, Part IV Web site at http://www.transcom.mil/dtr/part-iv/phaseiii.cfm . All identified changes... based on completion of Defense Personal Property System (DPS) Phase III programming projected for FY15...

SPSP Phase III Recruiting, Selecting, and Developing Secure Power Systems Professionals. Job Profiles

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Neil, Lori Ross; Conway, T. J.; Tobey, D. H.

The Secure Power Systems Professional Phase III final report was released last year which an appendix of Job Profiles. This new report is that appendix broken out as a standalone document to assist utilities in recruiting and developing Secure Power Systems Professionals at their site.

76 FR 53704 - 30-Day Notice of Proposed Information Collection: Passport Demand Forecasting Study Phase III...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-29

...: Passport Demand Forecasting Study Phase III, OMB Number 1405-0177 ACTION: Notice of request for public... approval in accordance with the Paperwork Reduction Act of 1995. Title of Information Collection: Passport... Passport Services CA/PPT. Form Number: SV2011-0010. [[Page 53705

76 FR 33398 - 60-Day Notice of Proposed Information Collection; Passport Demand Forecasting Study Phase III...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-08

...; Passport Demand Forecasting Study Phase III, 1405-0177 ACTION: Notice of request for public comments... the Paperwork Reduction Act of 1995. Title of Information Collection: Passport Demand Forecasting... Approved Collection. Originating Office: Bureau of Consular Affairs, Passport Services Office: CA/PPT. Form...

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.

PubMed

Yoneyama, Koichiro; Schmitt, Christophe; Kotani, Naoki; Levy, Gallia G; Kasai, Ryu; Iida, Satofumi; Shima, Midori; Kawanishi, Takehiko

2017-12-06

Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

Stability hierarchy between Piracetam forms I, II, and III from experimental pressure-temperature diagrams and topological inferences.

PubMed

Toscani, Siro; Céolin, René; Minassian, Léon Ter; Barrio, Maria; Veglio, Nestor; Tamarit, Josep-Lluis; Louër, Daniel; Rietveld, Ivo B

2016-01-30

The trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II-III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid-solid and solid-liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements. Copyright © 2015 Elsevier B.V. All rights reserved.

Chronology and pyroclastic stratigraphy of the May 18, 1980, eruption of Mount St. Helens, Washington

NASA Technical Reports Server (NTRS)

Criswell, C. William

1987-01-01

The eruption of Mount St. Helens on May 18, 1980 can be subdivided into six phases: the paroxysmal phase I, the early Plinian phase II, the early ash flow phase III, the climactic phase IV, the late ash flow phase V, and phase VI, the activity of which consisted of a low-energy ash plume. These phases are correlated with stratigraphic subunits of ash-fall tephra and pyroclastic flow deposits. Sustained vertical discharge of phase II produced evolved dacite with high S/Cl ratios. Ash flow activity of phase III is attributed to decreases in gas content, indicated by reduced S/Cl ratios and increased clast density of the less evolved gray pumice. Climactic events are attributed to vent clearing and exhaustion of the evolved dacite.

Design of Phase II Non-inferiority Trials.

PubMed

Jung, Sin-Ho

2017-09-01

With the development of inexpensive treatment regimens and less invasive surgical procedures, we are confronted with non-inferiority study objectives. A non-inferiority phase III trial requires a roughly four times larger sample size than that of a similar standard superiority trial. Because of the large required sample size, we often face feasibility issues to open a non-inferiority trial. Furthermore, due to lack of phase II non-inferiority trial design methods, we do not have an opportunity to investigate the efficacy of the experimental therapy through a phase II trial. As a result, we often fail to open a non-inferiority phase III trial and a large number of non-inferiority clinical questions still remain unanswered. In this paper, we want to develop some designs for non-inferiority randomized phase II trials with feasible sample sizes. At first, we review a design method for non-inferiority phase III trials. Subsequently, we propose three different designs for non-inferiority phase II trials that can be used under different settings. Each method is demonstrated with examples. Each of the proposed design methods is shown to require a reasonable sample size for non-inferiority phase II trials. The three different non-inferiority phase II trial designs are used under different settings, but require similar sample sizes that are typical for phase II trials.

Community shift of biofilms developed in a full-scale drinking water distribution system switching from different water sources.

PubMed

Li, Weiying; Wang, Feng; Zhang, Junpeng; Qiao, Yu; Xu, Chen; Liu, Yao; Qian, Lin; Li, Wenming; Dong, Bingzhi

2016-02-15

The bacterial community of biofilms in drinking water distribution systems (DWDS) with various water sources has been rarely reported. In this research, biofilms were sampled at three points (A, B, and C) during the river water source phase (phase I), the interim period (phase II) and the reservoir water source phase (phase III), and the biofilm community was determined using the 454-pyrosequencing method. Results showed that microbial diversity declined in phase II but increased in phase III. The primary phylum was Proteobacteria during three phases, while the dominant class at points A and B was Betaproteobacteria (>49%) during all phases, but that changed to Holophagae in phase II (62.7%) and Actinobacteria in phase III (35.6%) for point C, which was closely related to its water quality. More remarkable community shift was found at the genus level. In addition, analysis results showed that water quality could significantly affect microbial diversity together, while the nutrient composition (e.g. C/N ration) of the water environment might determine the microbial community. Furthermore, Mycobacterium spp. and Pseudomonas spp. were detected in the biofilm, which should give rise to attention. This study revealed that water source switching produced substantial impact on the biofilm community. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of Mg/Ga and V/III source ratios on hole concentration of N-polar (000\\bar{1}) p-type GaN grown by metalorganic vapor phase epitaxy

NASA Astrophysics Data System (ADS)

Nonoda, Ryohei; Shojiki, Kanako; Tanikawa, Tomoyuki; Kuboya, Shigeyuki; Katayama, Ryuji; Matsuoka, Takashi

2016-05-01

The effects of growth conditions such as Mg/Ga and V/III ratios on the properties of N-polar (000\\bar{1}) p-type GaN grown by metalorganic vapor phase epitaxy were studied. Photoluminescence spectra from Mg-doped GaN depended on Mg/Ga and V/III ratios. For the lightly doped samples, the band-to-acceptor emission was observed at 3.3 eV and its relative intensity decreased with increasing V/III ratio. For the heavily doped samples, the donor-acceptor pair emission was observed at 2.8 eV and its peak intensity monotonically decreased with V/III ratio. The hole concentration was maximum for the Mg/Ga ratio. This is the same tendency as in group-III polar (0001) growth. The V/III ratio also reduced the hole concentration. The higher V/III ratio reduced the concentration of residual donors such as oxygen by substituting nitrogen atoms. The surface became rougher with increasing V/III ratio and the hillock density increased.

Probability of success for phase III after exploratory biomarker analysis in phase II.

PubMed

Götte, Heiko; Kirchner, Marietta; Sailer, Martin Oliver

2017-05-01

The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses. In such a case, there is a tendency to overestimate the treatment effect. We investigate whether the overestimation of the treatment effect estimate from phase II is transformed into a positive bias for the probability of success for phase III. We simulate a phase II/III development program for targeted therapies. This simulation allows to investigate selection probabilities and allows to compare the estimated with the true probability of success. We consider the estimated probability of success with and without subgroup selection. Depending on the true treatment effects, there is a negative bias without selection because of the weighting by the phase II distribution. In comparison, selection increases the estimated probability of success. Thus, selection does not lead to a bias in probability of success if underestimation due to the phase II distribution and overestimation due to selection cancel each other out. We recommend to perform similar simulations in practice to get the necessary information about the risk and chances associated with such subgroup selection designs. Copyright © 2017 John Wiley & Sons, Ltd.

Maximizing return on socioeconomic investment in phase II proof-of-concept trials.

PubMed

Chen, Cong; Beckman, Robert A

2014-04-01

Phase II proof-of-concept (POC) trials play a key role in oncology drug development, determining which therapeutic hypotheses will undergo definitive phase III testing according to predefined Go-No Go (GNG) criteria. The number of possible POC hypotheses likely far exceeds available public or private resources. We propose a design strategy for maximizing return on socioeconomic investment in phase II trials that obtains the greatest knowledge with the minimum patient exposure. We compare efficiency using the benefit-cost ratio, defined to be the risk-adjusted number of truly active drugs correctly identified for phase III development divided by the risk-adjusted total sample size in phase II and III development, for different POC trial sizes, powering schemes, and associated GNG criteria. It is most cost-effective to conduct small POC trials and set the corresponding GNG bars high, so that more POC trials can be conducted under socioeconomic constraints. If δ is the minimum treatment effect size of clinical interest in phase II, the study design with the highest benefit-cost ratio has approximately 5% type I error rate and approximately 20% type II error rate (80% power) for detecting an effect size of approximately 1.5δ. A Go decision to phase III is made when the observed effect size is close to δ. With the phenomenal expansion of our knowledge in molecular biology leading to an unprecedented number of new oncology drug targets, conducting more small POC trials and setting high GNG bars maximize the return on socioeconomic investment in phase II POC trials. ©2014 AACR.

Structural and phase transformation of A{sup III}B{sup V}(100) semiconductor surface in interaction with selenium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bezryadin, N. N.; Kotov, G. I., E-mail: giktv@mail.ru; Kuzubov, S. V., E-mail: kuzub@land.ru

2015-03-15

Surfaces of GaAs(100), InAs(100), and GaP(100) substrates thermally treated in selenium vapor have been investigated by transmission electron microscopy and electron probe X-ray microanalysis. Some specific features and regularities of the formation of A{sub 3}{sup III}B{sub 4}{sup VI} (100)c(2 × 2) surface phases and thin layers of gallium or indium selenides A{sub 2}{sup III}B{sub 3}{sup VI} (100) on surfaces of different A{sup III}B{sup V}(100) semiconductors are discussed within the vacancy model of surface atomic structure.

Multiple-decker phthalocyaninato dinuclear lanthanoid(III) single-molecule magnets with dual-magnetic relaxation processes.

PubMed

Katoh, Keiichi; Horii, Yoji; Yasuda, Nobuhiro; Wernsdorfer, Wolfgang; Toriumi, Koshiro; Breedlove, Brian K; Yamashita, Masahiro

2012-11-28

The SMM behaviour of dinuclear Ln(III)-Pc multiple-decker complexes (Ln = Tb(3+) and Dy(3+)) with energy barriers and slow-relaxation behaviour were explained by using X-ray crystallography and static and dynamic susceptibility measurements. In particular, interactions among the 4f electrons of several dinuclear Ln(III)-Pc type SMMs have never been discussed on the basis of the crystal structure. For dinuclear Tb(III)-Pc complexes, a dual magnetic relaxation process was observed. The relaxation processes are due to the anisotropic centres. Our results clearly show that the two Tb(3+) ion sites are equivalent and are consistent with the crystal structure. On the other hand, the mononuclear Tb(III)-Pc complex exhibited only a single magnetic relaxation process. This is clear evidence that the magnetic relaxation mechanism depends heavily on the dipole-dipole (f-f) interactions between the Tb(3+) ions in the dinuclear systems. Furthermore, the SMM behaviour of dinuclear Dy(III)-Pc type SMMs with smaller energy barriers compared with that of Tb(III)-Pc and slow-relaxation behaviour was explained. Dinuclear Dy(III)-Pc SMMs exhibited single-component magnetic relaxation behaviour. The results indicate that the magnetic relaxation properties of dinuclear Ln(III)-Pc multiple-decker complexes are affected by the local molecular symmetry and are extremely sensitive to tiny distortions in the coordination geometry. In other words, the spatial arrangement of the Ln(3+) ions (f-f interactions) in the crystal is important. Our work shows that the SMM properties can be fine-tuned by introducing weak intermolecular magnetic interactions in a controlled SMM spatial arrangement.

Management of patients with rectocele, multiple pelvic floor dysfunctions and obstructed defecation syndrome.

PubMed

Murad-Regadas, Sthela Maria; Regadas, Francisco Sergio P; Rodrigues, Lusmar Veras; Fernandes, Graziela Olivia da Silva; Buchen, Guilherme; Kenmoti, Viviane T

2012-01-01

Management of patients with obstructed defecation syndrome is still controversial. To analyze the efficacy of clinical, clinical treatment followed by biofeedback, and surgical treatment in patients with obstructed defecation, rectocele and multiple dysfunctions evaluated with echodefecography. The study included 103 females aged 26-84 years with obstructed defecation, grade-II/III rectocele and multiple dysfunctions on echodefecography. Patients were distributed into three treatment groups and constipation scores were assigned. Group I: 34 (33%) patients with significant improvement of symptoms through clinical management only. Group II: 14 (14%) with improvement through clinical treatment plus biofeedback. Group III: 55 (53%) referred to surgery due to treatment failure. Group I: 20 (59%) patients had grade-II rectocele, 14 (41%) grade-III. Obstructed defecation syndrome was associated with intussusception (41%), mucosal prolapse (41%), anismus (29%), enterocele (9%) or 2 dysfunctions (23%). The average constipation score decreased significantly from 11 to 5. Group II: 11 (79%) grade-II rectocele, 3 (21%) grade-III, associated with intussusception (7%), mucosal prolapse (43%), anismus (71%) or 2 dysfunctions (29%). There was significant decrease in constipation score from 13 to 6. Group III: 8 (15%) grade-II rectocele, 47 (85%) grade-III, associated with intussusception (42%), mucosal prolapse (40%) or 2 dysfunctions (32%). The constipation score remained unchanged despite clinical treatment and biofeedback. Twenty-three underwent surgery had a significantly decrease in constipation score from 12 to 4. The remaining 32 (31%) patients which 22 refused surgery, 6 had low anal pressure and 4 had slow transit. Approximately 50% of patients with obstructed defecation, rectocele and multiple dysfunctions presented a satisfactory response to clinical treatment and/or biofeedback. Surgical repair was mainly required in patients with grade-III rectocele whose constipation scores remained high despite all efforts.

The history of couple therapy: a millennial review.

PubMed

Gurman, Alan S; Fraenkel, Peter

2002-01-01

In this article, we review the major conceptual and clinical influences and trends in the history of couple therapy to date, and also chronicle the history of research on couple therapy. The evolving patterns in theory and practice are reviewed as having progressed through four distinctive phases: Phase I--Atheoretical Marriage Counseling Formation (1930-1963); Phase II--Psychoanalytic Experimentation (1931-1966); Phase III--Family Therapy Incorporation (1963-1985); and Phase IV--Refinement, Extension, Diversification, and Integration (1986-present). The history of research in the field is described as having passed through three phases: Phase I--A Technique in Search of Some Data (1930-1974), Phase II--Irrational(?) Exuberance (1975-1992), and Phase III--Caution and Extension (1993-present). The article concludes with the identification of Four Great Historical Ironies in the History of Couple Therapy.

AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

ClinicalTrials.gov

2017-02-21

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

Multiple sclerosis and extract of cannabis: results of the MUSEC trial.

PubMed

Zajicek, John Peter; Hobart, Jeremy C; Slade, Anita; Barnes, David; Mattison, Paul G

2012-11-01

Multiple sclerosis (MS) is associated with chronic symptoms, including muscle stiffness, spasms, pain and insomnia. Here we report the results of the Multiple Sclerosis and Extract of Cannabis (MUSEC) study that aimed to substantiate the patient based findings of previous studies. Patients with stable MS at 22 UK centres were randomised to oral cannabis extract (CE) (N=144) or placebo (N=135), stratified by centre, walking ability and use of antispastic medication. This double blind, placebo controlled, phase III study had a screening period, a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase. The primary outcome measure was a category rating scale (CRS) measuring patient reported change in muscle stiffness from baseline. Further CRSs assessed body pain, spasms and sleep quality. Three validated MS specific patient reported outcome measures assessed aspects of spasticity, physical and psychological impact, and walking ability. The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo (29.4% vs. 15.7%; OR 2.26; 95% CI 1.24 to 4.13; p=0.004, one sided). Similar results were found after 4 weeks and 8 weeks, and also for all further CRSs. Results from the MS scales supported these findings. The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of muscle stiffness in MS. This was supported by results for secondary efficacy variables. Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids. No new safety concerns were observed. NCT00552604.

Vaccines for leishmaniasis in the fore coming 25 years.

PubMed

Palatnik-de-Sousa, Clarisa B

2008-03-25

Human vaccination against leishmaniasis using live Leishmania was used in Middle East and Russia (1941-1980). First-generation vaccines, composed by killed parasites induce low efficacies (54%) and were tested in humans and dogs Phase III trials in Asia and South America since 1940. Second-generation vaccines using live genetically modified parasites, or bacteria or viruses containing Leishmania genes, recombinant or native fractions are known since the 1990s. Due to the loss of PAMPs, the use of adjuvants increased vaccine efficacies of the purified antigens to 82%, in Phase III dog trials. Recombinant second-generation vaccines and third-generation DNA vaccines showed average values of parasite load reduction of 68% and 59% in laboratory animal models, respectively, but their success in field trials had not yet been reported. This review is focused on vaccine candidates that show any efficacy against leishmaniasis and that are already in different phase trials. A lot of interest though was generated in recent years, by the studies going on in experimental models. The promising candidates may find a place in the forth coming years. Among them most probably are the multiple-gene DNA vaccines that are stable and do not require cold-chain transportation. In the mean time, second-generation vaccines with native antigens and effective adjuvants are likely to be licensed and used in Public Health control programs in the fore coming 25 years. To date, only three vaccines have been licensed for use: one live vaccine for humans in Uzbekistan, one killed vaccine for human immunotherapy in Brazil and a second-generation vaccine for dog prophylaxis in Brazil.

HERMIES-3: A step toward autonomous mobility, manipulation, and perception

NASA Technical Reports Server (NTRS)

Weisbin, C. R.; Burks, B. L.; Einstein, J. R.; Feezell, R. R.; Manges, W. W.; Thompson, D. H.

1989-01-01

HERMIES-III is an autonomous robot comprised of a seven degree-of-freedom (DOF) manipulator designed for human scale tasks, a laser range finder, a sonar array, an omni-directional wheel-driven chassis, multiple cameras, and a dual computer system containing a 16-node hypercube expandable to 128 nodes. The current experimental program involves performance of human-scale tasks (e.g., valve manipulation, use of tools), integration of a dexterous manipulator and platform motion in geometrically complex environments, and effective use of multiple cooperating robots (HERMIES-IIB and HERMIES-III). The environment in which the robots operate has been designed to include multiple valves, pipes, meters, obstacles on the floor, valves occluded from view, and multiple paths of differing navigation complexity. The ongoing research program supports the development of autonomous capability for HERMIES-IIB and III to perform complex navigation and manipulation under time constraints, while dealing with imprecise sensory information.

Minimizing shrinkage of interdental papilla height when treating multiple Miller Class III gingival recession defects.

PubMed

Mahn, Douglas H

2015-04-01

Miller Class III and IV gingival recession defects have interdental bone and soft-tissue loss that limit root coverage. Given the importance of the interdental papilla, protecting the integrity of this structure would seem prudent. Tunnel techniques have been successfully used to protect the interdental papilla. This article discusses the results of two cases in which multiple Miller Class III gingival recession defects were treated using tunnel-grafting techniques and an acellular dermal matrix. In both cases, root coverage was achieved while protecting the interdental papilla height.

Anti-MRSA beta-lactams in development, with a focus on ceftobiprole: the first anti-MRSA beta-lactam to demonstrate clinical efficacy.

PubMed

Bush, Karen; Heep, Markus; Macielag, Mark J; Noel, Gary J

2007-04-01

Ceftobiprole is the first of the investigational beta-lactam antibiotics with in vitro activity against methicillin-resistant staphylococci to reach and complete Phase III therapeutic trials. Its antibacterial spectrum includes methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, penicillin-resistant streptococci and many Gram-negative pathogens. It has demonstrated in vivo activity against many experimental infections caused by these pathogens. Ceftobiprole has completed Phase III clinical trials for complicated skin and skin structure infections, is being studied in Phase III pneumonia trials and has demonstrated non-inferiority compared with vancomycin in a Phase III complicated skin and skin structure infections trial, resulting in > 90% clinical cures of infections caused by MRSA. Other anti-MRSA beta-lactams in therapeutic clinical trials include the carbapenem CS-023/RO-4908463 and the cephalosporin ceftaroline (PPI-0903). The future of all of these agents will depend on their clinical efficacy, safety and their ability to be accepted as beta-lactams for the reliable treatment of a broad spectrum of infections, including those caused by MRSA.

HST/COS Far-ultraviolet Spectroscopic Analysis of U Geminorum Following a Wide Outburst

NASA Astrophysics Data System (ADS)

Godon, Patrick; Shara, Michael M.; Sion, Edward M.; Zurek, David

2017-12-01

We used the Cosmic Origins Spectrograph (COS) on the Hubble Space Telescope (HST) to obtain a series of four far-ultraviolet (FUV; 915-2148 Å) spectroscopic observations of the prototypical dwarf nova U Geminorum during its cooling following a two-week outburst. Our FUV spectral analysis of the data indicates that the white dwarf (WD) cools from a temperature of ˜41,500 K, 15 days after the peak of the outburst, to ˜36,250 K, 56 days after the peak of the outburst, assuming a massive WD (log(g) = 8.8) and a distance of 100.4 ± 3.7 pc. These results are self-consistent with a ˜1.1 M ⊙ WD with a 5000 ± 200 km radius. The spectra show absorption lines of H I, He II, C II III IV, N III IV, O VI, S IV, Si II III IV, Al III, Ar III, and Fe II, but no emission features. We find suprasolar abundances of nitrogen, confirming the anomalous high N/C ratio. The FUV light curve reveals a ±5% modulation with the orbital phase, showing dips near phases 0.25 and ˜0.75, where the spectra exhibit an increase in the depth of some absorption lines and in particular strong absorption lines from Si II, Al III, and Ar III. The phase dependence we observe is consistent with material overflowing the disk rim at the hot spot, reaching a maximum elevation near phase 0.75, falling back at smaller radii near phase 0.5 where it bounces off the disk surface, and again rising above the disk near phase ˜0.25. There is a large scatter in the absorption lines’ velocities, especially for the silicon lines, while the carbon lines seem to match more closely the orbital velocity of the WD. This indicates that many absorption lines are affected by—or form in—the overflowing stream material veiling the WD, making the analysis of the WD spectra more difficult. Based on observations made with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by AURA, Inc., under NASA contract NAS 5-26555.

Microbial exudate promoted dissolution and transformation of chromium containing minerals

NASA Astrophysics Data System (ADS)

Saad, E. M.; Sun, J.; Tang, Y.

2015-12-01

Because of its utility in many industrial processes, chromium has become the second most common metal contaminant in the United States. The two most common oxidation states of chromium in nature are Cr(III), which is highly immobile, and Cr(VI), which is highly mobile and toxic. In both natural and engineered environments, the most common remediation of Cr(VI) is through reduction, which results in chromium sequestration in the low solubility mixed Cr(III)-Fe(III) (oxy)hydroxide phases. Consequently, the stability of these minerals must be examined to assess the fate of chromium in the subsurface. We examined the dissolution of mixed Cr(III)-Fe(III) (oxy)hydroxides in the presence of common microbial exudates, including the siderophore desferrioxamine B (DFOB; a common organic ligand secreted by most microbes with high affinity for ferric iron and other trivalent metal ions) and oxalate (a common organic acid produced by microbes). The solids exhibited incongruent dissolution with preferential leaching of Fe from the solid phase. Over time, this leads to a more Cr rich mineral, which is known to be more soluble than the corresponding mixed mineral phase. We are currently investigating the structure of the reacted mineral phases and soluble Cr(III) species, as well as the potential oxidation and remobilization of the soluble Cr species. Results from this study will provide insights regarding the long term transport and fate of chromium in the natural environment in the presence of microbial activities.

The role of order-disorder transitions in the quest for molecular multiferroics: structural and magnetic neutron studies of a mixed valence iron(II)-iron(III) formate framework.

PubMed

Cañadillas-Delgado, Laura; Fabelo, Oscar; Rodríguez-Velamazán, J Alberto; Lemée-Cailleau, Marie-Hélène; Mason, Sax A; Pardo, Emilio; Lloret, Francesc; Zhao, Jiong-Peng; Bu, Xian-He; Simonet, Virginie; Colin, Claire V; Rodríguez-Carvajal, Juan

2012-12-05

Neutron diffraction studies have been carried out to shed light on the unprecedented order-disorder phase transition (ca. 155 K) observed in the mixed-valence iron(II)-iron(III) formate framework compound [NH(2)(CH(3))(2)](n)[Fe(III)Fe(II)(HCOO)(6)](n). The crystal structure at 220 K was first determined from Laue diffraction data, then a second refinement at 175 K and the crystal structure determination in the low temperature phase at 45 K were done with data from the monochromatic high resolution single crystal diffractometer D19. The 45 K nuclear structure reveals that the phase transition is associated with the order-disorder of the dimethylammonium counterion that is weakly anchored in the cavities of the [Fe(III)Fe(II)(HCOO)(6)](n) framework. In the low-temperature phase, a change in space group from P31c to R3c occurs, involving a tripling of the c-axis due to the ordering of the dimethylammonium counterion. The occurrence of this nuclear phase transition is associated with an electric transition, from paraelectric to antiferroelectric. A combination of powder and single crystal neutron diffraction measurements below the magnetic order transition (ca. 37 K) has been used to determine unequivocally the magnetic structure of this Néel N-Type ferrimagnet, proving that the ferrimagnetic behavior is due to a noncompensation of the different Fe(II) and Fe(III) magnetic moments.

Relative Contributions of Regional and Sector Emissions to the Radiative Forcing of Aerosol-Radiation and Aerosol-Cloud Interactions Based on the AeroCOM Phase III/HTAP2 Experiment

NASA Astrophysics Data System (ADS)

Takemura, T.; Chin, M.

2014-12-01

It is important to understand relative contributions of each regional and sector emission of aerosols and their precursor gases to the regional and global mean radiative forcing of aerosol-radiation and aerosol-cloud interactions. This is because it is useful for international cooperation on controls of air pollution and anthropogenic climate change along most suitable reduction path of their emissions from each region and sector. The Task Force on Hemispheric Transport of Air Pollution (TF HTAP) under the United Nations researches the intercontinental transport of air pollutants including aerosols with strong support of the Aerosol Comparisons between Observations and Models (AeroCOM). The ongoing AeroCOM Phase III/HTAP2 experiment assesses relative contributions of regional and sector sources of aerosols and their precursor gases to the air quality using global aerosol transport models with latest emission inventories. In this study, the extended analyses on the relative contributions of each regional and sector emission to the radiative forcing of aerosol-radiation and aerosol-cloud interactions are done from the AeroCOM Phase III/HTAP2 experiment. Simulated results from MIROC-SPRINTARS and other some global aerosol models participating in the the AeroCOM Phase III/HTAP2 experiment are assessed. Acknowledgements: This study is based on the AeroCOM Phase III/HTAP2 experiment and partly supported by the Environment Research and Technology Development Fund (S-12-3) of the Ministry of the Environment, Japan.

Safety and hemostatic efficacy of fibrin pad in partial nephrectomy: Results of an open-label Phase I and a randomized, standard-of-care-controlled Phase I/II study

PubMed Central

2012-01-01

Background Bleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages. Methods We evaluated the safety and hemostatic efficacy of a new advanced biologic combination product―fibrin pad―to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level. Results Phase I (N = 10): All patients completed the study. Hemostasis was achieved within 3–4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled. Conclusions The first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage. Trial registration Phase I/II trial, NCT00598130 PMID:23137020

Characterization of the Solid-Phase Behavior of n-Nonylammonium Tetrachlorocuprate by Fourier Transform Infrared Spectroscopy

NASA Astrophysics Data System (ADS)

Ning, Guo

1995-06-01

The solid-phase behavior of [n-C9H19NH3]2CuCl4 was investigated by infrared spectroscopy. The nature of the three solid phases (phase I, phase II, and phase III) is discussed. A temperature-dependent study of infrared spectra provides evidence for the occurrence of structural phase transitions related to the dynamics of the alkyl chains and -NH3 polar heads. The phase transition at Tc1 (22°C) arises from variation in the interaction and packing structure of the chain. The phase transition at Tc2 (34°C) is related to variation in partial conformational order-disorder at the intramolecular level. The GTG or GTG‧ and small concentration of TG structures near the CH3 group are generated in phase III (above 38°C).

Chemically-modified activated carbon with ethylenediamine for selective solid-phase extraction and preconcentration of metal ions.

PubMed

Li, Zhenhua; Chang, Xijun; Zou, Xiaojun; Zhu, Xiangbing; Nie, Rong; Hu, Zheng; Li, Ruijun

2009-01-26

A new method that utilizes ethylenediamine-modified activated carbon (AC-EDA) as a solid-phase extractant has been developed for simultaneous preconcentration of trace Cr(III), Fe(III), Hg(II) and Pb(II) prior to the measurement by inductively coupled plasma optical emission spectrometry (ICP-OES). The new sorbent was prepared by oxidative surface modification. Experimental conditions for effective adsorption of trace levels of Cr(III), Fe(III), Hg(II) and Pb(II) were optimized with respect to different experimental parameters using batch and column procedures in detail. The optimum pH value for the separation of metal ions simultaneously on the new sorbent was 4.0. Complete elution of absorbed metal ions from the sorbent surface was carried out using 3.0 mL of 2% (%w/w) thiourea and 0.5 mol L(-1) HCl solution. Common coexisting ions did not interfere with the separation and determination of target metal ions. The maximum static adsorption capacity of the sorbent at optimum conditions was found to be 39.4, 28.9, 60.5 and 49.9 mg g(-1) for Cr(III), Fe(III), Hg(II) and Pb(II), respectively. The time for 94% adsorption of target metal ions was less than 2 min. The detection limits of the method was found to be 0.28, 0.22, 0.09 and 0.17 ng mL(-1) for Cr(III), Fe(III), Hg(II) and Pb(II), respectively. The precision (R.S.D.) of the method was lower 4.0% (n=8). The prepared sorbent as solid-phase extractant was successfully applied for the preconcentration of trace Cr(III), Fe(III), Hg(II) and Pb(II) in natural and certified samples with satisfactory results.

Cladribine tablets: in relapsing-remitting multiple sclerosis.

PubMed

Muir, Victoria J; Plosker, Greg L

2011-03-01

Cladribine, an immunosuppressant that selectively reduces peripheral lymphocyte levels, has potential as an oral therapy for relapsing-remitting multiple sclerosis. An oral (tablet) formulation is being investigated in clinical trials. In the large, well designed, phase III CLARITY trial, short-course treatment with oral cladribine (cumulative dose of 3.5 or 5.25 mg/kg) resulted in a significantly greater reduction in annualized relapse rates at 96 weeks compared with placebo in patients with relapsing-remitting multiple sclerosis. Improvements in the annualized relapse rate with oral cladribine were independent of key baseline patient characteristics which included age, sex, previous treatment with disease-modifying drugs and the number of relapses in the previous 12 months. In addition, a significantly higher proportion of patients were relapse-free at 96 weeks and there were significant reductions in the risk of 3-month sustained progression of disability in cladribine recipients compared with placebo recipients. The mean numbers of brain lesions on magnetic resonance imaging were also significantly reduced with cladribine compared with placebo in the CLARITY trial. Lymphocytopenia, herpes zoster infections and neoplasms (including malignancies) were more common in cladribine than placebo recipients.

Autologous Stem Cell Transplant Followed By Maintenance Therapy in Treating Elderly Patients With Multiple Myeloma

ClinicalTrials.gov

2018-02-27

Extramedullary Plasmacytoma; Isolated Plasmacytoma of Bone; Light Chain Deposition Disease; Primary Systemic Amyloidosis; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma

Maximizing Patient Recruitment and Retention in a Secondary Stroke Prevention Clinical Trial: Lessons Learned from the STAND FIRM Study.

PubMed

Thayabaranathan, Tharshanah; Cadilhac, Dominique A; Srikanth, Velandai K; Fitzgerald, Sharyn M; Evans, Roger G; Kim, Joosup; Gerraty, Richard P; Phan, Thanh G; Bladin, Christopher F; Nelson, Mark R; Frayne, Judith H; Thrift, Amanda G

2016-06-01

Recruitment and retention of patients in a clinical trial is important for generalizability and robustness of findings. We aimed to investigate features of a study design that were associated with recruitment and retention in a Phase II and Phase III trial of a secondary prevention program for stroke. Following informed consent in hospital, Phase II participants were randomized to intervention or usual care. Baseline clinical assessments were conducted at home approximately 3 months after discharge. In Phase III study, informed consent was obtained at home. We compared the characteristics of participants recruited and retained to 12 months for both phases. Interviews with study nurses were undertaken in order to ascertain their opinions of features of study design. Triangulation was used to identify the features of study design that nurses thought had improved recruitment and retention. All 24 eligible participants were recruited to the Phase II pilot study (100% recruitment), with 67% retention at 12 months. In Phase III study, 570 participants were recruited, and 93% of these participants had reached their 12-month assessment (n = 532) and were still participating. Consistent with the greater patient retention in Phase III study, nurses reported that patients' willingness to participate was greater when consent was obtained at home. Following a change in the consent process from hospital to home, more participants continued participation to 12 months. Pilot studies can provide important data to improve study design and better understand potential barriers to recruitment and retention. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Anal Cancer: An Examination of Radiotherapy Strategies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glynne-Jones, Rob; Lim, Faye

2011-04-01

The Radiation Therapy Oncology Group 9811, ACCORD-03, and ACT II Phase III trials in anal cancer showed no benefit for cisplatin-based induction and maintenance chemotherapy, or radiation dose-escalation >59 Gy. This review examines the efficacy and toxicity of chemoradiation (CRT) in anal cancer, and discusses potential alternative radiotherapy strategies. The evidence for the review was compiled from randomized and nonrandomized trials of radiation therapy and CRT. A total of 103 retrospective/observational studies, 4 Phase I/II studies, 16 Phase II prospective studies, 2 randomized Phase II studies, and 6 Phase III trials of radiotherapy or chemoradiation were identified. There are nomore » meta-analyses based on individual patient data. A 'one-size-fits-all' approach for all stages of anal cancer is inappropriate. Early T1 tumors are probably currently overtreated, whereas T3/T4 lesions might merit escalation of treatment. Intensity-modulated radiotherapy or the integration of biological therapy may play a role in future.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Noel, Donna

This project integrated state-of-the-art exploration technologies with a geologic framework and reservoir modeling to ultimately determine the efficacy of future geothermal production within the PLPT reservation. The information gained during this study should help the PLPT to make informed decisions regarding construction of a geothermal power plant. Additional benefits included the transfer of new technologies and geothermal data to the geothermal industry and it created and/or preserved nearly three dozen jobs accordance with the American Recovery and Reinvestment Act of 2009. A variety of tasks were conducted to achieve the above stated objectives. The following are the tasks completed withinmore » the project: 1. Permitting 2. Shallow temperature survey 3. Seismic data collection and analysis 4. Fracture stress analysis 5. Phase I reporting Permitting 7. Shallow temperature survey 8. Seismic data collection and analysis 9. Fracture stress analysis 10. Phase I reporting 11. Drilling two new wells 12. Borehole geophysics 13. Phase II reporting 14. Well testing and geochemical analysis 15. Three-dimensional geologic model 16. Three-dimensional reservoir analysis 17. Reservation wide geothermal potential analysis 18. Phase III reporting Phase I consisted of tasks 1 – 5, Phase II tasks 6 – 8, and Phase III tasks 9 – 13. This report details the results of Phase III tasks. Reports are available for Phase I, and II as separate documents.« less

Evaluation of early efficacy endpoints for proof-of-concept trials.

PubMed

Chen, Cong; Sun, Linda; Li, Chih-Lin

2013-03-11

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

Action of Brazilian propolis on hematological and serum biochemical parameters of Blue-fronted Amazons (Amazona aestiva, Linnaeus, 1758) in captivity.

PubMed

Silva, Cínthia R B; Putarov, Thaila C; Fruhvald, Erika; Destro, Flavia C; Marques Filho, Wolff C; Thomazini, Camila M; Barbosa, Tatiana S; Orsi, Ricardo O; Siqueira, Edson R

2014-07-01

The present study aimed to evaluate the effect of propolis use on hematological and serum biochemical parameters in Blue-fronted Amazons (Amazona aestiva). For this, 12 adult birds were distributed randomly into individual cages, divided into treatments with different propolis levels (A = 0.0%; B = 0.5%; and C = 1.0%), in 3 distinct phases (I, II, and III), with 15-d duration for phases I and III and 30 d for phase II, totaling 60 d. In phases I and III, all birds received treatment A ration, and in phase II received A, B, or C (4 birds per treatment). At the end of each phase, blood was collected for biochemical and hematological evaluations. The variables were analyzed by ANOVA (P < 0.05). Results suggest that 0.5% propolis reduced lactate dehydrogenase levels, whereas treatment B augmented hemoglobin concentrations and eosinophil count. It is concluded that 0.5% propolis improves levels of lactate dehydrogenase, hemoglobin, and eosinophils. © 2014 Poultry Science Association Inc.

Dynamics of amino acid utilization in Phaeobacter inhibens DSM 17395.

PubMed

Zech, Hajo; Hensler, Michael; Koßmehl, Sebastian; Drüppel, Katharina; Wöhlbrand, Lars; Trautwein, Kathleen; Colby, Thomas; Schmidt, Jürgen; Reinhardt, Richard; Schmidt-Hohagen, Kerstin; Schomburg, Dietmar; Rabus, Ralf

2013-10-01

Time-resolved utilization of multiple amino acids by Phaeobacter inhibens DSM 17395 was studied during growth with casamino acids. The 15 detected amino acids could be grouped according to depletion rate into four different categories, i.e. from rapid (category I) to nondepletion (category IV). Upon entry into stationary growth phase, amino acids of category I (e.g. glutamate) were (almost) completely depleted, while those of categories II (e.g. leucine) and III (e.g. serine) were further consumed at varying rates and to different extents. Thus, cultures entered stationary growth phase despite the ample presence of organic nutrients, i.e. under nonlimiting conditions. Integrated proteomic and metabolomic analysis identified 1747 proteins and 94 intracellular metabolites. Of these, 180 proteins and 86 metabolites displayed altered abundance levels during growth. Most strikingly, abundance and activity profiles of alanine dehydrogenase concomitantly increased with the onset of enhanced alanine utilization during transition into stationary growth phase. Most enzymes of amino acid and central metabolism, however, displayed unaltered abundances across exponential and stationary growth phases. In contrast, metabolites of the Entner-Doudoroff pathway and gluconeogenesis as well as cellular fatty acids increased markedly in abundance in early stationary growth phase. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structural, magnetic and phonon properties of Cr(III)-doped perovskite metal formate framework [(CH{sub 3}){sub 2}NH{sub 2}][Mn(HCOO){sub 3}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mączka, Mirosław, E-mail: m.maczka@int.pan.wroc.pl; Gągor, Anna; Hermanowicz, Krzysztof

2016-05-15

We have incorporated Cr(III) into [(CH{sub 3}){sub 2}NH{sub 2}][Mn(HCOO){sub 3}] (DMMn) multiferroic metal organic framework (MOF). The highest concentration of Cr(III) in the synthesized samples reached 15.9 mol%. The obtained samples were characterized by powder and single-crystal X-ray diffraction, DSC, magnetic susceptibility, dielectric, EPR, Raman and IR methods. These methods and the performed chemical analysis revealed that electrical charge neutrality after substitution of Cr(III) for Mn(II) is maintained by partial replacement of dimethylammonium (DMA{sup +}) cations by neutral HCOOH molecules. These changes in the chemical composition are responsible for weakening of the hydrogen bonds and decreased flexibility of the framework.more » This in turn leads to lowering of the ferroelectric phase transition temperature, observed around 185 K for undoped DMMn and around 155 K for the sample containing 3.1 mol% of Cr(III), and lack of macroscopic phase transition for the samples with Cr(III) content of 8.2 and 15.9 mol %. Another interesting effect observed for the studied samples is pronounced strengthening of the weak ferromagnetism of in Cr(III)-doped samples, associated with slight decrease of the ferromagnetic ordering temperature from 8.5 K for DMMn to 7.0 K for the sample with 15.9 mol % Cr(III) content. - Graphical abstract: Incorporation of Cr(III) into [(CH3)2NH2[Mn(HCOO)3] framework increases the magnetization. - Highlights: • Chromium(III) substitutes for Mn(II) in the studied MOF. • Charge neutrality is maintained by replacing DMA{sup +} cations by neutral HCOOH molecules. • Compounds with 8.2 and 15.9% of Cr(III) show no phase transition above 100 K. • Doping with Cr(III) increases magnetization.« less

A green separation strategy for neodymium (III) from cobalt (II) and nickel (II) using an ionic liquid-based aqueous two-phase system.

PubMed

Chen, Yuehua; Wang, Huiyong; Pei, Yuanchao; Wang, Jianji

2018-05-15

It is significant to develop sustainable strategies for the selective separation of rare earth from transition metals from fundamental and practical viewpoint. In this work, an environmentally friendly solvent extraction approach has been developed to selectively separate neodymium (III) from cobalt (II) and nickel (II) by using an ionic liquid-based aqueous two phase system (IL-ATPS). For this purpose, a hydrophilic ionic liquid (IL) tetrabutylphosphonate nitrate ([P 4444 ][NO 3 ]) was prepared and used for the formation of an ATPS with NaNO 3 . Binodal curves of the ATPSs have been determined for the design of extraction process. The extraction parameters such as contact time, aqueous phase pH, content of phase-formation components of NaNO 3 and the ionic liquid have been investigated systematically. It is shown that under optimal conditions, the extraction efficiency of neodymium (III) is as high as 99.7%, and neodymium (III) can be selectively separated from cobalt (II) and nickel (II) with a separation factor of 10 3 . After extraction, neodymium (III) can be stripped from the IL-rich phase by using dilute aqueous sodium oxalate, and the ILs can be quantitatively recovered and reused in the next extraction process. Since [P 4444 ][NO 3 ] works as one of the components of the ATPS and the extractant for the neodymium, no organic diluent, extra etractant and fluorinated ILs are used in the separation process. Thus, the strategy described here shows potential in green separation of neodymium from cobalt and nickel by using simple IL-based aqueous two-phase system. Copyright © 2018 Elsevier B.V. All rights reserved.

Clinical phase I/II research on ultrasound thermo-chemotherapy in oral and maxillofacial-head and neck carcinoma

NASA Astrophysics Data System (ADS)

Shen, Guofeng; Ren, Guoxin; Guo, Wei; Chen, Yazhu

2012-11-01

The principle of a ultrasound thermo-chemotherapy instrument and the clinical phase I/II research on short-term and long-term therapeutic effect and main side-effect of ultrasound hyperthermia combined with chemotherapy in oral and maxillofacial-head & neck carcinoma by the instrument will be presented in this paper.

SPSP Phase III Recruiting, Selecting, and Developing Secure Power Systems Professionals: Behavioral Interview Guidelines by Job Roles

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Neil, Lori Ross; Conway, T. J.; Tobey, D. H.

The Secure Power Systems Professional Phase III final report was released last year which an appendix of Behavioral Interview Guidelines by Job Roles. This new report is that appendix broken out as a standalone document to assist utilities in recruiting and developing Secure Power Systems Professionals at their site.

SPSP Phase III Recruiting, Selecting, and Developing Secure Power Systems Professionals. Individual and Team Performance Guidelines

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Neil, Lori Ross; Conway, T. J.; Tobey, D. H.

The Secure Power Systems Professional Phase III final report was released last year which an appendix of Individual and Team Performance Guidelines. This new report is that appendix broken out as a standalone document to assist utilities in recruiting and developing Secure Power Systems Professionals at their site.

Gas-phase infrared spectrum of phosphorus (III) oxycyanide, OPCN: experimental and theoretical investigations

NASA Astrophysics Data System (ADS)

Allaf, Abdul. W.; Kassem, M.; Alibrahim, M.; Boustani, Ihsan

1999-03-01

An attempt was made to observe the gas-phase infrared spectrum of Phosphorus (III) oxycyanide, OPCN for the first time. This molecule was produced by an on-line process using phosphorus (III) oxychloride, OPCl as precursor passed over heated AgCN. The products were characterised by the infrared spectra of their vapours. The low resolution gas-phase Fourier transform infrared spectrum shows two bands centered at 2165 and 1385 cm -1. These bands are assigned to, ν1 (CN stretch) and ν2 (OP stretch), respectively. Ab initio self-consistent-field (SCF) molecular orbital (MO) and Møller-Plesset second order perturbation theory (MP2) calculations were performed to determine the geometry, total energy and vibrational frequencies of OPCN.

Simultaneous determination and pharmacokinetic study of Atractylenolide I, II and III in rat plasma after intragastric administration of Baizhufuling extract and Atractylodis extract by UPLC-MS/MS.

PubMed

Yan, Han; Sun, Yuanyuan; Zhang, Qili; Yang, Mingjing; Wang, Xiaorui; Wang, Yang; Yu, Zhiguo; Zhao, Yunli

2015-07-01

A simple and rapid ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of Atractylenolide I, II and III in rat plasma. Plasma samples were processed by liquid-liquid extraction with ethyl acetate, using schisandrin as internal standard (IS). Chromatographic separation was accomplished on a Thermo Hypersil GOLD C18 column (2.1mm×50mm, 1.9μm) with mobile phase consisting of acetonitrile and 0.1% formic acid-water (50:50, v/v). The detection was carried out by ESI-MS (positive ionization mode) and low-energy collision dissociation tandem mass spectrometric analyses using the multiple-reaction monitoring (MRM) scan mode. The quantification was performed using the transitions of the protonated molecule→product ion at m/z 231.0→185.1 for Atractylenolide I, at m/z 233.1→187.1 for Atractylenolide II and at m/z 249.1→231.1 for Atractylenolide III, respectively. Method validation revealed excellent linearity over investigated range together with satisfactory intra- and inter-day precision, accuracy, matrix effects and extraction recoveries. This method was successfully applied to the comparative pharmacokinetic study of Atractylenolide I, II and III in rat plasma after intragastric administration of Baizhufuling extract and Atractylodis extract. Copyright © 2015 Elsevier B.V. All rights reserved.

Biogeochemical transformation of Fe minerals in a petroleum-contaminated aquifer

USGS Publications Warehouse

Zachara, John M.; Kukkadapu, Ravi K.; Glassman, Paul L.; Dohnalkova, Alice; Fredrickson, Jim K.; Anderson, Todd

2004-01-01

The Bemidji aquifer in Minnesota, USA is a well-studied site of subsurface petroleum contamination. The site contains an anoxic groundwater plume where soluble petroleum constituents serve as an energy source for a region of methanogenesis near the source and bacterial Fe(III) reduction further down gradient. Methanogenesis apparently begins when bioavailable Fe(III) is exhausted within the sediment. Past studies indicate that Geobacter species and Geothrix fermentens-like organisms are the primary dissimilatory Fe-reducing bacteria at this site. The Fe mineralogy of the pristine aquifer sediments and samples from the methanogenic (source) and Fe(III) reducing zones were characterized in this study to identify microbiologic changes to Fe valence and mineral distribution, and to identify whether new biogenic mineral phases had formed. Methods applied included X-ray diffraction; X-ray fluorescence (XRF); and chemical extraction; optical, transmission, and scanning electron microscopy; and Mössbauer spectroscopy.All of the sediments were low in total Fe content (≈ 1%) and exhibited complex Fe-mineralogy. The bulk pristine sediment and its sand, silt, and clay-sized fractions were studied in detail. The pristine sediments contained Fe(II) and Fe(III) mineral phases. Ferrous iron represented approximately 50% of FeTOT. The relative Fe(II) concentration increased in the sand fraction, and its primary mineralogic residence was clinochlore with minor concentrations found as a ferroan calcite grain cement in carbonate lithic fragments. Fe(III) existed in silicates (epidote, clinochlore, muscovite) and Fe(III) oxides of detrital and authigenic origin. The detrital Fe(III) oxides included hematite and goethite in the form of mm-sized nodular concretions and smaller-sized dispersed crystallites, and euhedral magnetite grains. Authigenic Fe(III) oxides increased in concentration with decreasing particle size through the silt and clay fraction. Chemical extraction and Mössbauer analysis indicated that this was a ferrihydrite like-phase. Quantitative mineralogic and Fe(II/III) ratio comparisons between the pristine and contaminated sediments were not possible because of textural differences. However, comparisons between the texturally-similar source (where bioavailable Fe(III) had been exhausted) and Fe(III) reducing zone sediments (where bioavailable Fe(III) remained) indicated that dispersed detrital, crystalline Fe(III) oxides and a portion of the authigenic, poorly crystalline Fe(III) oxide fraction had been depleted from the source zone sediment by microbiologic activity. Little or no effect of microbiologic activity was observed on silicate Fe(III). The presence of residual “ferrihydrite” in the most bioreduced, anoxic plume sediment (source) implied that a portion of the authigenic Fe(III) oxides were biologically inaccessible in weathered, lithic fragment interiors. Little evidence was found for the modern biogenesis of authigenic ferrous-containing mineral phases, perhaps with the exception of thin siderite or ferroan calcite surface precipitates on carbonate lithic fragments within source zone sediments.

Design and implementation of a software package to control a network of robotic observatories

NASA Astrophysics Data System (ADS)

Tuparev, G.; Nicolova, I.; Zlatanov, B.; Mihova, D.; Popova, I.; Hessman, F. V.

2006-09-01

We present a description of a reusable software package able to control a large, heterogeneous network of fully and semi-robotic observatories initially developed to run the MONET network of two 1.2 m telescopes. Special attention is given to the design of a robust, long-term observation scheduler which also allows the trading of observation time and facilities within various networks. The handling of the ``Phase I&II" project-development process, the time-accounting between complex organizational structures, and usability issues for making the package accessible not only to professional astronomers, but also to amateurs and high-school students is discussed. A simple RTML-based solution to link multiple networks is demonstrated.

Three years of experience: the Italian registry and safety data update.

PubMed

Mancardi, G L; Tedeschi, G; Amato, M P; D'Alessandro, R; Drago, F; Milanese, C; Popoli, P; Rossi, P; Savettieri, G; Tola, M R; Comi, G; Pozzilli, C; Bertolotto, A; Marrosu, M G; Grimaldi, L M E; Laroni, A; Vanacore, N; Covezzoli, A; De Rosa, M; Piccinni, C; Montanaro, N; Periotto, L; Iommelli, R; Tomino, C; Provinciali, L

2011-01-01

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series.

PubMed

Wolf, Jeffrey; Richardson, Paul G; Schuster, Michael; LeBlanc, Annette; Walters, Ian B; Battleman, David S

2008-10-01

Bortezomib therapy has become an important part of the standard of care for patients with relapsed multiple myeloma, and preliminary clinical evidence suggests that bortezomib retreatment in patients previously treated with the drug may prolong disease control. This retrospective study was designed to clarify the utility of bortezomib as a repeat therapy. We reviewed records from 3 major cancer centers that had participated in the phase II (SUMMIT or CREST) or phase III (APEX) registration studies to identify patients who were subsequently retreated off protocol with bortezomib-based therapy. We found 22 patients who received bortezomib retreatment following a 60 or more day gap between bortezomib treatments. Twelve patients had intervening therapy between initial bortezomib treatment and bortezomib retreatment. During retreatment, 14 of 22 patients received bortezomib in combination with another antineoplastic agent. The overall response rate for bortezomib retreatment was 50% (9% complete responses). The median length of retreatment was 5.1 months in responding patients and 2.4 months in nonresponding patients. Therapy was terminated due to unmanageable toxicity in 2 patients during retreatment, compared with 6 patients during initial treatment. During retreatment, no patients required dose reduction due to peripheral neuropathy, compared to 4 patients during their initial treatment. Thus, bortezomib retreatment appears to be safe and effective. Favorable observed response rates with bortezomib retreatment suggest that it may be a viable option for relapsed or refractory multiple myeloma, even in patients previously exposed to bortezomib.

Thermal neutron detector and gamma-ray spectrometer utilizing a single material

DOEpatents

Stowe, Ashley; Burger, Arnold; Lukosi, Eric

2017-05-02

A combined thermal neutron detector and gamma-ray spectrometer system, including: a detection medium including a lithium chalcopyrite crystal operable for detecting thermal neutrons in a semiconductor mode and gamma-rays in a scintillator mode; and a photodetector coupled to the detection medium also operable for detecting the gamma rays. Optionally, the detection medium includes a .sup.6LiInSe.sub.2 crystal. Optionally, the detection medium comprises a compound formed by the process of: melting a Group III element; adding a Group I element to the melted Group III element at a rate that allows the Group I and Group III elements to react thereby providing a single phase I-III compound; and adding a Group VI element to the single phase I-III compound and heating; wherein the Group I element includes lithium.

Etravirine: R165335, TMC 125, TMC-125, TMC125.

PubMed

2006-01-01

Etravirine [TMC 125] is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed by Tibotec (Tibotec-Virco Group; now Johnson & Johnson) for the treatment of HIV-1 infections. Etravirine is a highly flexible, di-aryl-pyrimidine (DAPY) compound. The flexibility enables favourable binding interactions with mutant HIV strains as well as wild-type virus. Etravirine has superseded dapivirine as Tibotec's lead NNRTI in clinical development worldwide. Tibotec merged with Virco to form Tibotec-Virco Group in March 2001. Subsequently, Tibotec-Virco Group was acquired by Johnson & Johnson on 18 April 2002. Etravirine was discovered by Tibotec in collaboration with the Janssen Research Foundation. However, the Janssen Research Foundation is no longer involved in the development of etravirine. Etravirine has received fast-track status from the US FDA for the treatment of HIV-1 infections. An expanded access programme for etravirine began in the US in September 2006. The programme made etravirine available to HIV-1 infected adults who have limited treatment options due to virological failure or intolerance to multiple antiretroviral regimens. The progamme will also be introduced in Canada and Europe. In November 2005, Tibotec initiated two randomised, placebo-controlled phase III trials of etravirine in treatment-experienced HIV-1 infected patients with NNRTI resistance and at least three primary protease mutations. The two trials will each enroll 600 patients and will be conducted in 18 countries. Darunavir will be used as the background protease inhibitor in the trials. This is the first time that two investigational antivirals have been evaluated in combination in heavily treatment-experienced patients. The trial design is supported by the FDA, the Committee for Medicinal Products for Human Use (CHMP) of the EMEA and the HIV patient community. Patient enrolment in the two phase III trials was completed in September 2006. A multicentre phase IIb dose-finding study (TMC125 C223) in Europe, Canada and the US found etravirine significantly reduced the HIV viral load in a subset of heavily treatment-experienced patients. Tibotec discontinued a single exploratory open-label phase II trial (TMC 125-C227) of etravirine in November 2005. The discontinuation was a result of 12-week data, which demonstrated a difference in the proportion of patients achieving or maintaining undetectable viral load in favour of the control group, who were receiving protease inhibitor-based treatment. There were no safety concerns and the discontinuation had no effect on phase III registration trials. Phase IIa clinical trials of etravirine for the treatment of HIV infections, initiated in November 2001, have been completed. Tibotec has conducted a phase I trial (TMC125-C157 study) evaluating etravirine + didanosine among healthy volunteers in Belgium; trial results have been presented.

Cd Mobility in Anoxic Fe-Mineral-Rich Environments - Potential Use of Fe(III)-Reducing Bacteria in Soil Remediation

NASA Astrophysics Data System (ADS)

Muehe, E. M.; Adaktylou, I. J.; Obst, M.; Schröder, C.; Behrens, S.; Hitchcock, A. P.; Tylsizczak, T.; Michel, F. M.; Krämer, U.; Kappler, A.

2014-12-01

Agricultural soils are increasingly burdened with heavy metals such as Cd from industrial sources and impure fertilizers. Metal contaminants enter the food chain via plant uptake from soil and negatively affect human and environmental health. New remediation approaches are needed to lower soil metal contents. To apply these remediation techniques successfully, it is necessary to understand how soil microbes and minerals interact with toxic metals. Here we show that microbial Fe(III) reduction initially mobilizes Cd before its immobilization under anoxic conditions. To study how microbial Fe(III) reduction influences Cd mobility, we isolated a new Cd-tolerant, Fe(III)-reducing Geobacter sp. from a heavily Cd-contaminated soil. In lab experiments, this Geobacter strain first mobilized Cd from Cd-loaded Fe(III) hydroxides followed by precipitation of Cd-bearing mineral phases. Using Mössbauer spectroscopy and scanning electron microscopy, the original and newly formed Cd-containing Fe(II) and Fe(III) mineral phases, including Cd-Fe-carbonates, Fe-phosphates and Fe-(oxyhydr)oxides, were identified and characterized. Using energy-dispersive X-ray spectroscopy and synchrotron-based scanning transmission X-ray microscopy, Cd was mapped in the Fe(II) mineral aggregates formed during microbial Fe(III) reduction. Microbial Fe(III) reduction mobilizes Cd prior to its precipitation in Cd-bearing mineral phases. The mobilized Cd could be taken up by phytoremediating plants, resulting in a net removal of Cd from contaminated sites. Alternatively, Cd precipitation could reduce Cd bioavailability in the environment, causing less toxic effects to crops and soil microbiota. However, the stability and thus bioavailability of these newly formed Fe-Cd mineral phases needs to be assessed thoroughly. Whether phytoremediation or immobilization of Cd in a mineral with reduced Cd bioavailability are feasible mechanisms to reduce toxic effects of Cd in the environment remains to be determined.

A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).

PubMed

Bellmunt, J; Kerst, J M; Vázquez, F; Morales-Barrera, R; Grande, E; Medina, A; González Graguera, M B; Rubio, G; Anido, U; Fernández Calvo, O; González-Billalabeitia, E; Van den Eertwegh, A J M; Pujol, E; Perez-Gracia, J L; González Larriba, J L; Collado, R; Los, M; Maciá, S; De Wit, R

2017-07-01

Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine. This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms. This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously. NCT01830231. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Solid phase extraction and spectrophotometric determination of Au(III) with 5-(2-hydroxy-5-nitrophenylazo)thiorhodanine.

PubMed

Hu, Qiufen; Chen, Xiubin; Yang, Xiangjun; Huang, Zhangjie; Chen, Jing; Yang, Guangyu

2006-04-01

A new chromogenic reagent, 5-(2-hydroxy-5-nitrophenylazo)thiorhodanine (HNATR) was synthesized. A highly sensitive, selective and rapid method for the determination microg l(-1) level of Au(III) based on the rapid reaction of Au(III) with HNATR and the solid phase extraction of the colored complex with a reversed phase polymer-based C(18) cartridge have been developed. The HNATR reacted with Au(III) to form a red complex of a molar ratio 1:2 (Au(III) to HNATR) in the presence of 0.05 - 0.5 mol l(-1) of phosphoric acid solution and emulsifier-OP medium. This complex was enriched by the solid phase extraction with a polymer-based C(18) cartridge. The enrichment factor of 100 was achieved. The molar absorptivity of the complex is 1.37 x 10(5) l mol(-1) cm(-1) at 520 nm in the measured solution. The system obeys Beer's law in the range of 0.01 - 3 microg ml(-1). The relative standard deviation for eleven replicates sample of 0.5 microg l(-1) level is 2.18%. The detection limit, based on the three times of standard deviation is 0.02 microg l(-1) in the original sample. This method was applied to the determination of gold in water and ore with good results.

Preparation of III-V semiconductor nanocrystals

DOEpatents

Alivisatos, A. Paul; Olshavsky, Michael A.

1996-01-01

Nanometer-scale crystals of III-V semiconductors are disclosed, They are prepared by reacting a group III metal source with a group V anion source in a liquid phase at elevated temperature in the presence of a crystallite growth terminator such as pyridine or quinoline.

A hybrid approach to device integration on a genetic analysis platform

NASA Astrophysics Data System (ADS)

Brennan, Des; Jary, Dorothee; Kurg, Ants; Berik, Evgeny; Justice, John; Aherne, Margaret; Macek, Milan; Galvin, Paul

2012-10-01

Point-of-care (POC) systems require significant component integration to implement biochemical protocols associated with molecular diagnostic assays. Hybrid platforms where discrete components are combined in a single platform are a suitable approach to integration, where combining multiple device fabrication steps on a single substrate is not possible due to incompatible or costly fabrication steps. We integrate three devices each with a specific system functionality: (i) a silicon electro-wetting-on-dielectric (EWOD) device to move and mix sample and reagent droplets in an oil phase, (ii) a polymer microfluidic chip containing channels and reservoirs and (iii) an aqueous phase glass microarray for fluorescence microarray hybridization detection. The EWOD device offers the possibility of fully integrating on-chip sample preparation using nanolitre sample and reagent volumes. A key challenge is sample transfer from the oil phase EWOD device to the aqueous phase microarray for hybridization detection. The EWOD device, waveguide performance and functionality are maintained during the integration process. An on-chip biochemical protocol for arrayed primer extension (APEX) was implemented for single nucleotide polymorphism (SNiP) analysis. The prepared sample is aspirated from the EWOD oil phase to the aqueous phase microarray for hybridization. A bench-top instrumentation system was also developed around the integrated platform to drive the EWOD electrodes, implement APEX sample heating and image the microarray after hybridization.

Ankle Sprain Treatment

MedlinePlus

... strengthening exercise"). Resume low-impact aerobic training; maintain general fitness. III Phase III treatment focuses on restoring ankle proprioception (balance and position awareness) as well as agility and ...

Higher plasma motilin levels in obese patients decrease after Roux-en-Y gastric bypass surgery and regulate hunger.

PubMed

Deloose, E; Janssen, P; Lannoo, M; Van der Schueren, B; Depoortere, I; Tack, J

2016-07-01

Motilin-induced phase III contractions of the migrating motor complex (MMC) signal hunger in healthy volunteers. The current aim was to study the role of motilin as a hunger-inducing factor in obese patients and to evaluate the effect of Roux-en-Y gastric bypass (RYGB) surgery on plasma motilin levels and hunger scores. Motilin and ghrelin plasma levels were determined during a complete MMC cycle in controls and obese patients selected for RYGB before, 6 months and 1 year after surgery. 20 min after the end of the second phase III, obese patients received an intravenous infusion of 40 mg erythromycin. Hunger was scored every 5 min. Hedonic hunger was assessed in obese patients with the Power of Food Scale questionnaire. Obesity caused a switch in the origin of phase III from antrum to duodenum. Obese patients had significantly higher motilin levels compared with controls during the MMC but tended to lack the motilin peak prior to phase III necessary to trigger hunger. Hunger scores during phase III were significantly lower in obese patients, but could be restored to control levels through the administration of a low dose of the motilin agonist, erythromycin. After RYGB surgery motilin, but not ghrelin, levels decreased in parallel with hedonic hunger scores. Motilin may be an important regulator involved in the pathogenesis of obesity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Stakeholder perspectives on the use of positron emission tomography in phase III oncology trials in the UK.

PubMed

Rojas-Anaya, Hector; Skogen, Karoline; Miles, Kenneth Alan

2012-06-01

To identify factors that influence the use of PET in phase III oncology trials in the UK by evaluating stakeholder perspectives. A wide range of UK PET research stakeholders with a potential interest in the use of PET in phase III trials were identified and invited to participate. These UK PET research stakeholders were consulted using a semistructured questionnaire on their personal experience with and involvement in PET research, the role of PET in phase III oncology clinical trials and on the promotion of UK PET research and unmet clinical needs in oncology. Responses were analysed quantitatively and by qualitative content analysis of free-text responses. A total of 118 responses were received from a wide range of stakeholders representing several professional groups and working environments. Of these respondents, 49 (42%) were using PET in their research. There was the general perception that using PET in clinical research is beneficial in oncology. The two major barriers identified were poor availability of PET and perceived difficulties in funding of excess treatment costs (75% of respondents). Other factors included limited coverage of PET in training, uncertainty about developing imaging protocols or the status of tracers other than 18F-fluorodeoxyglucose, and low awareness of the role of PET in patient selection for therapeutic trials. Patient concerns about radiation were not perceived as a research barrier. Interventions that improve the availability and funding pathways for PET research scans and that increase researcher awareness could help promote the use of PET for phase III oncology trials in the UK.

Objectives and methodology of BIOBADASER phase iii.

PubMed

Sanchez-Piedra, Carlos; Hernández Miguel, M Victoria; Manero, Javier; Roselló, Rosa; Sánchez-Costa, Jesús Tomás; Rodríguez-Lozano, Carlos; Campos, Cristina; Cuende, Eduardo; Fernández-Lopez, Jesús Carlos; Bustabad, Sagrario; Martín Domenech, Raquel; Pérez-Pampín, Eva; Del Pino-Montes, Javier; Millan-Arcineas, Ana Milena; Díaz-González, Federico; Gómez-Reino, Juan Jesús

2017-09-18

Describe the objectives, methods and results of the first year of the new version of the Spanish registry of adverse events involving biological therapies and synthetic drugs with an identifiable target in rheumatic diseases (BIOBADASER III). Multicenter prospective registry of patients with rheumatic inflammatory diseases being treated with biological drugs or synthetic drugs with an identifiable target in rheumatology departments in Spain. The main objective of BIOBADASER Phase III is the registry and analysis of adverse events; moreover, a secondary objective was added consisting of assessing the effectiveness by means of the registry of activity indexes. Patients in the registry are evaluated at least once every year and whenever they experience an adverse event or a change in treatment. The collection of data for phase iii began on 17 December 2015. During the first year, 35 centers participated. The number of patients included in this new phase in December 2016 was 2,664. The mean age was 53.7 years and the median duration of treatment was 8.1 years. In all, 40.4% of the patients were diagnosed with rheumatoid arthritis. The most frequent adverse events were infections and infestations. BIOBADASER Phase III has been launched to adapt to a changing pharmacological environment, with the introduction of biosimilars and small molecules in the treatment of rheumatic diseases. This new stage is adapted to the changes in the reporting of adverse events and now includes information related to activity scores. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Reactivation of intrabasement structures during rifting: A case study from offshore southern Norway

NASA Astrophysics Data System (ADS)

Phillips, Thomas B.; Jackson, Christopher A.-L.; Bell, Rebecca E.; Duffy, Oliver B.; Fossen, Haakon

2016-10-01

Pre-existing structures within crystalline basement may exert a significant influence over the evolution of rifts. However, the exact manner in which these structures reactivate and thus their degree of influence over the overlying rift is poorly understood. Using borehole-constrained 2D and 3D seismic reflection data from offshore southern Norway we identify and constrain the three-dimensional geometry of a series of enigmatic intrabasement reflections. Through 1D waveform modelling and 3D mapping of these reflection packages, we correlate them to the onshore Caledonian thrust belt and Devonian shear zones. Based on the seismic-stratigraphic architecture of the post-basement succession, we identify several phases of reactivation of the intrabasement structures associated with multiple tectonic events. Reactivation preferentially occurs along relatively thick (c. 1 km), relatively steeply dipping (c. 30°) structures, with three main styles of interactions observed between them and overlying faults: i) faults exploiting intrabasement weaknesses represented by intra-shear zone mylonites; ii) faults that initiate within the hangingwall of the shear zones, inheriting their orientation and merging with said structure at depth; or iii) faults that initiate independently from and cross-cut intrabasement structures. We demonstrate that large-scale discrete shear zones act as a long-lived structural template for fault initiation during multiple phases of rifting.

A Sequenced Instructional Program in Physical Education for the Handicapped, Phase III. Producing and Disseminating Demonstration Packages. Final Report.

ERIC Educational Resources Information Center

Carr, Dorothy B.; Avance, Lyonel D.

Presented is a sequenced instructional program in physical education which constitutes the third of a three-phase, 4-year project, funded by Title III, for handicapped children, preschool through high school levels, in the Los Angeles Unified School District. Described are the project setting and the following accomplishments: a curriculum guide…

About the Lung and Upper Aerodigestive Cancer Research Group | Division of Cancer Prevention

Cancer.gov

The Lung and Upper Aerodigestive Cancer Research Group conducts and supports research on the prevention and early detection of lung and head and neck cancers, as well as new approaches to clinical prevention studies including cancer immunoprevention.Phase 0/I/II Cancer Prevention Clinical Trials ProgramThe group jointly administers the Phase 0/I/II Cancer Prevention Clinical

Pressure effect on the long-range order in CeB6

NASA Astrophysics Data System (ADS)

Sera, M.; Ikeda, S.; Iwakubo, H.; Uwatoko, Y.; Hane, S.; Kosaka, M.; Kunii, S.

2006-08-01

The pressure effect of CeB6 was investigated. The pressure dependence of the Néel temperature, TN and the critical field from the antiferro-magnetic phase III to antiferro-quadrupolar phase II, HcIII-II of CeB6 exhibits the unusual pressure dependence that the suppression rate of HcIII-II is much larger than that of TN. In order to explain this unusual result, we have performed the mean field calculation for the 4-sublattice model assuming that the pressure dependence of TN, the antiferro-octupolar and quadrupolar temperatures, Toct and TQ as follows; dTN/dP<0, dToct/dP>dTQ/dP>0 and could explain the unusual pressure dependence of TN and HcIII-II.

Preparation of III-V semiconductor nanocrystals

DOEpatents

Alivisatos, A.P.; Olshavsky, M.A.

1996-04-09

Nanometer-scale crystals of III-V semiconductors are disclosed. They are prepared by reacting a group III metal source with a group V anion source in a liquid phase at elevated temperature in the presence of a crystallite growth terminator such as pyridine or quinoline. 4 figs.

Quantitative Determining of Ultra-Trace Aluminum Ion in Environmental Samples by Liquid Phase Microextraction Assisted Anodic Stripping Voltammetry.

PubMed

Zhang, Liuyang; Luo, Jinju; Shen, Xinyu; Li, Chunya; Wang, Xian; Nie, Bei; Fang, Huaifang

2018-05-10

Direct detecting of trace amount Al(III) in aqueous solution by stripping voltammetry is often frustrated by its irreversible reduction, resided at −1.75 V (vs. Ag/AgCl reference), which is in a proximal potential of proton reduction. Here, we described an electroanalytical approach, combined with liquid phase microextraction (LPME) using ionic liquid (IL), to quantitatively assess trace amount aluminum in environmental samples. The Al(III) was caged by 8-hydroxyquinoline, forming a superb hydrophobic metal⁻chelate, which sequentially transfers and concentrates in the bottom layer of IL-phase during LPME. The preconcentrated Al(III) was further analyzed by a square-wave anodic stripping voltammetry (SW-ASV). The resulting Al-deposited electrodes were characterized by scanning electron microscopy and powder X-ray diffraction, showing the intriguing amorphous nanostructures. The method developed provides a linear calibration ranging from 0.1 to 1.2 ng L −1 with a correlation coefficient of 0.9978. The LOD attains as low as 1 pmol L −1 , which reaches the lowest report for Al(III) detection using electroanalytical techniques. The applicable methodology was implemented for monitoring Al(III) in commercial distilled water.

Effect of Group-III precursors on unintentional gallium incorporation during epitaxial growth of InAlN layers by metalorganic chemical vapor deposition

NASA Astrophysics Data System (ADS)

Kim, Jeomoh; Ji, Mi-Hee; Detchprohm, Theeradetch; Dupuis, Russell D.; Fischer, Alec M.; Ponce, Fernando A.; Ryou, Jae-Hyun

2015-09-01

Unintentional incorporation of gallium (Ga) in InAlN layers grown with different molar flow rates of Group-III precursors by metalorganic chemical vapor deposition has been experimentally investigated. The Ga mole fraction in the InAl(Ga)N layer was increased significantly with the trimethylindium (TMIn) flow rate, while the trimethylaluminum flow rate controls the Al mole fraction. The evaporation of metallic Ga from the liquid phase eutectic system between the pyrolized In from injected TMIn and pre-deposited metallic Ga was responsible for the Ga auto-incorporation into the InAl(Ga)N layer. The theoretical calculation on the equilibrium vapor pressure of liquid phase Ga and the effective partial pressure of Group-III precursors based on growth parameters used in this study confirms the influence of Group-III precursors on Ga auto-incorporation. More Ga atoms can be evaporated from the liquid phase Ga on the surrounding surfaces in the growth chamber and then significant Ga auto-incorporation can occur due to the high equilibrium vapor pressure of Ga comparable to effective partial pressure of input Group-III precursors during the growth of InAl(Ga)N layer.

Exploring the Photoreduction of Au(III) Complexes in the Gas-Phase

NASA Astrophysics Data System (ADS)

Marcum, Jesse C.; Kaufman, Sydney H.; Weber, J. Mathias

2010-06-01

We have used photodissociation spectroscopy to probe the electronic structure and photoreduction of Au(III) in gas-phase complexes containing Cl- and OH-. The gas-phase electronic spectrum of [AuCl_4]- closely resembles the aqueous solution spectrum, showing a lack of strong solvatochromic shifts. Substitution of Cl- ligands with OH- results in a strong blue shift, in agreement with ligand-field theory. Upon excitation, [AuCl_4]- can dissociate by loss of either one or two neutral Cl atoms, resulting in the reduction of gold from Au(III) to Au(II) and Au(I) respectively. The hydroxide substituted complex, [AuCl_2(OH)_2]-, demonstrates similar behavior but the only observable fragment channel is the loss of two neutral OH ligands, leading only to Au(I).

Bortezomib and Filgrastim in Promoting Stem Cell Mobilization in Patients With Non-Hodgkin Lymphoma or Multiple Myeloma Undergoing Stem Cell Transplant

ClinicalTrials.gov

2017-05-23

Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

Polymerase III transcription factor B activity is reduced in extracts of growth-restricted cells.

PubMed Central

Tower, J; Sollner-Webb, B

1988-01-01

Extracts of cells that are down-regulated for transcription by RNA polymerase I and RNA polymerase III exhibit a reduced in vitro transcriptional capacity. We have recently demonstrated that the down-regulation of polymerase I transcription in extracts of cycloheximide-treated and stationary-phase cells results from a lack of an activated subform of RNA polymerase I which is essential for rDNA transcription. To examine whether polymerase III transcriptional down-regulation occurs by a similar mechanism, the polymerase III transcription factors were isolated and added singly and in pairs to control cell extracts and to extracts of cells that had reduced polymerase III transcriptional activity due to cycloheximide treatment or growth into stationary phase. These down-regulations result from a specific reduction in TFIIIB; TFIIIC and polymerase III activities remain relatively constant. Thus, although transcription by both polymerase III and polymerase I is substantially decreased in extracts of growth-arrested cells, this regulation is brought about by reduction of different kinds of activities: a component of the polymerase III stable transcription complex in the former case and the activated subform of RNA polymerase I in the latter. Images PMID:3352599

Selective solid-phase extraction using oxidized activated carbon modified with triethylenetetramine for preconcentration of metal ions

NASA Astrophysics Data System (ADS)

Zhang, Li; Chang, Xijun; Li, Zhenhua; He, Qun

2010-02-01

A new selective solid-phase extractant using activated carbon as matrix which was purified, oxidized and modified by triethylenetetramine (AC-TETA) was prepared and characterized by FT-IR spectroscopy. At pH 4, quantitative extraction of trace Cr(III), Fe(III) and Pb(II) was obtained and determined by inductively coupled plasma optical emission spectrometry (ICP-OES). Complete elution of the adsorbed metal ions from the sorbent surface was carried out using 0.5 mol L -1 HCl. The maximum static adsorption capacity of sorbent for Cr(III), Fe(III) and Pb(II) was 34.6, 36.5 and 51.9 mg g -1, respectively. The time of quantitative adsorption was less than 2 min. The detection limits of the method was found to be 0.71, 0.35 and 0.45 ng mL -1 for Cr(III), Fe(III) and Pb(II), and the relative standard deviation (RSD) was 3.7%, 2.2% and 2.5%, respectively. Moreover, the method was free from interference with common coexiting ions. The method was also successfully applied to the preconcentration of trace Cr(III), Fe(III) and Pb(II) in synthetic samples and a real sample with satisfactory results.

A study of solar preflare activity using two-dimensional radio and SMM-XRP observations

NASA Technical Reports Server (NTRS)

Kundu, M. R.; Gopalswamy, N.; Saba, J. L. R.; Schmelz, J. T. S.; Strong, K. T.

1987-01-01

A study of type III activity at meter-decameter wavelengths in the preflare phase of the February 3, 1986 flare is presented, using data obtained with the Clark Lake Multifrequency Radioheliograph. This activity is compared with similar type III burst activity during the impulsive phase, and it is found that there is a displacement of burst sources between the onset and end times of the activity. A comparison of this displacement at three frequencies suggests that the type III emitting electrons gain access progressively to diverging and different field lines relative to the initial field lines. The energetics of the type III emitting electrons are inferred from observations and compared with those of the associated hard X-ray emitting electrons. The soft X-ray data from SMM-XRP show enhanced emission measure, density, and temperature in the region associated with the preflare type III activity.

A study of solar preflare activity using two-dimensional radio and SMM-XRP observations

NASA Astrophysics Data System (ADS)

Kundu, M. R.; Gopalswamy, N.; Saba, J. L. R.; Schmelz, J. T. S.; Strong, K. T.

1987-09-01

The authors present a study of type III activity at meter-decameter wavelengths in the preflare phase of the 1986 February 3 flare using data obtained with the Clark Lake Multifrequency Radioheliograph. They compare this activity with similar type III burst activity during the impulsive phase and find that there is a displacement of burst sources between the onset and end times of the activity. A comparison of this displacement at three frequencies suggests that the type III emitting electrons gain access progressively to diverging and different field lines relative to the initial field lines. The energetics of the type III emitting electrons are inferred from observations and compared with those of the associated hard X-ray emitting electrons. The soft X-ray data from SMM-XRP shows enhanced emission measure, density and temperature in the region associated with the preflare type III activity.

Durability of lightweight concrete : Phase II : wetting and drying tests, Phase III : freezing and thawing tests.

DOT National Transportation Integrated Search

1966-12-01

This report describes a laboratory research program on the durability of lightweight concrete. Two phases of a three phase study are covered by this report, while the remaining phase is still under study. The two phases being reported are Phase II - ...

Orbital phase dependent IUE spectra of the nova like binary II Arietis

NASA Technical Reports Server (NTRS)

Guinan, E. F.; Sion, E. M.

1981-01-01

Nine low dispersion IUE spectra of the nova like binary TT Ari over its 3h17m orbital period were obtained. Four short wave spectra and five long wave spectra exhibit marked changes in line strength and continuum shape with orbital phase. The short wave spectra show the presence in absorption of C III, Lyman alpha, SiIII, NV, SiIV, CIV, HeII, AlIII, and NIV. The CIV shows a P Cygni profile on two of the spectra. Implications of these spectra for the nature of nova like variables are discussed.

Gunshot wounds and blast injuries to the face are associated with significant morbidity and mortality: results of an 11-year multi-institutional study of 720 patients.

PubMed

Shackford, Steven R; Kahl, Jessica E; Calvo, Richard Y; Kozar, Rosemary A; Haugen, Christine E; Kaups, Krista L; Willey, Marybeth; Tibbs, Brian M; Mutto, Susan M; Rizzo, Anne G; Lormel, Christy S; Shackford, Meghan C; Burlew, Clay Cothren; Moore, Ernest E; Cogbill, Thomas H; Kallies, Kara J; Haan, James M; Ward, Jeanette

2014-02-01

Gunshot wounds and blast injuries to the face (GSWBIFs) produce complex wounds requiring management by multiple surgical specialties. Previous work is limited to single institution reports with little information on processes of care or outcome. We sought to determine those factors associated with hospital complications and mortality. We performed an 11-year multicenter retrospective cohort analysis of patients sustaining GSWBIF. The face, defined as the area anterior to the external auditory meatuses from the top of the forehead to the chin, was categorized into three zones: I, the chin to the base of the nose; II, the base of the nose to the eyebrows; III, above the brows. We analyzed the effect of multiple factors on outcome. From January 1, 2000, to December 31, 2010, we treated 720 patients with GSWBIF (539 males, 75%), with a median age of 29 years. The wounding agent was handgun in 41%, explosive (shotgun and blast) in 20%, rifle in 6%, and unknown in 33%. Prehospital or resuscitative phase airway was required in 236 patients (33%). Definitive care was rendered by multiple specialties in 271 patients (38%). Overall, 185 patients died (26%), 146 (79%) within 48 hours. Of the 481 patients hospitalized greater than 48 hours, 184 had at least one complication (38%). Factors significantly associated with any of a total of 207 complications were total number of operations (p < 0.001), Revised Trauma Score (RTS, p < 0.001), and head Abbreviated Injury Scale (AIS) score (p < 0.05). Factors significantly associated with mortality were RTS (p < 0.001), head AIS score (p < 0.001), total number of operations (p < 0.001), and age (p < 0.05). An injury located in Zone III was independently associated with mortality (p < 0.001). GSWBIFs have high mortality and are associated with significant morbidity. The multispecialty involvement required for definitive care necessitates triage to a trauma center and underscores the need for an organized approach and the development of effective guidelines. Therapeutic/care management, level III.

Bilastine: in allergic rhinitis and urticaria.

PubMed

Carter, Natalie J

2012-06-18

Bilastine is an orally administered, second-generation antihistamine used in the symptomatic treatment of seasonal or perennial allergic rhinoconjunctivitis and urticaria. In two well designed phase III trials, 14 days' treatment with bilastine was associated with a significantly lower area under the effect curve (AUEC) for the reflective total symptom score (TSS) than placebo in patients with symptomatic seasonal allergic rhinitis. Additionally, reflective nasal symptom scores were significantly lower in bilastine than placebo recipients in patients with a history of seasonal allergic rhinitis who were challenged with grass pollen allergen in a single-centre, phase II study. Neither bilastine nor cetirizine was effective in the treatment of perennial allergic rhinitis with regard to the mean AUEC for reflective TSS in another well designed phase III trial. However, results may have been altered by differences in some baseline characteristics and placebo responses between study countries. In another well designed phase III trial, compared with placebo, bilastine was associated with a significantly greater change from baseline to day 28 in the mean reflective daily urticaria symptom score in patients with chronic urticaria. There were no significant differences in primary endpoint results between bilastine and any of the active comparators used in these trials (i.e. cetirizine, levocetirizine and desloratadine). Bilastine was generally well tolerated, with a tolerability profile that was generally similar to that of the other second-generation antihistamines included in phase III clinical trials.

Studies of phase transitions in the aripiprazole solid dosage form.

PubMed

Łaszcz, Marta; Witkowska, Anna

2016-01-05

Studies of the phase transitions in an active substance contained in a solid dosage form are very complicated but essential, especially if an active substance is classified as a BCS Class IV drug. The purpose of this work was the development of sensitive methods for the detection of the phase transitions in the aripiprazole tablets containing initially its form III. Aripiprazole exhibits polymorphism and pseudopolymorphism. Powder diffraction, Raman spectroscopy and differential scanning calorimetry methods were developed for the detection of the polymorphic transition between forms III and I as well as the phase transition of form III into aripiprazole monohydrate in tablets. The study involved the initial 10 mg and 30 mg tablets, as well as those stored in Al/Al blisters, a triplex blister pack and HDPE bottles (with and without desiccant) under accelerated and long term conditions. The polymorphic transition was not observed in the initial and stored tablets but it was visible on the DSC curve of the Abilify(®) 10 mg reference tablets. The formation of the monohydrate was observed in the diffractograms and Raman spectra in the tablets stored under accelerated conditions. The monohydrate phase was not detected in the tablets stored in the Al/Al blisters under long term conditions. The results showed that the Al/Al blisters can be recommended as the packaging of the aripiprazole tablets containing form III. Copyright © 2015 Elsevier B.V. All rights reserved.

Lubiprostone: in constipation-predominant irritable bowel syndrome.

PubMed

Carter, Natalie J; Scott, Lesley J

2009-06-18

Lubiprostone is an oral bicyclic fatty acid that selectively activates type 2 chloride channels in the apical membrane of human gastrointestinal epithelial cells, thereby increasing chloride-rich fluid secretion. Although the mechanism is unclear, this may then decrease intestinal transit time, allowing the passage of stool and alleviating symptoms of constipation. Oral lubiprostone was effective in the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C) in large (n = 193-583) phase II (dose-finding) and phase III randomized, double-blind, placebo-controlled, multicentre trials. The number of patients with IBS-C demonstrating an overall response to treatment (primary endpoint) in the two phase III trials was significantly greater in patients receiving lubiprostone 8 microg twice daily for 3 months than in those receiving placebo. In addition, a randomized, 4-week withdrawal period at the end of one of the phase III trials demonstrated that discontinuation of lubiprostone was not associated with rebound of IBS symptoms. Lubiprostone was generally well tolerated in clinical trials, with the majority of adverse events being of mild to moderate severity. In patients with IBS-C who received lubiprostone 8 microg twice daily, nausea was the most frequently occurring adverse event that was considered possibly or probably treatment related. No serious treatment-related adverse events were reported in a 36-week open-label extension to the phase III trials.

76 FR 33589 - Standards Improvement Project-Phase III

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-08

... rule: I. Background A. Introduction B. Regulatory History II. Legal Considerations III. Summary and... without diminishing worker protections. B. Regulatory History The Standards Improvement Project (SIP...

Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.

PubMed

Graham, Mark J; Lee, Richard G; Bell, Thomas A; Fu, Wuxia; Mullick, Adam E; Alexander, Veronica J; Singleton, Walter; Viney, Nick; Geary, Richard; Su, John; Baker, Brenda F; Burkey, Jennifer; Crooke, Stanley T; Crooke, Rosanne M

2013-05-24

Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic. To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels. Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations. Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.

Brush Day & Night Phase III to Phase IV: ensuring that good oral health habits are sustainable.

PubMed

Melo, Paulo; Fine, Charlotte; Malone, Sinead; Horn, Virginie

2018-05-01

Over the past 10 years, the FDI-Unilever Brush Day & Night partnership has significantly influenced the life of children worldwide through the implementation of school programmes for oral health education and prevention. This article reports the key facts and outcomes of Phase III of the partnership, and announces the launch of Phase IV. During Phase III, the expert advisors of the Brush Day & Night partnership conducted a longitudinal study to evaluate the impact of the '21 Day' programme in almost 8,000 children in 10 countries. Analysis revealed the effectiveness of the 21 Day programme in sustainably educating children to brush their teeth twice a day, with the greatest impact observed in children aged 7-9 years. With the launch of Phase IV, the Brush Day & Night partnership will continue to deliver its oral health school programme for 7-9 year-old children with a strengthened methodology, including randomized sampling and control groups. The scope of the evaluation will be broadened to include oral health-related quality of life indicators, and monitoring of the oral health knowledge of children's parents/carers. © 2018 FDI World Dental Federation.

Phase I and II feasibility study report for the 300-FF-5 operable unit

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1993-12-31

The purpose of this Phase I/II feasibility study is to assemble and screen a list of alternatives for remediation of the 300-FF-5 operable site on the Hanford Reservation. This screening is based on information gathered in the Phase I Remedial Investigation (RI) and on currently available information on remediation technologies. The alternatives remaining after screening provide a range of response actions for remediation. In addition, key data needs are identified for collection during a Phase II RI (if necessary). This Phase I/II FS represents a primary document as defined by the Tri-Party Agreement, but will be followed by a Phasemore » III FS that will further develop the alternatives and provide a detailed evaluation of them. The following remedial action objectives were identified for the 300-FF-5 operable unit: Limit current human exposure to contaminated groundwater in the unit; Limit discharge of contaminated groundwater to the Columbia River; Reduce contaminant concentrations in groundwater below acceptable levels by the year 2018.« less

Recent updates of precision therapy for gastric cancer: Towards optimal tailored management.

PubMed

Joo, Moon Kyung; Park, Jong-Jae; Chun, Hoon Jai

2016-05-21

Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among them, hepatocyte growth factor (HGF)/c-MET, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. Recently, aberrations of immune checkpoints including programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of novel agents targeting these signaling pathways. However, phase III studies of selective anti-HGF/c-MET antibodies and mTOR inhibitor failed to show significant benefits in terms of overall survival and progression-free survival. Few agents directly targeting STAT3 have been developed. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link to effectively inhibit STAT3 activity. Inhibition of PD-1/PD-L1 showed durable efficacy in phase I studies, and phase III evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to identify good responders. Regorafenib has shown promising effectiveness in prolonging progression-free survival in a phase II study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways.

Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma

PubMed Central

Schadendorf, Dirk; Hodi, F. Stephen; Robert, Caroline; Weber, Jeffrey S.; Margolin, Kim; Hamid, Omid; Patt, Debra; Chen, Tai-Tsang; Berman, David M.; Wolchok, Jedd D.

2015-01-01

Purpose To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies. Methods The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method. Results Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3. Conclusion To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma. PMID:25667295

Protocol and recruitment results from a randomized controlled trial comparing group phone-based versus newsletter interventions for weight loss maintenance among rural breast cancer survivors.

PubMed

Befort, Christie A; Klemp, Jennifer R; Fabian, Carol; Perri, Michael G; Sullivan, Debra K; Schmitz, Kathryn H; Diaz, Francisco J; Shireman, Theresa

2014-03-01

Obesity is a risk factor for breast cancer recurrence and death. Women who reside in rural areas have higher obesity prevalence and suffer from breast cancer treatment-related disparities compared to urban women. The objective of this 5-year randomized controlled trial is to compare methods for delivering extended care for weight loss maintenance among rural breast cancer survivors. Group phone-based counseling via conference calls addresses access barriers, is more cost-effective than individual phone counseling, and provides group support which may be ideal for rural breast cancer survivors who are more likely to have unmet support needs. Women (n=210) diagnosed with Stage 0 to III breast cancer in the past 10 years who are ≥ 3 months out from initial cancer treatments, have a BMI 27-45 kg/m(2), and have physician clearance were enrolled from multiple cancer centers. During Phase I (months 0 to 6), all women receive a behavioral weight loss intervention delivered through group phone sessions. Women who successfully lose 5% of weight enter Phase II (months 6 to 18) and are randomized to one of two extended care arms: continued group phone-based treatment or a mail-based newsletter. During Phase III, no contact is made (months 18 to 24). The primary outcome is weight loss maintenance from 6 to 18 months. Secondary outcomes include quality of life, serum biomarkers, and cost-effectiveness. This study will provide essential information on how to reach rural survivors in future efforts to establish weight loss support for breast cancer survivors as a standard of care. Copyright © 2014 Elsevier Inc. All rights reserved.

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies.

PubMed

Luo, Xiaoping; Hou, Ling; Liang, Li; Dong, Guanping; Shen, Shuixian; Zhao, Zhuhui; Gong, Chun Xiu; Li, Yuchuan; Du, Min-Lian; Su, Zhe; Du, Hongwei; Yan, Chaoying

2017-08-01

We assessed the efficacy and safety of a weekly pegylated human growth hormone (PEG-rhGH) (Jintrolong) vs daily rhGH for children with growth hormone deficiency (GHD). Phase II and III, multicenter, open-label, randomized controlled trials. 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively. Patients in the phase II study were randomized 1:1:1 to weekly Jintrolong (0.1 mg/kg/week PEG-rhGH complex), weekly Jintrolong (0.2 mg/kg/week PEG-rhGH complex) or daily rhGH (0.25 mg/kg/week) for 25 weeks. Patients in the phase III study were randomized in a 2:1 ratio to weekly Jintrolong (0.2 mg/kg/week) or daily rhGH (0.25 mg/kg/week) for 25 weeks. The primary endpoint for both studies was height velocity (HV) increase at the end of treatment. Other growth-related parameters, safety and compliance were also monitored. The phase II study established the preliminary efficacy, safety and recommended dose of Jintrolong PEG-rhGH. In the phase III study, we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment (from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year) vs daily rhGH (from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year) at the end of treatment ( P  < 0.05). Additionally, significantly greater improvement in the height standard deviation scores was associated with Jintrolong throughout the treatment ( P  < 0.05). Adverse event rates and treatment compliance were comparable between the two groups. Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH. © 2017 The authors.

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

PubMed Central

Hou, Ling; Liang, Li; Dong, Guanping; Shen, Shuixian; Zhao, Zhuhui; Gong, Chun Xiu; Li, Yuchuan; Du, Min-lian; Su, Zhe; Du, Hongwei; Yan, Chaoying

2017-01-01

Objective We assessed the efficacy and safety of a weekly pegylated human growth hormone (PEG-rhGH) (Jintrolong) vs daily rhGH for children with growth hormone deficiency (GHD). Design Phase II and III, multicenter, open-label, randomized controlled trials. Methods 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively. Patients in the phase II study were randomized 1:1:1 to weekly Jintrolong (0.1 mg/kg/week PEG-rhGH complex), weekly Jintrolong (0.2 mg/kg/week PEG-rhGH complex) or daily rhGH (0.25 mg/kg/week) for 25 weeks. Patients in the phase III study were randomized in a 2:1 ratio to weekly Jintrolong (0.2 mg/kg/week) or daily rhGH (0.25 mg/kg/week) for 25 weeks. The primary endpoint for both studies was height velocity (HV) increase at the end of treatment. Other growth-related parameters, safety and compliance were also monitored. Results The phase II study established the preliminary efficacy, safety and recommended dose of Jintrolong PEG-rhGH. In the phase III study, we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment (from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year) vs daily rhGH (from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year) at the end of treatment (P < 0.05). Additionally, significantly greater improvement in the height standard deviation scores was associated with Jintrolong throughout the treatment (P < 0.05). Adverse event rates and treatment compliance were comparable between the two groups. Conclusion Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH. PMID:28566441

Prevention of Posttraumatic Contractures with Ketotifen (PERK)

DTIC Science & Technology

2017-10-01

opportunity to design a Phase III RCT on the use of ketotifen in post -traumatic joint contractures. The goal is to design and develop the infrastructure to...Research (CIHR) for the Phase III RCT. 2. KEYWORDS Post -traumatic contractures, elbow fractures, randomized clinical trial, multicenter, ketotifen...application to use ketotifen in post -traumatic joint contracture prevention was submitted to the Division of Pulmonary, Allergy, and Rheumatology

What Works in Oklahoma Schools: A Comprehensive Needs Assessment of Oklahoma Schools. Phase III Action Steps

ERIC Educational Resources Information Center

Marzano Research Laboratory, 2011

2011-01-01

This document contains the Phase III report from the "What Works in Oklahoma Schools" study. As opposed to describing the findings from the study that was conducted, it provides a tool-kit that can be used by Oklahoma principals and teachers to determine the best courses of action for their schools and classrooms. The tools provided in…

Army Enlisted Personnel Competency Assessment Program: Phase III Pilot Tests

DTIC Science & Technology

2007-03-01

Officer’s Representatives and Subject Matter POCs: Tonia Heffner and Peter Greenston Contract for Manpower, Personnel, Leader Development, and Training ...3926 March 2007 Army Project Number Personnel Performance 622785A790 and Training Technology Approved for public release; distribution is unlimited. 111...8217 ARMY ENLISTED PERSONNEL COMPETENCY ASSESSMENT PROGRAM: PHASE III PILOT TESTS EXECUTIVE SUMMARY Research Requirement: The Army Training and Leader

Rimonabant Sanofi-Synthélabo.

PubMed

Fernandez, Jose R; Allison, David B

2004-04-01

Rimonabant, an antagonist of central cannabinoid type 1 (CB1) receptors, is being developed by Sanofi-Synthélabo for the potential treatment of obesity and as a potential smoking cessation agent. Phase III trials were initiated for obesity in August 2001 and were ongoing in September 2003. By September 2002, the compound had entered phase III trials for smoking cessation, and these trials were ongoing in September 2003.

Ultracompact electro-optic phase modulator based on III-V-on-silicon microdisk resonator.

PubMed

Lloret, J; Kumar, R; Sales, S; Ramos, F; Morthier, G; Mechet, P; Spuesens, T; Van Thourhout, D; Olivier, N; Fédéli, J-M; Capmany, J

2012-06-15

A novel ultracompact electro-optic phase modulator based on a single 9 μm-diameter III-V microdisk resonator heterogeneously integrated on and coupled to a nanophotonic waveguide is presented. Modulation is enabled by effective index modification through carrier injection. Proof-of-concept implementation involving binary phase shift keying modulation format is assembled. A power imbalance of ∼0.6  dB between both symbols and a modulation rate up to 1.8 Gbps are demonstrated without using any special driving technique.

US-UK Collaboration on Fossil Energy Advanced Materials: Task 1—Steam Oxidation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holcomb, Gordon R.; Tylczak, Joseph; Carney, Casey

This presentation goes over the following from the US-UK collaboration on Fossil Energy Advanced Materials: Task 1, Steam Oxidation: US-led or co-led deliverables, Phase II products (US), 2011-present, Phase III products, Phase III Plan, an explanation of sCO 2 compared with sH 2O, an explanation of Ni-base Alloys, an explanation of 300 Series (18Cr-8Ni)/E-Brite, an explanation of the typical Microchannel HX Fabrication process, and an explanation of diffusion bonded Ni-base superalloys.

Manufacturing Technology for Apparel Automation. Phase 1, 2 and 3 Activity.

DTIC Science & Technology

1987-10-15

A189 129 MANUFACTURING TECHNOLOGY FOR APPAREL AUTOMATION PHASE I t/l 2 AND I ACTIVITY(U) NORTH CAROLINA STATE UNIV ATRALEIGH SCHOOL OF TEXTILES E M...34III 1.8 - iai T ON HART St 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 MTC FILE coax Report: NCSU/DLA-87/2 CDRL A004 MANUFACTURING TECHNOLOGY FOR APPAREL...I Report: NCSU/DLA-87/2 CDRL A004 MANUFACTURING TECHNOLOGY FOR APPAREL AUTOMATION Phase I, II and III Activity Edwin M. McPherson North Carolina

Raman spectra of solid benzene under high pressure

NASA Technical Reports Server (NTRS)

Thiery, M.-M.; Kobashi, K.; Spain, I. L.

1985-01-01

Raman spectra of solid benzene have been measured at room temperature up to about 140 kbar, using the diamond anvil cell. Effort has been focused upon the lattice vibration spectra at pressures above that of phase II. It is found that a change in slopes occurs in the frequency-pressure curves at about 40 kbar. Furthermore, a new band appears above 90 kbar. These features probably correspond respectively to the II-III phase transition, which has been reported previously, and a III-IV phase transition, reported here for the first time.

Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

ClinicalTrials.gov

2017-05-17

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Myeloid Leukemia in Remission; Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

An update on the role of daratumumab in the treatment of multiple myeloma

PubMed Central

Costello, Caitlin

2016-01-01

Monoclonal antibodies (mAbs) have emerged as a promising new drug class for the treatment of multiple myeloma (MM). Daratumumab (DARA), a CD38 mAb, has demonstrated safety, tolerability and activity in a range of clinical trials, both as monotherapy and in combination strategies for MM. The favorable efficacy results in heavily pretreated patients with advanced MM have provided the rationale for the investigation of DARA in a number of ongoing and future phase II and III trials. The general tolerability of mAbs has allowed for widespread investigation and use of DARA among a variety of MM patients, however their use requires special consideration. Infusion-related reactions (IRRs), interference with blood compatibility assays and response assessments are all unique factors related to the use of DARA. This review provides an update of the results from the DARA clinical trials conducted to date, its future plans for investigation, and practical management considerations for the use of DARA in daily practice. PMID:28042457

On Bayesian methods of exploring qualitative interactions for targeted treatment.

PubMed

Chen, Wei; Ghosh, Debashis; Raghunathan, Trivellore E; Norkin, Maxim; Sargent, Daniel J; Bepler, Gerold

2012-12-10

Providing personalized treatments designed to maximize benefits and minimizing harms is of tremendous current medical interest. One problem in this area is the evaluation of the interaction between the treatment and other predictor variables. Treatment effects in subgroups having the same direction but different magnitudes are called quantitative interactions, whereas those having opposite directions in subgroups are called qualitative interactions (QIs). Identifying QIs is challenging because they are rare and usually unknown among many potential biomarkers. Meanwhile, subgroup analysis reduces the power of hypothesis testing and multiple subgroup analyses inflate the type I error rate. We propose a new Bayesian approach to search for QI in a multiple regression setting with adaptive decision rules. We consider various regression models for the outcome. We illustrate this method in two examples of phase III clinical trials. The algorithm is straightforward and easy to implement using existing software packages. We provide a sample code in Appendix A. Copyright © 2012 John Wiley & Sons, Ltd.

Ocrelizumab: a B-cell depleting therapy for multiple sclerosis.

PubMed

Jakimovski, Dejan; Weinstock-Guttman, Bianca; Ramanathan, Murali; Kolb, Channa; Hojnacki, David; Minagar, Alireza; Zivadinov, Robert

2017-09-01

Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.

Isolation, identification and synthesis of four novel antioxidant peptides from rice residue protein hydrolyzed by multiple proteases.

PubMed

Yan, Qiao-Juan; Huang, Lin-Hua; Sun, Qian; Jiang, Zheng-Qiang; Wu, Xia

2015-07-15

Multiple proteases were optimized to hydrolyze the rice residue protein (RRP) to produce novel antioxidant peptides. An antioxidant peptide fraction (RRPB3) with IC50 of 0.25 mg/ml was purified from the RRP hydrolysate using membrane ultrafiltration followed by size exclusion chromatography and reversed-phase FPLC. RRPB3 was found to include four peptides (RRPB3 I-IV) and their amino acid sequences were RPNYTDA (835.9 Da), TSQLLSDQ (891.0 Da), TRTGDPFF (940.0 Da) and NFHPQ (641.7 Da), respectively. Furthermore, four peptides were chemically synthesized and their antioxidant activities were assessed by DPPH radical scavenging, ABTS radical scavenging assay and FRAP-Fe(3+) reducing assay, respectively. Both RRPB3 I and III showed synergistic antioxidant activity compared to each of them used alone. All four synthetic peptides showed excellent stability against simulated gastrointestinal proteases. Therefore, the peptides isolated from RRP may be used as potential antioxidants in the food and drug industries. Copyright © 2015 Elsevier Ltd. All rights reserved.

A comparison study of the Born effective charges and dielectric properties of the cubic, tetragonal, monoclinic, ortho-I, ortho-II and ortho-III phases of zirconia

NASA Astrophysics Data System (ADS)

Zhang, Yan; Chen, Hua-Xin; Duan, Li; Fan, Ji-Bin; Ni, Lei; Ji, Vincent

2018-07-01

Using density-functional perturbation theory, we systematically investigate the Born effective charges and dielectric properties of cubic, tetragonal, monoclinic, ortho-I (Pbca), ortho-II (Pnma) and ortho-III (Pca21) phases of ZrO2. The magnitudes of the Born effective charges of the Zr and oxygen atoms are greater than their nominal ionic valences (+4 for Zr and -2 for oxygen), indicating a strong dynamic charge transfer from Zr atoms to O atoms and a mixed covalent-ionic bonding in six phases of ZrO2. For all six phases of ZrO2, the electronic contributions εij∞ to the static dielectric constant are rather small (range from 5 to 6.5) and neither strongly anisotropic nor strongly dependent on the structural phase, while the ionic contributions εijion to the static dielectric constant are large and not only anisotropic but also dependent on the structural phase. The average dielectric constant εbar0 of the six ZrO2 phases decreases in the sequence of tetragonal, cubic, ortho-II (Pnma), ortho-I (Pbca), ortho-III (Pca21) and monoclinic. So among six phases of ZrO2, the tetragonal and cubic phases are two suitable phases to replace SiO2 as the gate dielectric material in modern integrated-circuit technology. Furthermore, for the tetragonal ZrO2 the best orientation is [100].

Broadband microwave photonic fully tunable filter using a single heterogeneously integrated III-V/SOI-microdisk-based phase shifter.

PubMed

Lloret, Juan; Morthier, Geert; Ramos, Francisco; Sales, Salvador; Van Thourhout, Dries; Spuesens, Thijs; Olivier, Nicolas; Fédéli, Jean-Marc; Capmany, José

2012-05-07

A broadband microwave photonic phase shifter based on a single III-V microdisk resonator heterogeneously integrated on and coupled to a nanophotonic silicon-on-insulator waveguide is reported. The phase shift tunability is accomplished by modifying the effective index through carrier injection. A comprehensive semi-analytical model aiming at predicting its behavior is formulated and confirmed by measurements. Quasi-linear and continuously tunable 2π phase shifts at radiofrequencies greater than 18 GHz are experimentally demonstrated. The phase shifter performance is also evaluated when used as a key element in tunable filtering schemes. Distortion-free and wideband filtering responses with a tuning range of ~100% over the free spectral range are obtained.

Motor associations of iron accumulation in deep grey matter nuclei in Parkinson's disease: a cross-sectional study of iron-related magnetic resonance imaging susceptibility.

PubMed

Martin-Bastida, A; Lao-Kaim, N P; Loane, C; Politis, M; Roussakis, A A; Valle-Guzman, N; Kefalopoulou, Z; Paul-Visse, G; Widner, H; Xing, Y; Schwarz, S T; Auer, D P; Foltynie, T; Barker, R A; Piccini, P

2017-02-01

To determine whether iron deposition in deep brain nuclei assessed using high-pass filtered phase imaging plays a role in motor disease severity in Parkinson's disease (PD). Seventy patients with mild to moderate PD and 20 age- and gender-matched healthy volunteers (HVs) underwent susceptibility-weighted imaging on a 3 T magnetic resonance imaging scanner. Phase shifts (radians) in deep brain nuclei were derived from high-pass filtered phase images and compared between groups. Analysis of clinical laterality and correlations with motor severity (Unified Parkinson's Disease Rating Scale, Part III, UPDRS-III) were performed. Phase shifts (in radians) were compared between HVs and three PD subgroups divided according to UPDRS-III scores using analysis of covariance, adjusting for age and regional area. Parkinson's disease patients had significantly (P < 0.001) higher radians than HVs bilaterally in the putamen, globus pallidus and substantia nigra (SN). The SN contralateral to the most affected side showed higher radians (P < 0.001) compared to the less affected side. SN radians positively correlated with UPDRS-III and bradykinesia-rigidity subscores, but not with tremor subscores. ancova followed by post hoc Bonferroni-adjusted pairwise comparisons revealed that SN radians were significantly greater in the PD subgroup with higher UPDRS-III scores compared to both lowest UPDRS-III PD and HV groups (P < 0.001). Increased nigral iron accumulation in PD appears to be stratified according to disease motor severity and correlates with symptoms related to dopaminergic neurodegeneration. This semi-quantitative in vivo iron assessment could prove useful for objectively monitoring PD progression, especially in clinical trials concerning iron chelation therapies. © 2016 EAN.

Method for the determination of chromium in feed matrix by HPLC.

PubMed

Umesh, Balakrishnan; Rajendran, Rajendra Moorthy; Manoharan, Muthu Tamizh

2015-11-01

An improved method for the chromatographic separation and determination of chromium (III) and (VI) [ CRIII AND CRVI: ] in mineral mixtures and feed samples has been developed. The method uses precolumn derivatization using ammonium pyrrolidinedithiocarbamate ( APD: ) followed by reversed-phase liquid chromatography to separate the chromium ions. Both Cr(III) and Cr(VI) species are chelated with ammonium pyrrolidinedithiocarbamate prior to separation by mixing with acetonitrile and 0.5 mmol acetate buffer (pH 4.5). Optimum chromatographic separations were obtained with a polymer-based reversed-phase column (Kinetex, 5 μ, 250 × 4.5 mm, Phenomenex, Torrance, CA) and a mobile phase containing acetonitrile and water (7:3). Both Cr(III) and Cr(VI) ion concentrations were directly determined from the corresponding areas in the chromatogram. The effect of analytical parameters, including pH, concentration of ligand, incubation temperature, and mobile phase, was optimized for both chromium complexes. The range of the procedure was found to be linear for Cr(III) and Cr(VI) concentrations between 0.125 and 4 μg/mL (r² = 0.9926) and 0.1 and 3.0 μg/mL (r² = 0.9983), respectively. Precision was evaluated by replicate analysis in which the percentage relative standard deviation values for chromium complex were found to be below 4.0. The recoveries obtained (85-115%) for both Cr(III) and Cr(VI) complexes indicated the accuracy of the developed method. The degradation products, as well as the excipients, were well resolved from the chromium complex peak in the chromatogram. Finally, the new method proved to be suitable for routine analysis of Cr(III) and Cr(VI) species in raw materials, mineral mixtures, and feed samples. © 2015 Poultry Science Association Inc.

The influence of different sets of surgical instrumentation in Oxford UKA on bearing size and component position.

PubMed

Walker, Tilman; Heinemann, Pascal; Bruckner, Thomas; Streit, Marcus R; Kinkel, Stefan; Gotterbarm, Tobias

2017-07-01

The Oxford unicompartmental knee arthroplasty (OUKA) has been proven to be an effective treatment for anteromedial osteoarthritis of the knee joint. New instrumentation has been introduced to improve the reproducibility of implant positioning and to minimize bone loss during tibial resection (Oxford Microplasty; Zimmer Biomet, Warsaw, Indiana, USA). To assess the effect of the new instrumentation, we retrospectively evaluated the postoperative radiographs and surgical records of 300 OUKAs in three consecutive cohorts of patients. The first cohort consists of the first 100 minimal invasive implantations of the OUKA using the conventional phase III instrumentation, the second cohort consists of the 100 most recent minimal invasive OUKA with the conventional phase III instrumentation and the third cohort consists of the first 100 minimal invasive OUKA using the new Oxford Microplasty instrumentation. Mean bearing thickness was statistically significant and lower in OUKA with use of the updated instrumentation than with the conventional instrumentation (p = 0.01 and p = 0.04). Additionally, statistically significant and more femoral components were aligned within the accepted range of tolerance in both the coronal and the sagittal plane with use of the updated instrumentation compared to the conventional phase III instrumentation in group A (p = 0.029 and p = 0.038) and in the sagittal plane with use of the updated instrumentation compared to the conventional phase III instrumentation in group B (p = 0.002). The new modified instrumentation seems to be an effective tool to reduce the risk of malalignment of the femoral component in the coronal and in the sagittal plane compared to the conventional phase III instrumentation. Furthermore, the instrumentation is also effective in determining an adequate level of tibial resection and thus avoiding unnecessary bone loss.

The Combination Process for Preparative Separation and Purification of Paclitaxel and 10-Deacetylbaccatin III Using Diaion® Hp-20 Followed by Hydrophilic Interaction Based Solid Phase Extraction.

PubMed

Shirshekanb, Mahsa; Rezadoost, Hassan; Javanbakht, Mehran; Ghassempour, Ali Reza

2017-01-01

There is no other naturally occurring defense agent against cancer that has a stronger effect than paclitaxel, commonly known under the brand name of Taxol ® . The major drawback for the more widespread use of paclitaxel and its precious precursor, 10-deacetylbaccatin III (10-DAB III), is that they require large-scale extraction from different parts of yew trees ( Taxus species), cell cultures, taxane-producing endophytic fungi, and Corylus species. In our previous work, a novel online two-dimensional heart-cut liquid chromatography process using hydrophilic interaction/ reversed-phase chromatography was used to introduce a semi-preparative treatment for the separation of polar (10-deacetylbaccatin III) and non-polar (paclitaxel) taxanes from Taxus baccata L. In this work, a combination of the absorbent (Diaion ®  HP-20) and a silica based solid phase extraction is utilized as a new, efficient, and cost effective method for large-scale production of taxanes. This process avoids the technical problem of two-dimensional preparative liquid chromatography. The first stage of the process involves discarding co-extractive polar compounds including chlorophylls and pigments using a non-polar synthetic hydrophobic absorbent, Diaion ®  HP-20. Extract was then loaded on to a silica based hydrophilic interaction solid phase extraction (silica 40-60 micron). Taxanes was eluted using a mixture of water and methanol at the optimized ratio of 70:30. Finally, the fraction containing taxanes was applied to semi-preparative reversed phase HPLC. The results revealed that using this procedure, paclitaxel and 10-DAB III could be obtained at 8 and 3 times more, respectively than by the traditional method of extraction.

Comparison between publicly accessible publications, registries, and protocols of phase III trials indicated persistence of selective outcome reporting.

PubMed

Zhang, Sheng; Liang, Fei; Li, Wenfeng

2017-11-01

The decision to make protocols of phase III randomized controlled trials (RCTs) publicly accessible by leading journals was a landmark event in clinical trial reporting. Here, we compared primary outcomes defined in protocols with those in publications describing the trials and in trial registration. We identified phase III RCTs published between January 1, 2012, and June 30, 2015, in The New England Journal of Medicine, The Lancet, The Journal of the American Medical Association, and The BMJ with available protocols. Consistency in primary outcomes between protocols and registries (articles) was evaluated. We identified 299 phase III RCTs with available protocols in this analysis. Out of them, 25 trials (8.4%) had some discrepancy for primary outcomes between publications and protocols. Types of discrepancies included protocol-defined primary outcome reported as nonprimary outcome in publication (11 trials, 3.7%), protocol-defined primary outcome omitted in publication (10 trials, 3.3%), new primary outcome introduced in publication (8 trials, 2.7%), protocol-defined nonprimary outcome reported as primary outcome in publication (4 trials, 1.3%), and different timing of assessment of primary outcome (4 trials, 1.3%). Out of trials with discrepancies in primary outcome, 15 trials (60.0%) had discrepancies that favored statistically significant results. Registration could be seen as a valid surrogate of protocol in 237 of 299 trials (79.3%) with regard to primary outcome. Despite unrestricted public access to protocols, selective outcome reporting persists in a small fraction of phase III RCTs. Only studies from four leading journals were included, which may cause selection bias and limit the generalizability of this finding. Copyright © 2017 Elsevier Inc. All rights reserved.

Lorcaserin: an investigational serotonin 2C agonist for weight loss.

PubMed

Hurren, Kathryn M; Berlie, Helen D

2011-11-01

The pharmacology, pharmacokinetics, and adverse effects of the selective serotonin (5-HT) agonist lorcaserin are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials. Lorcaserin is highly selective for a subtype of 5-HT receptors important in appetite regulation, with low affinity for other 5-HT-receptor subtypes whose activation is thought to underlie serious cardiovascular adverse effects; such effects have been seen with nonselective serotonergic agents for weight loss (e.g., fenfluramine). In two Phase III trials of lorcaserin, the cumulative proportion of patients who achieved weight loss of ≥5% over 12 months was about 47% with lorcaserin use versus 20-25% among placebo users (p < 0.0001 for both trials). Lorcaserin was generally well tolerated in the clinical trials to date; nausea and vomiting, headache, and dizziness were the most commonly reported adverse effects. In two of the three Phase III trials to date, lorcaserin use was not found to increase the risk of cardiac valvulopathy; however, in the other Phase III trial, which focused on patients with diabetes, lorcaserin use was associated with an increased rate of new valvulopathy. In a carcinogenicity evaluation involving laboratory rats, lorcaserin was linked to the development of various malignancies, a finding with uncertain implications for its potential future use in humans. Lorcaserin, a 5-HT(2C) agonist, has demonstrated efficacy in patients who are obese or are overweight with associated comorbidities. Phase III trials have found that more than 35% of patients lost greater than 5% of their baseline weight. The maker of lorcaserin has indicated it will continue to seek U.S. marketing approval of the drug for the indications of long-term weight loss and weight-loss maintenance in specific patient populations.

Printed health information materials: evaluation of readability and suitability.

PubMed

Shieh, Carol; Hosei, Barbara

2008-01-01

This study examined readability and suitability of printed health information materials colleted from multiple sources. In phase I, nursing students used Simple Measure of Gobbledygook (SMOG; McLaughlin, 1969) to assess the readability of 21 materials collected from the community. In phases II and III, nursing students and registered nurses used SMOG and the Suitability Assessment of Materials (SAM; Doak, Doak, & Root, 1996) to evaluate 15 prenatal materials from a Healthy Start program. SMOG assigns a reading grade level based on the number of words with 3 or more syllables. SAM has 22 items in 6 evaluation areas: content, literacy demand, graphics, layout and typography, learning stimulation and motivation, and cultural appropriateness. Major findings included that 53% to 86% of the printed materials had a reading level at or higher than 9th grade; materials lacked summary, interaction, and modeled behaviors, and registered nurses rated more materials as not suitable and fewer as superior for suitability qualities than students. Improving printed materials to have lower reading levels and better suitability qualities are indicated.

Mechanism of selenite removal by a mixed adsorbent based on Fe-Mn hydrous oxides studied using X-ray absorption spectroscopy.

PubMed

Chubar, Natalia; Gerda, Vasyl; Szlachta, Małgorzata

2014-11-18

Selenium cycling in the environment is greatly controlled by various minerals, including Mn and Fe hydrous oxides. At the same time, such hydrous oxides are the main inorganic ion exchangers suitable (on the basis of their chemical nature) to sorb (toxic) anions, separating them from water solutions. The mechanism of selenite adsorption by the new mixed adsorbent composed of a few (amorphous and crystalline) phases [maghemite, MnCO3, and X-ray amorphous Fe(III) and Mn(III) hydrous oxides] was studied by extended X-ray absorption fine structure (EXAFS) spectroscopy [supported by Fourier transform infrared (FTIR) and X-ray diffraction (XRD) data]. The complexity of the porous adsorbent, especially the presence of the amorphous phases of Fe(III) and Mn(III) hydrous oxides, is the main reason for its high selenite removal performance demonstrated by batch and column adsorption studies shown in the previous work. Selenite was bound to the material via inner-sphere complexation (via oxygen) to the adsorption sites of the amorphous Fe(III) and Mn(III) oxides. This anion was attracted via bidentate binuclear corner-sharing coordination between SeO3(2-) trigonal pyramids and both FeO6 and MnO6 octahedra; however, the adsorption sites of Fe(III) hydrous oxides played a leading role in selenite removal. The contribution of the adsorption sites of Mn(III) oxide increased as the pH decreased from 8 to 6. Because most minerals have a complex structure (they are seldom based on individual substances) of various crystallinity, this work is equally relevant to environmental science and environmental technology because it shows how various solid phases control cycling of chemical elements in the environment.

Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins.

PubMed

Furtado, Jeremy D; Wedel, Mark K; Sacks, Frank M

2012-04-01

Mipomersen, an antisense oligonucleotide that reduces hepatic production of apoB, has been shown in phase 2 studies to decrease plasma apoB, LDL cholesterol (LDL-C), and triglycerides. ApoC-III inhibits VLDL and LDL clearance, and it stimulates inflammatory responses in vascular cells. Concentrations of VLDL or LDL with apoC-III independently predict cardiovascular disease. We performed an exploratory posthoc analysis on a subset of hypercholesterolemic subjects obtained from a randomized controlled dose-ranging phase 2 study of mipomersen receiving 100, 200, or 300 mg/wk, or placebo for 13 wk (n = 8 each). ApoC-III-containing lipoproteins were isolated by immuno-affinity chromatography and ultracentrifugation. Mipomersen 200 and 300 mg/wk reduced total apoC-III from baseline by 6 mg/dl (38-42%) compared with placebo group (P < 0.01), and it reduced apoC-III in both apoB lipoproteins and HDL. Mipomersen 100, 200, and 300 mg doses reduced apoB concentration of LDL with apoC-III (27%, 38%, and 46%; P < 0.05). Mipomersen reduced apoC-III concentration in HDL. The drug had no effect on apoE concentration in total plasma and in apoB lipoproteins. In summary, antisense inhibition of apoB synthesis reduced plasma concentrations of apoC-III and apoC-III-containing lipoproteins. Lower concentrations of apoC-III and LDL with apoC-III are associated with reduced risk of coronary heart disease (CHD) in epidemiologic studies independent of traditional risk factors.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify Phase III

PubMed Central

Kaufmann, Petra; Thompson, John L.P.; Levy, Gilberto; Buchsbaum, Richard; Shefner, Jeremy; Krivickas, Lisa S.; Katz, Jonathan; Rollins, Yvonne; Barohn, Richard J.; Jackson, Carlayne E.; Tiryaki, Ezgi; Lomen-Hoerth, Catherine; Armon, Carmel; Tandan, Rup; Rudnicki, Stacy A.; Rezania, Kourosh; Sufit, Robert; Pestronk, Alan; Novella, Steven P.; Heiman-Patterson, Terry; Kasarskis, Edward J.; Pioro, Erik P.; Montes, Jacqueline; Arbing, Rachel; Vecchio, Darleen; Barsdorf, Alexandra; Mitsumoto, Hiroshi; Levin, Bruce

2010-01-01

Objective Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. Methods We designed and implemented a multi-center trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. Results Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns. Interpretation CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial. PMID:19743457

Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials.

PubMed

Yang, Haichen; Laurenza, Antonio; Williams, Betsy; Patten, Anna; Hussein, Ziad; Ferry, Jim

2015-08-01

Perampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled Phase III studies. The Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6 mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12 mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N = 261). Electrocardiograms were recorded at baseline, Day 7 (post 6 mg dose), and Day 16 (post 12 mg dose). Statistical comparisons were between the highest approved perampanel dose (12 mg) versus placebo, a "mid-therapeutic" dose (6 mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I thorough QT study could not incorporate a true "supratherapeutic" dose due to length of titration and tolerability concerns in healthy subjects, Phase III studies of perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration-QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses ≤ 12 mg (N = 1038, total perampanel; and N=442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas. In the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (ΔΔ) QTcF of 12.15 ms at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Δ) QTcF versus nominal time curves were comparable between perampanel 12 mg and placebo, with most ΔQTcF values being slightly negative. Healthy subjects receiving perampanel 6 and 12 mg doses for 7 days showed no evidence of effects on cardiac repolarization. Peak ΔΔQTcF was 2.34 ms at 1.5h postdose for perampanel 6 mg and 3.92 ms at 0.5h postdose for perampanel 12 mg. At every time point, the upper 95% confidence limit of ΔΔQTcF for perampanel 6 and 12 mg was <10 ms. Phase III studies revealed no clinically significant difference between patients with partial seizures treated with perampanel or placebo in QTcF and QTcB values >450 ms, with no dose-dependent increases or large incremental changes from baseline of >60 ms. Regression analysis of individual plasma perampanel concentrations versus corresponding QTc interval values in Phase I thorough QT and Phase III studies demonstrated no relationship between perampanel concentrations and QT interval duration. Treatment with perampanel 6 mg and 12 mg for 7 days did not delay cardiac repolarization in healthy volunteers. In a population analysis of 1480 patients with partial seizures treated with perampanel doses ≤ 12 mg or placebo, no clinically significant trends in QT interval data were noted. Based on the thorough QT study and evaluations from pooled Phase III studies, there is no evidence of prolonged QT interval duration with perampanel treatment. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Method of analyzing multiple sample simultaneously by detecting absorption and systems for use in such a method

DOEpatents

Yeung, Edward S.; Gong, Xiaoyi

2004-09-07

The present invention provides a method of analyzing multiple samples simultaneously by absorption detection. The method comprises: (i) providing a planar array of multiple containers, each of which contains a sample comprising at least one absorbing species, (ii) irradiating the planar array of multiple containers with a light source and (iii) detecting absorption of light with a detetion means that is in line with the light source at a distance of at leaat about 10 times a cross-sectional distance of a container in the planar array of multiple containers. The absorption of light by a sample indicates the presence of an absorbing species in it. The method can further comprise: (iv) measuring the amount of absorption of light detected in (iii) indicating the amount of the absorbing species in the sample. Also provided by the present invention is a system for use in the abov metho.The system comprises; (i) a light source comrnpising or consisting essentially of at leaat one wavelength of light, the absorption of which is to be detected, (ii) a planar array of multiple containers, and (iii) a detection means that is in line with the light source and is positioned in line with and parallel to the planar array of multiple contiainers at a distance of at least about 10 times a cross-sectional distance of a container.

Improved quality-by-design compliant methodology for method development in reversed-phase liquid chromatography.

PubMed

Debrus, Benjamin; Guillarme, Davy; Rudaz, Serge

2013-10-01

A complete strategy dedicated to quality-by-design (QbD) compliant method development using design of experiments (DOE), multiple linear regressions responses modelling and Monte Carlo simulations for error propagation was evaluated for liquid chromatography (LC). The proposed approach includes four main steps: (i) the initial screening of column chemistry, mobile phase pH and organic modifier, (ii) the selectivity optimization through changes in gradient time and mobile phase temperature, (iii) the adaptation of column geometry to reach sufficient resolution, and (iv) the robust resolution optimization and identification of the method design space. This procedure was employed to obtain a complex chromatographic separation of 15 antipsychotic basic drugs, widely prescribed. To fully automate and expedite the QbD method development procedure, short columns packed with sub-2 μm particles were employed, together with a UHPLC system possessing columns and solvents selection valves. Through this example, the possibilities of the proposed QbD method development workflow were exposed and the different steps of the automated strategy were critically discussed. A baseline separation of the mixture of antipsychotic drugs was achieved with an analysis time of less than 15 min and the robustness of the method was demonstrated simultaneously with the method development phase. Copyright © 2013 Elsevier B.V. All rights reserved.

Can high pressure I-II transitions in semiconductors be affected by plastic flow and nanocrystal precipitation in phase I?

NASA Astrophysics Data System (ADS)

Weinstein, B. A.; Lindberg, G. P.

Pressure-Raman spectroscopy in ZnSe and ZnTe single crystals reveals that Se and Te nano-crystals (NCs) precipitate in these II-VI hosts for pressures far below their I-II phase transitions. The inclusions are evident from the appearance and negative pressure-shift of the A1 Raman peaks of Se and Te (trigonal phase). The Se and Te NCs nucleate at dislocations and grain boundaries that arise from pressure-induced plastic flow. This produces chemical and structural inhomogeneities in the zincblende phase of the host. At substantially higher pressures, the I-II transition proceeds in the presence of these inhomogenities. This can affect the transition's onset pressure Pt and width ΔPt, and the occurrence of metastable phases along the transition path. Precipitation models in metals show that nucleation of inclusions depends on the Peierls stress τp and a parameter α related to the net free energy gained on nucleation. For favorable values of τp and α, NC precipitation at pressures below the I-II transition could occur in other compounds. We propose criteria to judge whether this is likely based on the observed ranges of τp in the hosts, and estimates of α derived from the cohesive energy densities of the NC materials. One finds trends that can serve as a useful guide, both to test the proposed criteria, and to decide when closer scrutiny of phase transition experiments is warranted, e.g., in powders where high dislocation densities are initially created

A Model System for the Design and Maintenance of Related Instruction Curriculum for Approved U.S. Department of Labor Apprenticeship Programs; Phase III. Final Report and Final Evaluation Report.

ERIC Educational Resources Information Center

Lane Community Coll., Eugene, OR.

A final report and final evaluation report of Phase III are provided for a project to establish a national clearinghouse for apprenticeship-related instructional materials. The final report provides a summary and a narrative account of these project activities: identification of materials; identification of apprenticeship curriculum needs;…

The Effects of PECS Teaching to Phase III on the Communicative Interactions between Children with Autism and Their Teachers

ERIC Educational Resources Information Center

Carr, Deborah; Felce, Janet

2007-01-01

The study investigated the impact of mastery of the Picture Exchange Communication System (PECS) to Phase III, on the communications of children with autism. Children aged between 3 and 7 years, formed a PECS intervention group and a non-intervention control group. The intervention group received 15 h of PECS teaching over 5 weeks. Three 2-h…

Phase 2 Site Investigations Report. Volume 3 of 3: Appendices

DTIC Science & Technology

1994-09-01

Phase II Site Investigations Ee Report Cn Volume III of III Appendices Fort Devens Sudbury Training Annex, Massachusetts September 1994 Contract No...laboratory quality control (QC) samples collected during field investigations at the Sudbury Training Annex of Fort Devens , Massachusetts. The QC...returned to its original condition. E & E performed this procedure for each monitoring well tested during the 1993 slug testing activities at Fort Devens

A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy-induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10-09.

PubMed

Lee, Ki Hyeong; Kim, Ji-Yeon; Lee, Moon Hee; Han, Hye Sook; Lim, Joo Han; Park, Keon Uk; Park, In Hae; Cho, Eun Kyung; Yoon, So Young; Kim, Jee Hyun; Choi, In Sil; Park, Jae Hoo; Choi, Young Jin; Kim, Hee-Jun; Jung, Kyung Hae; Kim, Si-Young; Oh, Do-Youn; Im, Seock-Ah

2016-04-01

Pegylated granulocyte-colony-stimulating factor (G-CSF) is frequently used to prevent febrile neutropenia (FN) in patients undergoing chemotherapy with a high risk of myelosuppression. This phase II/III study was conducted to determine the adequate dose of pegteograstim, a new formulation of pegylated G-CSF, and to evaluate the efficacy and safety of pegteograstim compared to pegfilgrastim. In the phase II part, 60 breast cancer patients who were undergoing DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy were randomly selected to receive a single subcutaneous injection of 3.6 or 6.0 mg pegteograstim on day 2 of each chemotherapy cycle. The phase III part was seamlessly started to compare the dose of pegteograstim at selected in phase II with 6.0 mg pegfilgrastim in 117 breast cancer patients. The primary endpoint of both the phase II and III parts was the duration of grade 4 neutropenia in the chemotherapy cycle 1. The mean duration of grade 4 neutropenia for the 3.6 mg pegteograstim (n = 33) was similar to that for the 6.0 mg pegteograstim (n = 26) (1.97 ± 1.79 days vs. 1.54 ± 0.95 days, p = 0.33). The 6.0 mg pegteograstim was selected to be compared with the 6.0 mg pegfilgrastim in the phase III part. In the phase III part, the primary analysis revealed that the efficacy of pegteograstim (n = 56) was non-inferior to that of pegfilgrastim (n = 59) [duration of grade 4 neutropenia, 1.64 ± 1.18 days vs. 1.80 ± 1.05 days; difference, -0.15 ± 1.11 (p = 0.36, 97.5 % confidence intervals = 0.57 and 0.26)]. The time to the absolute neutrophil count (ANC) recovery of pegteograstim (≥2000/μL) was significantly shorter than that of pegfilgrastim (8.85 ± 1.45 days vs. 9.83 ± 1.20 days, p < 0.0001). Other secondary endpoints showed no significant difference between the two groups. The safety profiles of the two groups did not differ significantly. Pegteograstim was shown to be as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in the breast cancer patients who were undergoing chemotherapy with a high risk of myelosuppression.

The Utilization of the Microflora Indigenous to and Present in Oil-Bearing Formations to Selectively Plug the More Porous Zones Thereby Increasing Oil Recovery During Waterflooding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Lewis R.; Byrnes, Martin J.; Stephens, James O.

This project was designed to demonstrate that a microbially enhanced oil recovery process (MEOR), developed in part under DOE Contract No. DE-AC22-90BC14665, will increase oil recovery from fluvial dominated deltaic oil reservoirs. The process involves stimulating the in-situ indigenous microbial population in the reservoir to grow in the more permeable zones, thus diverting flow to other areas of the reservoir, thereby increasing the effectiveness of the waterflood. This five and a half year project is divided into three phases, Phase I, Planning and Analysis (9 months), Phase II, Implementation (45 months), and Phase III, Technology Transfer (12 months). Phase Imore » was completed and reported in the first annual report. This fifth annual report covers the completion of Phase II and the first six months of Phase III.« less

Antisense technology: an emerging platform for cardiovascular disease therapeutics.

PubMed

Lee, Richard G; Crosby, Jeff; Baker, Brenda F; Graham, Mark J; Crooke, Rosanne M

2013-12-01

Antisense oligonucleotides and small interfering RNAs, which suppress the translation of specific mRNA target proteins, are emerging as important therapeutic modalities for the treatment of cardiovascular disease. Over the last 25 years, the advances in all aspects of antisense technology, as well as a detailed understanding of the mechanism of action of antisense drugs, have enabled their use as therapeutic agents. These advancements culminated in the FDA approval of the first chronically administered cardiovascular antisense therapeutic, mipomersen, which targets hepatic apolipoprotein B mRNA. This review provides a brief history of antisense technology, highlights the progression of mipomersen from preclinical studies to multiple Phase III registration trials, and gives an update on the status of other cardiovascular antisense therapeutics currently in the clinic.

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions.

PubMed

Kumaran, Neruban; Moore, Anthony T; Weleber, Richard G; Michaelides, Michel

2017-09-01

Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A Phase III Clinical Trial Showing Limited Efficacy of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury.

PubMed

Oh, Sun Kyu; Choi, Kyoung Hyo; Yoo, Jong Yoon; Kim, Dae Yul; Kim, Sang Joon; Jeon, Sang Ryong

2016-03-01

In our previous report, 3 of 10 patients with spinal cord injury who were injected with autologous mesenchymal stem cells (MSCs) showed motor improvement in the upper extremities and in activities of daily living. To report on the results of a phase III clinical trial of autologous MSCs therapy. Patients were selected based on the following criteria: chronic American Spinal Injury Association B status patients who had more than 12 months of cervical injury, and no neurological changes during the recent 3 months of vigorous rehabilitation. We injected 1.6 × 10 autologous MSCs into the intramedullary area at the injured level and 3.2 × 10 autologous MSCs into the subdural space. Outcome data were collected over 6 months regarding neurological examination, magnetic resonance imaging with diffusion tensor imaging, and electrophysiological analyses. Among the 16 patients, only 2 showed improvement in neurological status (unilateral right C8 segment from grade 1 to grade 3 in 1 patient and bilateral C6 from grade 3 to grade 4 and unilateral right C8 from grade 0 to grade 1 in 1 patient). Both patients with neurological improvement showed the appearance of continuity in the spinal cord tract by diffusion tensor imaging. There were no adverse effects associated with MSCs injection. Single MSCs application to intramedullary and intradural space is safe, but has a very weak therapeutic effect compared with multiple MSCs injection. Further clinical trials to enhance the effect of MSCs injection are necessary.

Interlayer interaction in Ca-Fe layered double hydroxides intercalated with nitrate and chloride species

NASA Astrophysics Data System (ADS)

Al-Jaberi, Muayad; Naille, Sébastien; Dossot, Manuel; Ruby, Christian

2015-12-01

Ca-Fe layered double hydroxide (LDH) intercalated with chloride and nitrate ions has been synthesized with varying CaII:FeIII molar ratios of the initial solution. Phase pure LDH is observed with CaII:FeIII molar ratio of 2:1 and a mixture of LDH and Ca(OH)2 is formed for CaII:FeIII molar ratios higher than 2:1. Vibrational spectroscopies (Raman and IR) were used successfully to understand the interaction between the cationic and anionic sheets. The Raman bands positions at lower frequencies (150-600 cm-1) are intimately correlated to the nature of the divalent and trivalent ions but also to the nature of the anions. Indeed, a shift of ˜9 cm-1 is observed for the Raman double bands situated in the 300-400 cm-1 region when comparing Raman spectra of CaFe-LDH containing either nitrate or chloride ions. Two types of nitrate environments are observed namely free (non-hydrogen bonded) nitrate and nitrate hydrogen bonded to the interlayer water or to the 'brucite-like' hydroxyl surface. Multiple types of water structure are observed and would result from different hydrogen bond structures. Water bending modes are identified at 1645 cm-1 greater than the one observed for LDH intercalated with chloride anions (1618 cm-1), indicating that the water is strongly hydrogen bonded to the nitrate anions.

Microscale imaging and identification of Fe speciation and distribution during fluid-mineral reactions under highly reducing conditions.

PubMed

Mayhew, L E; Webb, S M; Templeton, A S

2011-05-15

The oxidation state, speciation, and distribution of Fe are critical determinants of Fe reactivity in natural and engineered environments. However, it is challenging to follow dynamic changes in Fe speciation in environmental systems during progressive fluid-mineral interactions. Two common geological and aquifer materials-basalt and Fe(III) oxides-were incubated with saline fluids at 55 °C under highly reducing conditions maintained by the presence of Fe(0). We tracked changes in Fe speciation after 48 h (incipient water-rock reaction) and 10 months (extensive water-rock interaction) using synchrotron-radiation μXRF maps collected at multiple energies (ME) within the Fe K-edge. Immediate PCA analysis of the ME maps was used to optimize μXANES analyses; in turn, refitting the ME maps with end-member XANES spectra enabled us to detect and spatially resolve the entire variety of Fe-phases present in the system. After 48 h, we successfully identified and mapped the major Fe-bearing components of our samples (Fe(III) oxides, basalt, and rare olivine), as well as small quantities of incipient brucite associated with olivine. After 10 months, the Fe(III)-oxides remained stable in the presence of Fe(0), whereas significant alteration of basalt to minnesotaite and chlinochlore had occurred, providing new insights into heterogeneous Fe speciation in complex geological media under highly reducing conditions.

Methods for forming particles

DOEpatents

Fox, Robert V.; Zhang, Fengyan; Rodriguez, Rene G.; Pak, Joshua J.; Sun, Chivin

2016-06-21

Single source precursors or pre-copolymers of single source precursors are subjected to microwave radiation to form particles of a I-III-VI.sub.2 material. Such particles may be formed in a wurtzite phase and may be converted to a chalcopyrite phase by, for example, exposure to heat. The particles in the wurtzite phase may have a substantially hexagonal shape that enables stacking into ordered layers. The particles in the wurtzite phase may be mixed with particles in the chalcopyrite phase (i.e., chalcopyrite nanoparticles) that may fill voids within the ordered layers of the particles in the wurtzite phase thus produce films with good coverage. In some embodiments, the methods are used to form layers of semiconductor materials comprising a I-III-VI.sub.2 material. Devices such as, for example, thin-film solar cells may be fabricated using such methods.

Effect of Group-III precursors on unintentional gallium incorporation during epitaxial growth of InAlN layers by metalorganic chemical vapor deposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Jeomoh, E-mail: jkim610@gatech.edu; Ji, Mi-Hee; Detchprohm, Theeradetch

2015-09-28

Unintentional incorporation of gallium (Ga) in InAlN layers grown with different molar flow rates of Group-III precursors by metalorganic chemical vapor deposition has been experimentally investigated. The Ga mole fraction in the InAl(Ga)N layer was increased significantly with the trimethylindium (TMIn) flow rate, while the trimethylaluminum flow rate controls the Al mole fraction. The evaporation of metallic Ga from the liquid phase eutectic system between the pyrolized In from injected TMIn and pre-deposited metallic Ga was responsible for the Ga auto-incorporation into the InAl(Ga)N layer. The theoretical calculation on the equilibrium vapor pressure of liquid phase Ga and the effectivemore » partial pressure of Group-III precursors based on growth parameters used in this study confirms the influence of Group-III precursors on Ga auto-incorporation. More Ga atoms can be evaporated from the liquid phase Ga on the surrounding surfaces in the growth chamber and then significant Ga auto-incorporation can occur due to the high equilibrium vapor pressure of Ga comparable to effective partial pressure of input Group-III precursors during the growth of InAl(Ga)N layer.« less

The European Medicines Agency Review of Carfilzomib for the Treatment of Adult Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy.

PubMed

Tzogani, Kyriaki; Camarero Jiménez, Jorge; Garcia, Isabel; Sancho-López, Arantxa; Martin, Marc; Moreau, Alexandre; Demolis, Pierre; Salmonson, Tomas; Bergh, Jonas; Laane, Edward; Ludwig, Heinz; Gisselbrecht, Christian; Pignatti, Francesco

2017-11-01

On November 19, 2015, a marketing authorization valid through the European Union was issued for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.In a phase III trial in patients with relapsed MM, median progression-free survival (PFS) for patients treated with carfilzomib in combination with lenalidomide and dexamethasone (CRd) was 26.3 months versus 17.6 months for those receiving lenalidomide and dexamethasone alone (hazard ratio = 0.69; 95% confidence interval, 0.57-0.83; one-sided log-rank p value < .0001). The most frequently observed toxicity (grade ≥3, treatment arm vs. control arm) in the phase III trial included neutropenia (29.6% vs. 26.5%), anemia (17.9% vs. 17.7%), thrombocytopenia (16.8% vs. 12.3%), pneumonia (12.5% vs. 10.5%), fatigue (7.7% vs. 6.4%), hypertension (4.6% vs. 2.1%), diarrhea (3.8% vs. 4.1%), and respiratory tract infection (4.1% vs. 2.1%).The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the European Union. The scientific review concluded that the gain in PFS of 8.7 months observed with the combination of CRd was considered clinically meaningful and was supported by a clear trend in overall survival benefit, although the data were not mature. The delay in disease progression appeared superior to available alternatives in the setting of relapsed MM at the time of the marketing authorization of carfilzomib. Therefore, given the overall accepted safety profile, which was considered manageable in the current context, the benefit risk for CRd was considered positive. Carfilzomib (Kyprolis) was approved in the European Union in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The addition of carfilzomib to lenalidomide and dexamethasone resulted in a clinically meaningful and statistically significant improvement of progression-free survival compared with lenalidomide and dexamethasone, which was supported by a clear trend in overall survival benefit, although the data were not mature. At the time of the marketing authorization of carfilzomib, the delay in disease progression appeared superior to available alternatives in the setting of relapsed multiple myeloma. In terms of safety, the overall accepted safety profile was considered manageable. © AlphaMed Press 2017.

Humin as an electron donor for enhancement of multiple microbial reduction reactions with different redox potentials in a consortium.

PubMed

Zhang, Dongdong; Zhang, Chunfang; Xiao, Zhixing; Suzuki, Daisuke; Katayama, Arata

2015-02-01

A solid-phase humin, acting as an electron donor, was able to enhance multiple reductive biotransformations, including dechlorination of pentachlorophenol (PCP), dissimilatory reduction of amorphous Fe (III) oxide (FeOOH), and reduction of nitrate, in a consortium. Humin that was chemically reduced by NaBH4 served as an electron donor for these microbial reducing reactions, with electron donating capacities of 0.013 mmol e(-)/g for PCP dechlorination, 0.15 mmol e(-)/g for iron reduction, and 0.30 mmol e(-)/g for nitrate reduction. Two pairs of oxidation and reduction peaks within the humin were detected by cyclic voltammetry analysis. 16S rRNA gene sequencing-based microbial community analysis of the consortium incubated with different terminal electron acceptors, suggested that Dehalobacter sp., Bacteroides sp., and Sulfurospirillum sp. were involved in the PCP dechlorination, dissimilatory iron reduction, and nitrate reduction, respectively. These findings suggested that humin functioned as a versatile redox mediator, donating electrons for multiple respiration reactions with different redox potentials. Copyright © 2014 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Optical fluoride sensor based on monomer-dimer equilibrium of scandium(III)-octaethylporphyrin in a plasticized polymeric film.

PubMed

Kang, Youngjea; Kampf, Jeff W; Meyerhoff, Mark E

2007-08-29

A fluoride-selective optical sensor based on scandium(III)-octaethylporphyrin (Sc(III)OEP) as an ionophore within a plasticized PVC film is described. The presence of fluoride ion in the aqueous sample phase increases the formation of a difluoro-bridged Sc(III)OEP dimer species in the polymer film. The ability of the Sc(III) porphyrin to form the dimeric structure in the presence of fluoride is confirmed by UV-vis spectroscopy and X-ray crystallography. For more practical sensing applications, a pH chromoionophore (ETH 7075) is added to the plasticized PVC film along with Sc(III)OEP and the observed optical response is based on coextraction of protons with sample phase fluoride to create the dimeric porphyrin and a protonated chromoionophore species. The selectivity pattern observed is F- > ClO4(-), SCN-, NO3(-) > Br-, Cl-. Only organic salicylate is a significant interferent. Fast and reversible fluoride response is observed over the range of 10(-4) to 10(-2) M fluoride, allowing use of the sensing film in a waveguide configuration for flow-injection measurements.

Optical Fluoride Sensor Based on Monomer-Dimer Equilibrium of Scandium(III)-Octaethylporphyrin in a Plasticized Polymeric Film

PubMed Central

Kang, Youngjea; Kampf, Jeff W.; Meyerhoff, Mark E.

2007-01-01

A fluoride-selective optical sensor based on scandium(III) octaethylporphyrin (Sc(III)OEP) as an ionophore within a plasticized PVC film is described. The presence of fluoride ion in the aqueous sample phase increases the formation of a difluoro-bridged Sc(III)OEP dimer species in the polymer film. The ability of the Sc(III) porphyrin to form the dimeric structure in the presence of fluoride is confirmed by UV-Vis spectroscopy and X-ray crystallography. For more practical sensing applications, a pH chromoionophore (ETH 7075) is added to the plasticized PVC film along with Sc(III)OEP and the observed optical response is based on co-extraction of protons with sample phase fluoride to create the dimeric porphyrin and a protonated chromoionophore species. The selectivity pattern observed is F-≫ClO4-, SCN-, NO3->Br-, Cl-. Only organic salicylate is a significant interferent. Fast and reversible fluoride response is observed over the range of 10-4 ~10-2 M fluoride, allowing use of the sensing film in a waveguide configuration for flow-injection measurements. PMID:17719905

The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma.

PubMed

Brown, Sarah; Hinsley, Samantha; Ballesteros, Mónica; Bourne, Sue; McGarry, Paul; Sherratt, Debbie; Flanagan, Louise; Gregory, Walter; Cavenagh, Jamie; Owen, Roger; Williams, Cathy; Kaiser, Martin; Low, Eric; Yong, Kwee

2016-01-01

Multiple myeloma is a plasma cell tumour with an annual incidence in the UK of approximately 40-50 per million i.e. about 4500 new cases per annum. The triple combination cyclophosphamide, bortezomib (Velcade®) and dexamethasone (CVD) is an effective regimen at relapse and has emerged in recent years as the standard therapy at first relapse in the UK. Carfilzomib has good activity as a single agent in the relapsed setting, and it is expected that efficacy will be improved when used in combination with dexamethasone and cyclophosphamide. MUK Five is a phase II open label, randomised, controlled, parallel group, multi-centre trial that will compare the activity of carfilzomib, cyclophosphamide and dexamethasone (CCD) with that of CVD, given over an equivalent treatment period (24 weeks), in participants with multiple myeloma at first relapse, or refractory to no more than 1 line of treatment. In addition, the study also aims to assess the utility of a maintenance schedule of carfilzomib in these participants. The primary objective of the trial is to assess whether CCD provides non-inferior activity in terms of ≥ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with carfilzomib to CCD provides superior activity in terms of progression-free survival, as compared to CCD with no maintenance. Secondary objectives include comparing toxicity profiles, further summarizing and comparing the activity of the different treatment arms and analysis of the effect of each treatment arm on minimal residual disease status. The development of carfilzomib offers the opportunity to further explore the anti-tumour efficacy of proteasome inhibition and, based on the available evidence, it is important and timely to obtain data on the activity, toxicity and tolerability of this drug. In contrast to ongoing phase III trials, this phase II trial has a unique subset of participants diagnosed with multiple myeloma at first relapse or refractory to no more than 1 line of treatment and will also evaluate the utility of maintenance with carfilzomib for up to 18 months and investigate minimal residual disease status to provide information on depth of response and the prognostic impact thereof. The trial is registered under ISRCTN17354232, December 2012.

Translation of a Motor Learning Walking Rehabilitation Program Into a Group-Based Exercise Program for Community-Dwelling Older Adults.

PubMed

Brach, Jennifer S; Francois, Sara J; VanSwearingen, Jessie M; Gilmore, Sandra; Perera, Subashan; Studenski, Stephanie A

2016-06-01

Traditional exercise programs for older adults, which focus on aerobic and strength training, have had only modest effects on walking. Recently, a motor learning exercise program was shown to have greater effects on walking compared with a traditional exercise program. Translating this novel motor learning exercise program into a group exercise program would allow it to be offered as an evidence-based, community-based program for older adults. To translate a walking rehabilitation program based on motor learning theory from one-on-one to group delivery (On the Move) and evaluate multiple aspects of implementation in older adults with impaired mobility. The translation process involved multiple iterations, including meetings of experts in the field (Phase I), focus groups (Phase II), and implementation of the newly developed program (Phase III). Phase III was based on a one-group model of intervention development for feasibility, safety, potential effects, and acceptability. Community sites, including 2 independent living facilities, an apartment building, and a community center. Adults 65 years of age or older who could ambulate independently and who were medically stable. Thirty-one adults, mean age 82.3 ± 5.6 years, were eligible to participate. The group exercise program was held twice a week for 12 weeks. Acceptability of the program was determined by retention and adherence rates and a satisfaction survey. Risk was measured by adverse events and questions on perceived challenge and safety. Mobility was assessed pre- and postintervention by gait speed, Figure of 8 Walk Test, and 6-minute walk test. Modifications to the program included adjustments to format/length, music, education, and group interaction. The 12-week program was completed by 24 of 31 entrants (77%). Adherence was high, with participants attending on average 83% of the classes. Safety was excellent, with only 1 subject experiencing a controlled, noninjurious fall. There was preliminary evidence for improved mobility after the intervention: gait speed improved from 0.76 ± 0.21 to 0.81 ± 0.22 m/s, P = .06; Figure of 8 Walk Test from 13.0 ± 3.9 to 12.0 ± 3.9 seconds, P = .07; and 6-minute walk test from 246 ± 75 to 281 ± 67 m, P = .02. The group-based program was safe and acceptable to older adults with impaired mobility and resulted in potentially clinically meaningful improvements in mobility. Copyright © 2016 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Intensified chemotherapy with stem-cell rescue in germ-cell tumors.

PubMed

Simonelli, M; Rosti, G; Banna, G L; Pedrazzoli, P

2012-04-01

Based on the high chemosensitivity of germ-cell tumors (GCTs), the concept of high-dose chemotherapy (HDCT) has been developed worldwide and investigated through many clinical trials. It has been carried out in different clinical settings, ranging from resistant or absolute refractory disease to chemosensitive relapse. HDCT with stem-cell support has been also explored as a part of first-line strategy for poor-prognosis patients. Our review summarized results from clinical trials evaluating the role of HDCT in patients with advanced GCTs. So far available data were obtained through a Medline search of English-language literature. Several phase II trials and retrospective series have shown a possible benefit for GCT patients with recurrent disease as well as in first-line setting. Despite these results, data derived from randomized phase III studies failed to demonstrate any survival advantage for HDCT over conventional chemotherapy. The role of HDCT in GCTs remains controversial. We need new prospective studies based on prognostic factors with multiple transplants of carboplatin and etoposide as the preferred high dose regimen. At present, based mainly on retrospective and phase II studies, HDCT may represent a therapeutic option for patients with primary refractory disease or for those with a second or further relapse.

Correction of malocclusion and oral rehabilitation in a case of amelogenesis imperfecta by insertion of dental implants followed by Le Fort I distraction osteogenesis of the edentulous atrophic maxilla.

PubMed

Apaydin, Aysegul; Sermet, Bulent; Ureturk, Sevin; Kundakcioglu, Abdulsamet

2014-09-17

Amelogenesis imperfecta refers a group of hereditary diseases affecting the teeth and can present a variety of clinical forms and appearances, compromising esthetic appearance. Amelogenesis imperfecta variably reduces oral health quality and can result in severe psychological problems. We present the management of an amelogenesis imperfecta Angle class III malocclusion case with speech, esthetics and functional problems. This is an example of the rarely presented delayed eruption with multiple morphologic dental alterations and edentulous maxilla.There are only a few available reports in which this method is used method to correct sagittal discrepancies in edentulous patients.Our treatment plan consisted of a preoperative diagnostic and prosthodontics phase (including preparation of guiding prosthesis), followed by a surgical phase of Le Fort I osteotomy, distraction osteogenesis to correct the malocclusion, implant insertion and a follow up final restorative phase. Our treatment strategy attempts to serve patient needs, achieving function and esthetics while also minimizing the risk of reconstruction failure. Treatment not only restored function and esthetics, but also showed a positive psychological impact and thereby improved perceived quality of life.

Formation, Phase, and Elemental Composition of Micro- and Nano-Dimensional Particles of the Fe-Ti System

NASA Astrophysics Data System (ADS)

Dresvyannikov, A. F.; Kolpakov, M. E.

2018-05-01

X-ray fluorescence, X-ray phase analysis, and transmission Mössbauer and NGR spectrometry are used to study the formation, phase, and elemental composition of Fe-Ti particles. The interaction between Fe(III) ions and dispersed titanium in an aqueous solution containing chloride ions and HF is studied. It is shown that the resulting Fe-Ti samples are a set of core-shell microparticles with titanium cores coated with micro- and nanosized α-Fe nucleation centers with the thinness outer layer of iron(III) oxide characterized by a developed surface.

Validation of the phase II feasibility study in a palliative care setting: gastrografin in malignant bowel obstruction.

PubMed

Lee, Cindy; Vather, Ryash; O'Callaghan, Anne; Robinson, Jackie; McLeod, Briar; Findlay, Michael; Bissett, Ian

2013-12-01

Malignant bowel obstruction (MBO) is common in patients with advanced cancer. To perform a phase II study to assess the feasibility of conducting a phase III trial investigating the therapeutic value of gastrografin in MBO. Randomized double-blinded placebo-controlled feasibility study. Participants received 100 mL of either gastrografin or placebo. Over 8 months, 57 patients were screened and 9 enrolled (15.8% recruitment rate). Of the 9 enrolled, 4 received gastrografin (with 2 completing assessment) and 5 received placebo (with 4 completing assessment). It is not feasible to conduct a phase III trial using the same study protocol. This study validates the use of the phase II feasibility study to assess protocol viability in a palliative population prior to embarking on a larger trial.

The emplacement of long lava flows in Mare Imbrium, the Moon

NASA Astrophysics Data System (ADS)

Garry, W. B.

2012-12-01

Lava flow margins are scarce on the lunar surface. The best developed lava flows on the Moon occur in Mare Imbrium where flow margins are traceable nearly their entire flow length. The flow field originates in the southwest part of the basin from a fissure or series of fissures and cones located in the vicinity of Euler crater and erupted in three phases (Phases I, II, III) over a period of 0.5 Billion years (3.0 - 2.5 Ga). The flow field was originally mapped with Apollo and Lunar Orbiter data by Schaber (1973) and shows the flow field extends 200 to 1200 km from the presumed source area and covers an area of 2.0 x 10^5 km^2 with an estimated eruptive volume of 4 x 10^4 km^3. Phase I flows extend 1200 km and have the largest flow volume, but interestingly do not exhibit visible topography and are instead defined by difference in color from the surrounding mare flows. Phases II and III flows have well-defined flow margins (10 - 65 m thick) and channels (0.4 - 2.0 km wide, 40 - 70 m deep), but shorter flow lengths, 600 km and 400 km respectively. Recent missions, including Lunar Reconnaissance Orbiter (LRO), Kaguya (Selene), and Clementine, provide high resolution data sets of these lava flows. Using a combination of data sets including images from LRO Wide-Angle-Camera (WAC)(50-100 m/pixel) and Narrow-Angle-Camera (NAC) (up to 0.5m/pixel), Kaguya Terrain Camera (TC) (10 m/pixel), and topography from LRO Lunar Orbiter Laser Altimeter (LOLA), the morphology has been remapped and topographic measurements of the flow features have been made in an effort to reevaluate the emplacement of the flow field. Morphologic mapping reveals a different flow path for Phase I compared to the original mapping completed by Schaber (1973). The boundaries of the Phase I flow field have been revised based on Moon Mineralogy Mapper color ratio images (Staid et al., 2011). This has implications for the area covered and volume erupted during this stage, as well as, the age of Phase I. Flow features and margins have been identified in the Phase I flow within the LROC WAC mosaic and in Narrow Angle Camera (NAC) images. These areas have a mottled appearance. LOLA profiles over the more prominent flow lobes in Phase I reveal these margins are less 10 m thick. Phase II and III morphology maps are similar to previous flow maps. Phase III lobes near Euler are 10-12 km wide and 20-30 m thick based on measurements of the LOLA 1024ppd Elevation Digital Terrain Model (DTM) in JMoon. One of the longer Phase III lobes varies between 15 to 50 km wide and 25 to 60 m thick, with the thickest section at the distal end of the lobe. The Phase II lobe is 15 to 25 m thick and up to 35 km wide. The eruptive volume of the Mare Imbrium lava flows has been compared to terrestrial flood basalts. The morphology of the lobes in Phase II and III, which includes levees, thick flow fronts, and lobate margins suggests these could be similar to terrestrial aa-style flows. The Phase I flows might be more representative of sheet flows, pahoehoe-style flows, or inflated flows. Morphologic comparisons will be made with terrestrial flows at Askja volcano in Iceland, a potential analog to compare different styles of emplacement for the flows in Mare Imbrium.

The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

PubMed Central

Seymour, Lesley; Ivy, S. Percy; Sargent, Daniel; Spriggs, David; Baker, Laurence; Rubinstein, Larry; Ratain, Mark J; Le Blanc, Michael; Stewart, David; Crowley, John; Groshen, Susan; Humphrey, Jeffrey S; West, Pamela; Berry, Donald

2010-01-01

The optimal design of phase II studies continues to be the subject of vigorous debate, especially with regards to studies of newer molecularly targeted agents. The observations that many new therapeutics ‘fail’ in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials further emphasizes the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force(CTD-TF)of the NCI Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on Phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations regarding aspects of phase II trial design which are the subject of frequent debate such as endpoints(response vs. progression free survival), randomization(single arm designs vs. randomization), inclusion of biomarkers, biomarker based patient enrichment strategies, and statistical design(e.g. two stage designs vs. multiple-group adaptive designs). While these recommendations in general encourage the use of progression-free survival as the primary endpoint, the use of randomization, the inclusion of biomarkers and the incorporation of newer designs, we acknowledge that objective response as an endpoint, and single arm designs, remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on the characteristic specific to the situation. PMID:20215557

Reward modulates oculomotor competition between differently valued stimuli.

PubMed

Bucker, Berno; Silvis, Jeroen D; Donk, Mieke; Theeuwes, Jan

2015-03-01

The present work explored the effects of reward in the well-known global effect paradigm in which two objects appear simultaneously in close spatial proximity. The experiment consisted of three phases (i) a pre-training phase that served as a baseline, (ii) a reward-training phase to associate differently colored stimuli with high, low and no reward value, and (iii) a post-training phase in which rewards were no longer delivered, to examine whether objects previously associated with higher reward value attracted the eyes more strongly than those associated with low or no reward value. Unlike previous reward studies, the differently valued objects directly competed with each other on the same trial. The results showed that initially eye movements were not biased towards any particular stimulus, while in the reward-training phase, eye movements started to land progressively closer towards stimuli that were associated with a high reward value. Even though rewards were no longer delivered, this bias remained robustly present in the post-training phase. A time course analysis showed that the effect of reward was present for the fastest saccades (around 170 ms) and increased with increasing latency. Although strategic effects for slower saccades cannot be ruled out, we suggest that fast oculomotor responses became habituated and were no longer under strategic attentional control. Together the results imply that reward affects oculomotor competition in favor of stimuli previously associated high reward, when multiple reward associated objects compete for selection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Thermodynamic considerations of the vapor phase reactions in III-nitride metal organic vapor phase epitaxy

NASA Astrophysics Data System (ADS)

Sekiguchi, Kazuki; Shirakawa, Hiroki; Chokawa, Kenta; Araidai, Masaaki; Kangawa, Yoshihiro; Kakimoto, Koichi; Shiraishi, Kenji

2017-04-01

We analyzed the metal organic vapor phase epitaxial growth mechanism of the III-nitride semiconductors GaN, AlN, and InN by first-principles calculations and thermodynamic analyses. In these analyses, we investigated the decomposition processes of the group III source gases X(CH3)3 (X = Ga, Al, In) at finite temperatures and determined whether the (CH3)2GaNH2 adduct can be formed or not. The results of our calculations show that the (CH3)2GaNH2 adduct cannot be formed in the gas phase in GaN metal organic vapor phase epitaxy (MOVPE), whereas, in AlN MOVPE, the formation of the (CH3)2AlNH2 adduct in the gas phase is exclusive. In the case of GaN MOVPE, trimethylgallium (TMG, [Ga(CH3)3]) decomposition into Ga gas on the growth surface with the assistance of H2 carrier gas, instead of the formation of the (CH3)2GaNH2 adduct, occurs almost exclusively. Moreover, in the case of InN MOVPE, the formation of the (CH3)2InNH2 adduct does not occur and it is relatively easy to produce In gas even without H2 in the carrier gas.

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

PubMed

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

Metalloporphyrin Co(III)TMPyP ameliorates acute, sublethal cyanide toxicity in mice.

PubMed

Benz, Oscar S; Yuan, Quan; Amoscato, Andrew A; Pearce, Linda L; Peterson, Jim

2012-12-17

The formation of Co(III)TMPyP(CN)(2) at pH 7.4 has been shown to be completely cooperative (α(H) = 2) with an association constant of 2.1 (±0.2) × 10(11). The kinetics were investigated by stopped-flow spectrophotometry and revealed a complicated net reaction exhibiting 4 phases at pH 7.4 under conditions where cyanide was in excess. The data suggest molecular HCN (rather than CN(-)) to be the attacking nucleophile around neutrality. The two slower phases do not seem to be present when cyanide is not in excess, and the other two phases have rates comparable to that observed for cobalamin, a known effective cyanide scavenger. Addition of bovine serum albumin (BSA) did not affect the cooperativity of cyanide binding to Co(III)TMPyP, only lowered the equilibrium constant slightly to 1.2 (±0.2) × 10(11) and had an insignificant effect on the observed rate. A sublethal mouse model was used to assess the effectiveness of Co(III)TMPyP as a potential cyanide antidote. The administration of Co(III)TMPyP to sodium cyanide intoxicated mice resulted in the time required for the surviving mice to right themselves from a supine position being significantly decreased (9 ± 2 min) compared to that of the controls (33 ± 2 min). All observations were consistent with the demonstrated antidotal activity of Co(III)TMPyP operating through a cyanide-binding (i.e., scavenging) mechanism.

Fludarabine Phosphate, Melphalan, Total-Body Irradiation, Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Bone Marrow Failure Disorders

ClinicalTrials.gov

2017-11-29

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Fanconi Anemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Paroxysmal Nocturnal Hemoglobinuria; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Waldenström Macroglobulinemia

The GKSS beamlines at PETRA III and DORIS III

NASA Astrophysics Data System (ADS)

Haibel, A.; Beckmann, F.; Dose, T.; Herzen, J.; Utcke, S.; Lippmann, T.; Schell, N.; Schreyer, A.

2008-08-01

Due to the high brilliance of the new storage ring PETRA III at DESY in Hamburg, the low emittance of 1 nmrad and the high fraction of coherent photons also in the hard X-ray range extremely intense and sharply focused X-ray light will be provided. These advantages of the beam fulfill excellently the qualifications for the planned Imaging BeamLine IBL and the High Energy Materials Science Beamline (HEMS) at PETRA III, i.e. for absorption tomography, phase enhanced and phase contrast experiments, for diffraction, for nano focusing, for nano tomography, and for high speed or in-situ experiments with highest spatial resolution. The existing HARWI II beamline at the DORIS III storage ring at DESY completes the GKSS beamline concept with setups for high energy tomography (16-150 keV) and diffraction (16-250 keV), characterized by a large field of view and an excellent absorption contrast with spatial resolutions down to 2 μm.

General Improvement of Reading Instruction, Grades 1-12, Teacher Training Program of Title III, P.L. 89-10. Evaluation of Second Phase of Program, Summer 1968.

ERIC Educational Resources Information Center

Brookland-Cayce Schools, West Columbia, SC.

An evaluation of the second phase of a projected 3-year Title III inservice reading instruction program for teaching personnel is presented after one and one-half years of operation in 16 Cayce-West Columbia, South Carolina, schools. Included is an evaluation prepared by each of the 11 elementary supervisors which includes objectives and how they…

Installation Restoration Program Records Search for Westover Air Force Base, Massachusetts.

DTIC Science & Technology

1982-04-01

Phase III (not part of this contract) consists of a technology base development study to support the development of project plans for controlling...determine the extent and magnitude of the contaminant migration. Phase III (not part of this contract) consists of a technology base development study to...number of vegetation studies have attempted to classify the potential climax vegetation within the region of Westover AFB (Braun, 1972; Kuchler, 1975

OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma.

PubMed

Kaufman, Howard L; Bines, Steven D

2010-06-01

There are few effective treatment options available for patients with advanced melanoma. An oncolytic herpes simplex virus type 1 encoding granulocyte macrophage colony-stimulating factor (GM-CSF; Oncovex(GM-CSF)) for direct injection into accessible melanoma lesions resulted in a 28% objective response rate in a Phase II clinical trial. Responding patients demonstrated regression of both injected and noninjected lesions highlighting the dual mechanism of action of Oncovex(GM-CSF) that includes both a direct oncolytic effect in injected tumors and a secondary immune-mediated anti-tumor effect on noninjected tumors. Based on these preliminary results a prospective, randomized Phase III clinical trial in patients with unresectable Stage IIIb or c and Stage IV melanoma has been initiated. The rationale, study design, end points and future development of the Oncovex(GM-CSF) Pivotal Trial in Melanoma (OPTIM) trial are discussed in this article.

Chemoradiation in elderly esophageal cancer patients: rationale and design of a phase I/II multicenter study (OSAGE).

PubMed

Servagi-Vernat, Stéphanie; Créhange, Gilles; Bonnetain, Franck; Mertens, Cécile; Brain, Etienne; Bosset, Jean François

2017-07-13

The management of elderly patients with cancer is a therapeutic challenge and a public health problem. Definitive chemoradiotherapy (CRT) is an accepted standard treatment for patients with locally advanced esophageal cancer who cannot undergo surgery. However, there are few reports regarding tolerance to CRT in elderly patients. We previously reported results for CRT in patients aged ≥75 years. Following this first phase II trial, we propose to conduct a phase I/II study to evaluate the combination of carboplatin and paclitaxel, with concurrent RT in unresectable esophageal cancer patients aged 75 years or older. This prospective multicenter phase I/II study will include esophageal cancer in patients aged 75 years or older. Study procedures will consist to determinate the tolerated dose of chemotherapy (Carboplatin, paclitaxel) and of radiotherapy (41.4-45 and 50.4 Gy) in the phase I. Efficacy will be assessed using a co-primary endpoint encompassing health related quality of life and the progression-free survival in the phase II with the dose recommended of CRT in the phase I. This geriatric evaluation was defined by the French geriatric oncology group (GERICO). This trial has been designed to assess the tolerated dose of CRT in selected patient aged 75 years or older. Clinicaltrials.gov ID: NCT02735057 . Registered on 18 March 2016.

Effect of intravenous amino acids on interdigestive antroduodenal motility and small bowel transit time.

PubMed

Gielkens, H A; van den Biggelaar, A; Vecht, J; Onkenhout, W; Lamers, C B; Masclee, A A

1999-02-01

Patients on total parenteral nutrition have an increased risk of developing gallstones because of gall bladder hypomotility. High dose amino acids may prevent biliary stasis by stimulating gall bladder emptying. To investigate whether intravenous amino acids also influence antroduodenal motility. Eight healthy volunteers received, on three separate occasions, intravenous saline (control), low dose amino acids (LDA), or high dose amino acids (HDA). Antroduodenal motility was recorded by perfusion manometry and duodenocaecal transit time (DCTT) using the lactulose breath hydrogen test. DCTT was significantly prolonged during LDA and HDA treatment compared with control. The interdigestive motor pattern was maintained and migrating motor complex (MMC) cycle length was significantly reduced during HDA compared with control and LDA due to a significant reduction in phase II duration. Significantly fewer phase IIIs originated in the gastric antrum during LDA and HDA compared with control. Duodenal phase II motility index was significantly reduced during HDA, but not during LDA, compared with control. Separate intravenous infusion of high doses of amino acids in healthy volunteers: (1) modulates interdigestive antroduodenal motility; (2) shortens MMC cycle length due to a reduced duration of phase II with a lower contractile incidence both in the antrum and duodenum (phase I remains unchanged whereas the effect on phase III is diverse: in the antrum phase III is suppressed and in the duodenum the frequency is increased); and (3) prolongs interdigestive DCTT.

Refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians: detection of naturally occurring osteoarthritis in laboratory cats.

PubMed

Klinck, Mary P; Monteiro, Beatriz P; Lussier, Bertrand; Guillot, Martin; Moreau, Maxim; Otis, Colombe; Steagall, Paulo Vm; Frank, Diane; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre; Del Castillo, Jérôme Re; Troncy, Eric

2017-09-01

Objectives Feline osteoarthritis causes pain and disability. Detection and measurement is challenging, relying heavily on owner report. This study describes refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians. Methods A video analysis of osteoarthritic (n = 6) and non-osteoarthritic (n = 4) cats facilitated expansion of scale items. Three successive therapeutic trials (using gabapentin, tramadol and oral transmucosal meloxicam spray) in laboratory cats with and without natural osteoarthritis (n = 12-20), permitted construct validation (assessments of disease status sensitivity and therapeutic responsiveness) and further scale refinements based on performance. Results Scale osteoarthritic sensitivity improved from phase I to phase III; phase III scale total score ( P = 0.0001) and 4/5 subcategories - body posture ( P = 0.0006), gait ( P = 0.0031), jumping (0.0824) and global distance examination ( P = 0.0001) - detected osteoarthritic cats. Total score inter-rater (intra-class correlation coefficients [ICC] = 0.64-0.75), intra-rater (ICC = 0.90-0.91) and overall internal consistency (Cronbach's alpha = 0.85) reliability were good to excellent. von Frey anesthesiometer-induced paw withdrawal threshold increased with gabapentin in phase I, in osteoarthritic cats ( P <0.001) but not in non-osteoarthritic cats ( P = 0.075). Night-time activity increased during gabapentin treatment. Objective measures also detected tramadol and/or meloxicam treatment effects in osteoarthritic cats in phases II and III. There was some treatment responsiveness: in phase I, 3/10 subcategory scores improved ( P <0.09) in treated osteoarthritic cats; in phase II, 3/8 subcategories; and in phase III, 1/5 subcategories improved ( P <0.096). Conclusions and relevance The revised scale detected naturally occurring osteoarthritis, but not treatment effects, in laboratory cats, suggesting future potential for screening of at-risk cats. Further study is needed to confirm reliability, validity (disease sensitivity and treatment responsiveness) and clinical feasibility, as well as cut-off scores for osteoarthritic vs non-osteoarthritic status, in client-owned cats.

A crossover study of the combination therapy of metformin and exenatide or biphasic insulin aspart 30 in overweight or obese patients newly diagnosed with type 2 diabetes mellitus

PubMed Central

Quan, Huibiao; Zhang, Huachuan; Wei, Weiping; Fang, Tuanyu; Chen, Daoxiong; Chen, Kaining

2017-01-01

The aim of the present study was to explore the effects of various combinations of exenatide, metformin (MET) and biphasic insulin aspart 30 (BIA30) on type 2 diabetes mellitus (T2DM). Two hundred overweight or obese patients newly diagnosed with T2DM were evenly randomized into two groups: A (twice daily for all: Phase I, 5 µg exenatide + 0.5 g MET for 4 weeks, then 10 µg exenatide + 0.5 g MET for 8 weeks; Phase II, 0.5 g MET for 12 weeks; Phase III, 0.3–0.4 U/kg/day BIA30 + 0.5 g MET for 12 weeks) and B (Phases I, II, III matched the phases III, II and I in group A). In groups A and B a significant decrease and increase, respectively, in glycated hemoglobin (HbAlc) and body mass index (BMI) was noted during Phase I. A 3.2±0.4-kg decrease in body weight in group A and a 2.6±0.3-kg increase in group B was observed. In Phase II, HbAlc was significantly increased in both groups (P<0.05). In Phase III, the BMI was increased in group A and reduced in group B (P<0.05). There was a 3.8±0.4-kg weight decrease in group B and 4.2±0.5-kg increase in group A (P<0.05). The combination of exenatide and MET promoted weight loss, glycemic control, β-cell function index, C peptide and adiponectin levels. These results suggested that the combination of exenatide and MET is better than the combination of BIA and MET for the therapy of overweight or obese patients newly diagnosed with T2DM. PMID:28912879

Guideline-based intervention to reduce telemetry rates in a large tertiary centre.

PubMed

Ramkumar, Satish; Tsoi, Edward H; Raghunath, Ajay; Dias, Floyd F; Li Wai Suen, Christopher; Tsoi, Andrew H; Mansfield, Darren R

2017-07-01

Inappropriate cardiac telemetry use is associated with reduced patient flow and increased healthcare costs. To evaluate the outcomes of guideline-based application of cardiac telemetry. Phase I involved a prospective audit (March to August 2011) of telemetry use at a tertiary hospital. Data were collected on indication for telemetry and clinical outcomes. Phase II prospectively included patients more than 18 years under general medicine requiring ward-based telemetry. As phase II occurred at a time remotely from phase I, an audit similar to phase I (phase II - baseline) was completed prior to a 3-month intervention (May to August 2015). The intervention consisted of a daily telemetry ward round and an admission form based on the American Heart Association guidelines (class I, telemetry indicated; class II, telemetry maybe indicated; class III, telemetry not indicated). Patient demographics, telemetry data, and clinical outcomes were studied. Primary endpoint was the percentage reduction of class III indications, while secondary endpoint included telemetry duration. In phase I (n = 200), 38% were admitted with a class III indication resulting in no change in clinical management. A total of 74 patients was included in phase II baseline (mean ± standard deviation (SD) age 73 years ± 14.9, 57% male), whilst 65 patients were included in the intervention (mean ± SD age 71 years ± 18.4, 35% male). Both groups had similar baseline characteristics. There was a reduction in class III admissions post-intervention from 38% to 11%, P < 0.001. Intervention was associated with a reduction in median telemetry duration (1.8 ± 1.8 vs 2.4 ± 2.5 days, P = 0.047); however, length of stay was similar in both groups (P > 0.05). Guideline-based telemetry admissions and a regular telemetry ward round are associated with a reduction in inappropriate telemetry use. © 2017 Royal Australasian College of Physicians.

Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease.

PubMed

Hey, John A; Yu, Jeremy Y; Versavel, Mark; Abushakra, Susan; Kocis, Petr; Power, Aidan; Kaplan, Paul L; Amedio, John; Tolar, Martin

2018-03-01

ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max ) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

The local magnetic properties of [MnIII6 CrIII]3+ and [FeIII6 CrIII]3+ single-molecule magnets deposited on surfaces studied by spin-polarized photoemission and XMCD with circularly polarized synchrotron radiation

NASA Astrophysics Data System (ADS)

Heinzmann, U.; Helmstedt, A.; Dohmeier, N.; Müller, N.; Gryzia, A.; Brechling, A.; Hoeke, V.; Krickemeyer, E.; Glaser, T.; Fonin, M.; Bouvron, S.; Leicht, P.; Tietze, T.; Goering, E.; Kuepper, K.

2014-04-01

It is demonstrated that local magnetic moments of single molecule magnets (SMM) normally studied by XMCD at very low temperatures and high magnetic fields can be measured by means of spin-resolved electron emission in the paramagnetic phase at room temperature by use of circularly polarized radiation.

Final Technical Report. Project Boeing SGS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bell, Thomas E.

Boeing and its partner, PJM Interconnection, teamed to bring advanced “defense-grade” technologies for cyber security to the US regional power grid through demonstration in PJM’s energy management environment. Under this cooperative project with the Department of Energy, Boeing and PJM have developed and demonstrated a host of technologies specifically tailored to the needs of PJM and the electric sector as a whole. The team has demonstrated to the energy industry a combination of processes, techniques and technologies that have been successfully implemented in the commercial, defense, and intelligence communities to identify, mitigate and continuously monitor the cyber security of criticalmore » systems. Guided by the results of a Cyber Security Risk-Based Assessment completed in Phase I, the Boeing-PJM team has completed multiple iterations through the Phase II Development and Phase III Deployment phases. Multiple cyber security solutions have been completed across a variety of controls including: Application Security, Enhanced Malware Detection, Security Incident and Event Management (SIEM) Optimization, Continuous Vulnerability Monitoring, SCADA Monitoring/Intrusion Detection, Operational Resiliency, Cyber Range simulations and hands on cyber security personnel training. All of the developed and demonstrated solutions are suitable for replication across the electric sector and/or the energy sector as a whole. Benefits identified include; Improved malware and intrusion detection capability on critical SCADA networks including behavioral-based alerts resulting in improved zero-day threat protection; Improved Security Incident and Event Management system resulting in better threat visibility, thus increasing the likelihood of detecting a serious event; Improved malware detection and zero-day threat response capability; Improved ability to systematically evaluate and secure in house and vendor sourced software applications; Improved ability to continuously monitor and maintain secure configuration of network devices resulting in reduced vulnerabilities for potential exploitation; Improved overall cyber security situational awareness through the integration of multiple discrete security technologies into a single cyber security reporting console; Improved ability to maintain the resiliency of critical systems in the face of a targeted cyber attack of other significant event; Improved ability to model complex networks for penetration testing and advanced training of cyber security personnel« less

High efficiency III-nitride light-emitting diodes

DOEpatents

Crawford, Mary; Koleske, Daniel; Cho, Jaehee; Zhu, Di; Noemaun, Ahmed; Schubert, Martin F; Schubert, E. Fred

2013-05-28

Tailored doping of barrier layers enables balancing of the radiative recombination among the multiple-quantum-wells in III-Nitride light-emitting diodes. This tailored doping enables more symmetric carrier transport and uniform carrier distribution which help to reduce electron leakage and thus reduce the efficiency droop in high-power III-Nitride LEDs. Mitigation of the efficiency droop in III-Nitride LEDs may enable the pervasive market penetration of solid-state-lighting technologies in high-power lighting and illumination.

High-pressure phase transitions, amorphization, and crystallization behaviors in Bi2Se3.

PubMed

Zhao, Jinggeng; Liu, Haozhe; Ehm, Lars; Dong, Dawei; Chen, Zhiqiang; Gu, Genda

2013-03-27

The phase transition, amorphization, and crystallization behaviors of the topological insulator bismuth selenide (Bi2Se3) were discovered by performing in situ high-pressure angle-dispersive x-ray diffraction experiments during an increasing, decreasing, and recycling pressure process. In the compression process, Bi2Se3 transforms from the original rhombohedral structure (phase I(A)) to a monoclinic structure (phase II) at about 10.4 GPa, and further to a body-centered tetragonal structure (phase III) at about 24.5 GPa. When releasing pressure to ambient conditions after the complete transformation from phase II to III, Bi2Se3 becomes an amorphous solid (AM). In the relaxation process from this amorphous state, Bi2Se3 starts crystallizing into an orthorhombic structure (phase I(B)) about five hours after releasing the pressure to ambient. A review of the pressure-induced phase transition behaviors of A2B3-type materials composed from the V and VI group elements is presented.

Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins

PubMed Central

Furtado, Jeremy D.; Wedel, Mark K.; Sacks, Frank M.

2012-01-01

Mipomersen, an antisense oligonucleotide that reduces hepatic production of apoB, has been shown in phase 2 studies to decrease plasma apoB, LDL cholesterol (LDL-C), and triglycerides. ApoC-III inhibits VLDL and LDL clearance, and it stimulates inflammatory responses in vascular cells. Concentrations of VLDL or LDL with apoC-III independently predict cardiovascular disease. We performed an exploratory posthoc analysis on a subset of hypercholesterolemic subjects obtained from a randomized controlled dose-ranging phase 2 study of mipomersen receiving 100, 200, or 300 mg/wk, or placebo for 13 wk (n = 8 each). ApoC-III–containing lipoproteins were isolated by immuno-affinity chromatography and ultracentrifugation. Mipomersen 200 and 300 mg/wk reduced total apoC-III from baseline by 6 mg/dl (38–42%) compared with placebo group (P < 0.01), and it reduced apoC-III in both apoB lipoproteins and HDL. Mipomersen 100, 200, and 300 mg doses reduced apoB concentration of LDL with apoC-III (27%, 38%, and 46%; P < 0.05). Mipomersen reduced apoC-III concentration in HDL. The drug had no effect on apoE concentration in total plasma and in apoB lipoproteins. In summary, antisense inhibition of apoB synthesis reduced plasma concentrations of apoC-III and apoC-III–containing lipoproteins. Lower concentrations of apoC-III and LDL with apoC-III are associated with reduced risk of coronary heart disease (CHD) in epidemiologic studies independent of traditional risk factors. PMID:22301884

Method for Improving Mg Doping During Group-III Nitride MOCVD

DOEpatents

Creighton, J. Randall; Wang, George T.

2008-11-11

A method for improving Mg doping of Group III-N materials grown by MOCVD preventing condensation in the gas phase or on reactor surfaces of adducts of magnesocene and ammonia by suitably heating reactor surfaces between the location of mixing of the magnesocene and ammonia reactants and the Group III-nitride surface whereon growth is to occur.

Impact of Availability of Companion Diagnostics on the Clinical Development of Anticancer Drugs.

PubMed

Tibau, Ariadna; Díez-González, Laura; Navarro, Beatriz; Galán-Moya, Eva M; Templeton, Arnoud J; Seruga, Bostjan; Pandiella, Atanasio; Amir, Eitan; Ocana, Alberto

2017-06-01

Companion diagnostics permit the selection of patients likely to respond to targeted anticancer drugs; however, it is unclear if the drug development process differs between drugs developed with or without companion diagnostics. Identification of differences in study design could help future clinical development. Anticancer drugs approved for use in solid tumors between 28 September 2000 and 4 January 2014 were identified using a search of the US FDA website. Phase III trials supporting registration were extracted from the drug label. Each published study was reviewed to obtain information about the phase I and II trials used for the development of the respective drug. We identified 35 drugs and 59 phase III randomized trials supporting regulatory approval. Fifty-three phase I trials and 47 phase II trials were cited in the studies and were used to support the design of these phase III trials. The approval of drugs using a companion diagnostic has increased over time (p for trend 0.01). Expansion cohorts were more frequently observed with drugs developed with a companion diagnostic (62 vs. 20%; p = 0.005). No differences between drugs developed with or without a companion diagnostic were observed for the design of phase I and II studies. The approval of drugs developed with a companion diagnostic has increased over time. The availability of a companion diagnostic was associated with more frequent use of phase I expansion cohorts comprising patients selected by the companion diagnostic.

Sorption of Ferrioxime B to Synthetic and Biogenic layer type Mn Oxides

NASA Astrophysics Data System (ADS)

Duckworth, O. W.; Bargar, J. R.; Sposito, G.

2005-12-01

Siderophores are biogenic chelating agents produced in terrestrial and marine environments to increase the bioavailablity of ferric iron. Recent work has suggested that both aqueous and solid-phase Mn(III) may affect siderophore-mediated iron transport, but no information appears to be available about the effect of solid-phase Mn(IV). To probe the effect of solid-phase Mn(IV), we studied the sorption reaction of ferrioxamine B [principally the species, Fe(III)HDFOB+, an Fe(III) chelate of the trihydroxamate siderophore, desferrioxamine B (DFOB)] with two synthetic birnessites [layer type Mn(IV) oxides] and a biogenic birnessite produced by Pseudomonas putida MnB1. We found that all of these predominantly Mn(IV) oxides greatly reduced the aqueous concentration of Fe(III)HDFOB+ over the pH range between 5 and 9. After 72 h equilibration time at pH 8, the sorption behavior for the synthetic birnessites could be accurately described by a Langmuir isotherm; for the biogenic oxide, a Freundlich isotherm was best utilized to model the sorption data. To study the molecular nature of the interaction between the Fe(III)HDFOB+ complex and the oxide surface, Fe K-edge extended X-Ray absorption fine structure (EXAFS) spectroscopy was employed. Analysis of the X-ray absorption spectra indicated that Fe(III) associated with the Mn(IV) oxides is not complexed with DFOB, but instead is incorporated into the mineral structure, thus implying that the Mn(IV) oxides displaced Fe(III) from the siderophore complex. These results indicate that manganese oxides, including biominerals, may strongly sequester iron from soluble ferric complexes and thus may play a significant role in the biogeochemical cycling of iron.

The Importance of pH, Oxygen, and Bitumen on the Oxidation and Precipitation of Fe(III)-(oxy)hydroxides during Hydraulic Fracturing of Oil/Gas Shales

NASA Astrophysics Data System (ADS)

Jew, A. D.; Dustin, M. K.; Harrison, A. L.; Joe-Wong, C. M.; Thomas, D.; Maher, K.; Brown, G. E.; Bargar, J.

2016-12-01

Due to the rapid growth of hydraulic fracturing in the United States, understanding the cause for the rapid production drop off of new wells over the initial months of production is paramount. One possibility for the production decrease is pore occlusion caused by the oxidation of Fe(II)-bearing phases resulting in Fe(III) precipitates. To understand the release and fate of Fe in the shale systems, we reacted synthesized fracture fluid at 80oC with shale from four different geological localities (Marcellus Fm., Barnett Fm., Eagle Ford Fm., and Green River Fm.). A variety of wet chemical and synchrotron-based techniques (XRF mapping and x-ray absorption spectroscopy) were used to understand Fe release and solid phase Fe speciation. Solution pH was found to be the greatest factor for Fe release. Carbonate-poor Barnett and Marcellus shale showed rapid Fe release into solution followed by a plateau or significant drop in Fe concentrations indicating mineral precipitation. Conversely, in high carbonate shales, Eagle Ford and Green River, no Fe was detected in solution indicating fast Fe oxidation and precipitation. For all shale samples, bulk Fe EXAFS data show that a significant amount of Fe in the shales is bound directly to organic carbon. Throughout the course of the experiments inorganic Fe(II) phases (primarily pyrite) reacted while Fe(II) bound to C showed no indication of reaction. On the micron scale, XRF mapping coupled with μ-XANES spectroscopy showed that at pH < 4.0, Fe(III) bearing phases precipitated as diffuse surface precipitates of ferrihydrite, goethite, and magnetite away from Fe(II) point sources. In near circum-neutral pH systems, Fe(III)-bearing phases (goethite and hematite) form large particles 10's of μm's in diameter near Fe(II) point sources. Idealized systems containing synthesized fracturing fluid, dissolved ferrous chloride, and bitumen showed that bitumen released during reaction with fracturing fluids is capable of oxidizing Fe(II) to Fe(III) at pH's 2.0 and 7.0. This indicates that bitumen can play a large role in Fe oxidation and speciation in the subsurface. This work shows that shale mineralogy has a significant impact on the morphology and phases of Fe(III) precipitates in the subsurface which in turn can significantly impact subsurface solution flow.

A "First Principles" Potential Energy Surface for Liquid Water from VRT Spectroscopy of Water Clusters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldman, N; Leforestier, C; Saykally, R J

We present results of gas phase cluster and liquid water simulations from the recently determined VRT(ASP-W)III water dimer potential energy surface. VRT(ASP-W)III is shown to not only be a model of high ''spectroscopic'' accuracy for the water dimer, but also makes accurate predictions of vibrational ground-state properties for clusters up through the hexamer. Results of ambient liquid water simulations from VRT(ASP-W)III are compared to those from ab initio Molecular Dynamics, other potentials of ''spectroscopic'' accuracy, and to experiment. The results herein represent the first time that a ''spectroscopic'' potential surface is able to correctly model condensed phase properties of water.

Recurrence of water bodies in the hyperarid core of the Atacama Desert - New insights into the Late Pleistocene paleoclimate history of Northern Chile

NASA Astrophysics Data System (ADS)

Diederich, J. L.; Wennrich, V.; Fernández Galego, E.; Ritter, B.; Brill, D.; Niemann, K.; Rolf, C.; Melles, M.

2017-12-01

The Atacama Desert of northern Chile is regarded as the driest desert on Earth. Although still controversially discussed, overall arid to hyperarid conditions in the Atacama are thought to have persisted at least since the early Miocene, but were frequently punctuated by pluvial phases. The knowledge of past changes in humidity is strongly hampered by the fact that sediment records from the central Atacama Desert, which enable longer-scale precipitation reconstructions, are rare and mostly restricted to the Miocene/Pliocene or the late Pleistocene <50 kyrs. In this study, we focus on a sediment record from the hyperarid core of the Atacama Desert, derived from a tectonically blocked clay pan in the Coastal Cordillera (20°04'33.64"S, 69°55'01.75"W). This clay pan `Huara' has been initially investigated by a geophysical survey in spring 2015, followed by drilling of a short core (HU-III) covering the uppermost 4 m of sediment. Initial results of the ground penetrating radar (GPR) and horizontal to vertical (H/V) spectral ratio measurements indicate well-stratified sediment bodies in the basin with a maximum sediment infill of 30 ± 4 m. The chronology of core HU-III was established by a combination of optically stimulated luminescence (OSL) and paleomagnetic dating. The sedimentological and geochemical data of core HU-III as well as it's sediment geophysical properties indicate the primary accumulation of fine-grained sediments over the past ca. 50 kyrs, interpreted to be deposited under arid conditions with only sporadic precipitation. Intercalated coarser horizons indicate several periods of semiarid climate conditions, causing multiple phases of local alluvial deposition from the interior catchment area into the clay pan. The results are in agreement with a cosmogenic nuclide study from an adjacent meander system, indicating that the whole sediment sequence of the Huara clay pan covers the regional climate history of the past 500 - 700 kyrs.

Review article: novel oral-targeted therapies in inflammatory bowel disease.

PubMed

White, J R; Phillips, F; Monaghan, T; Fateen, W; Samuel, S; Ghosh, S; Moran, G W

2018-06-01

There is a great unmet clinical need for efficacious, tolerable, economical and orally administrated drugs for the treatment of inflammatory bowel disease (IBD). New therapeutic avenues have become possible including the development of medications that target specific genetic pathways found to be relevant in other immune mediated diseases. To provide an overview of recent clinical trials for new generation oral targeted medications that may have a future role in IBD management. Pubmed and Medline searches were performed up to 1 March 2018 using keywords: "IBD", "UC", "CD", "inflammatory bowel disease" "ulcerative colitis", "Crohn's disease" in combination with "phase", "study", "trial" and "oral". A manual search of the clinical trial register, article reference lists, abstracts from meetings of Digestive Disease Week, United European Gastroenterology Week and ECCO congress were also conducted. In randomised controlled trials primary efficacy endpoints were met for tofacitinib (JAK 1/3 inhibitor-phase III), upadacitinib (JAK 1 inhibitor-phase II) and AJM300 (α4-integrin antagonist-phase II) in ulcerative colitis. Ozanimod (S1P receptor agonist-phase II) also demonstrated clinical remission. For Crohn's disease, filgotinib (JAK1 inhibitor-phase II) met primary endpoints and laquinimod (quinolone-3-carboxide small molecule-phase II) was also efficacious. Trials using mongersen (SMAD7 inhibitor) and vidofludimus (dihydroorotate dehydrogenase inhibitor) have been halted. This is potentially the start of an exciting new era in which multiple therapeutic options are at the disposal of physicians to treat IBD on an individualised basis. Head-to-head studies with existing treatments and longer term safety data are needed for this to be possible. © 2018 John Wiley & Sons Ltd.

School Emergencies--Preparation Not Panic.

ERIC Educational Resources Information Center

Sousa, Barbara

1982-01-01

A three-phase emergency recognition course was designed to train 26 faculty and staff members to recognize and respond to emergency school medical situations. Phase I included comprehensive first aid, cardiopulmonary resuscitation (CPR), and injections. Phase II dealt with recognition of medical emergencies, and Phase III recertified those who had…

Puzzling calcite-III dimorphism: crystallography, high-pressure behavior, and pathway of single-crystal transitions

NASA Astrophysics Data System (ADS)

Pippinger, T.; Miletich, R.; Merlini, M.; Lotti, P.; Schouwink, P.; Yagi, T.; Crichton, W. A.; Hanfland, M.

2015-01-01

High-pressure phase transformations between the polymorphic forms I, II, III, and IIIb of CaCO3 were investigated by analytical in situ high-pressure high-temperature experiments on oriented single-crystal samples. All experiments at non-ambient conditions were carried out by means of Raman scattering, X-ray, and synchrotron diffraction techniques using diamond-anvil cells in the pressure range up to 6.5 GPa. The composite-gasket resistive heating technique was applied for all high-pressure investigations at temperatures up to 550 K. High-pressure Raman spectra reveal distinguishable characteristic spectral differences located in the wave number range of external modes with the occurrence of band splitting and shoulders due to subtle symmetry changes. Constraints from in situ observations suggest a stability field of CaCO3-IIIb at relatively low temperatures adjacent to the calcite-II field. Isothermal compression of calcite provides the sequence from I to II, IIIb, and finally, III, with all transformations showing volume discontinuities. Re-transformation at decreasing pressure from III oversteps the stability field of IIIb and demonstrates the pathway of pressure changes to determine the transition sequence. Clausius-Clapeyron slopes of the phase boundary lines were determined as: Δ P/Δ T = -2.79 ± 0.28 × 10-3 GPa K-1 (I-II); +1.87 ± 0.31 × 10-3 GPa K-1 (II/III); +4.01 ± 0.5 × 10-3 GPa K-1 (II/IIIb); -33.9 ± 0.4 × 10-3 GPa K-1 (IIIb/III). The triple point between phases II, IIIb, and III was determined by intersection and is located at 2.01(7) GPa/338(5) K. The pathway of transition from I over II to IIIb can be interpreted by displacement with small shear involved (by 2.9° on I/II and by 8.2° on II/IIIb). The former triad of calcite-I corresponds to the [20-1] direction in the P21/ c unit cell of phase II and to [101] in the pseudomonoclinic C setting of phase IIIb. Crystal structure investigations of triclinic CaCO3-III at non-ambient pressure-temperature conditions confirm the reported structure, and the small changes associated with the variation in P and T explain the broad stability of this structure with respect to variations in P and T. PVT equation of state parameters was determined from experimental data points in the range of 2.20-6.50 GPa at 298-405 K providing = 87.5(5.1) GPa, ( δK T/ δT) P = -0.21(0.23) GPa K-1, α 0 = 0.8(21.4) × 10-5 K-1, and α 1 = 1.0(3.7) × 10-7 K-1 using a second-order Birch-Murnaghan equation of state formalism.

Joint Operations 2030 - Phase III Report: The JO 2030 Capability Set (Operations interarmees 2030 - Rapport Phase III: L’ensemble capacitaire JO 2030)

DTIC Science & Technology

2011-04-01

a ‘strategy as process’ manner to develop capabilities that are flexible, adaptable and robust. 3.4 Future structures The need for agile...to develop models of the future security environment 3.4.10 Planning Under Deep Uncertainty Future structures The need for agile, flexible and... Organisation NEC Network Enabled Capability NGO Non Government Organisation NII Networking and Information Infrastructure PVO Private Voluntary

Phase fluctuation spectra: New radio science information to become available in the DSN tracking system Mark III-77

NASA Technical Reports Server (NTRS)

Berman, A. L.

1977-01-01

An algorithm was developed for the continuous and automatic computation of Doppler noise concurrently at four sample rate intervals, evenly spanning three orders of magnitude. Average temporal Doppler phase fluctuation spectra will be routinely available in the DSN tracking system Mark III-77 and require little additional processing. The basic (noise) data will be extracted from the archival tracking data file (ATDF) of the tracking data management system.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Lei; Xiao, Yongsheng; Wang, Yinsheng, E-mail: yinsheng.wang@ucr.edu

Human exposure to arsenic in drinking water is a widespread public health concern, and such exposure is known to be associated with many human diseases. The detailed molecular mechanisms about how arsenic species contribute to the adverse human health effects, however, remain incompletely understood. Monomethylarsonous acid [MMA(III)] is a highly toxic and stable metabolite of inorganic arsenic. To exploit the mechanisms through which MMA(III) exerts its cytotoxic effect, we adopted a quantitative proteomic approach, by coupling stable isotope labeling by amino acids in cell culture (SILAC) with LC-MS/MS analysis, to examine the variation in the entire proteome of GM00637 humanmore » skin fibroblasts following acute MMA(III) exposure. Among the ∼ 6500 unique proteins quantified, ∼ 300 displayed significant changes in expression after exposure with 2 μM MMA(III) for 24 h. Subsequent analysis revealed the perturbation of de novo cholesterol biosynthesis, selenoprotein synthesis and Nrf2 pathways evoked by MMA(III) exposure. Particularly, MMA(III) treatment resulted in considerable down-regulation of several enzymes involved in cholesterol biosynthesis. In addition, real-time PCR analysis showed reduced mRNA levels of select genes in this pathway. Furthermore, MMA(III) exposure contributed to a distinct decline in cellular cholesterol content and significant growth inhibition of multiple cell lines, both of which could be restored by supplementation of cholesterol to the culture media. Collectively, the present study demonstrated that the cytotoxicity of MMA(III) may arise, at least in part, from the down-regulation of cholesterol biosynthesis enzymes and the resultant decrease of cellular cholesterol content. - Highlights: • MMA(III)-induced perturbation of the entire proteome of GM00637 cells is studied. • Quantitative proteomic approach revealed alterations of multiple cellular pathways. • MMA(III) inhibits de novo cholesterol biosynthesis. • MMA(III) perturbs Nrf2 pathway and selenoprotein synthesis.« less

Phase III Archives | NOAA Gulf Spill Restoration

Science.gov Websites

III Early Restoration Plan and Draft Early Restoration PEIS Executive Summary (pdf, 3.4 MB) Project Summary Table (pdf, 80 KB) Public Repositories (pdf, 113 KB) Press Release (pdf, 501 KB) Press Release

Solid phase extraction of gold(III) on attapulgite modified with triocarbohydrazide prior to its determination in environmental samples by ICP-OES.

PubMed

Zhang, Li; Li, Zhenhua; Hu, Zheng; Chang, Xijun

2011-09-01

The first study on the high efficiency of triocarbohydrazide modified attapulgite as solid-phase extractant for preconcentration of trace Au(III) prior to the measurement by inductively coupled plasma optical emission spectrometry (ICP-OES) has been reported. Experimental conditions for effective adsorption of trace levels of Au(III) were optimized with respect to different experimental parameters using batch and column procedures in detail. At pH 3, Au(III) could be quantitatively adsorbed on the new sorbent, and the adsorbed Au(III) could be completely eluted from the sorbent surface by 2.0mL 1.0molL(-1) of HCl+2% CS(NH(2))(2) solution. An enrichment factor of 150 was accomplished. Moreover, common interfering ions did not interfere in both separation and determination. The maximum adsorption capacity of the sorbent for Au(III) was found to be 66.7mgg(-1). The detection limit (3σ) of this method was 0.32μgL(-1) and the relative standard deviation (RSD) was 3.3% (n=8). The method, with high selectivity, sensitivity and reproducibility, was validated using certified reference materials, and had been applied for the determination of trace Au(III) with satisfactory results. Copyright © 2011 Elsevier B.V. All rights reserved.

Chromium(iii) oxidation by biogenic manganese oxides with varying structural ripening.

PubMed

Tang, Yuanzhi; Webb, Samuel M; Estes, Emily R; Hansel, Colleen M

2014-09-20

Manganese (Mn) oxides, which are generally considered biogenic in origin within natural systems, are the only oxidants of Cr(iii) under typical environmental conditions. Yet the influence of Mn biooxide mineral structural evolution on Cr(iii) oxidation under varying geochemical conditions is unknown. In this study we examined the role of light, organic carbon, pH, and the structure of biogenic Mn oxides on Cr(iii) oxidation. Aging of Mn oxides produced by a marine bacterium within the widespread Roseobacter clade resulted in structural ripening from a colloidal hexagonal to a particulate triclinic birnessite phase. The structurally diverse Mn oxides were then reacted with aqueous Cr(iii) within artificial seawater in the presence or absence of carbon and light. Here we found that Cr(iii) oxidation capacity was highest at near neutral pH and in the combined presence of carbon and light. Mn oxide ripening from a hexagonal to a triclinic birnessite phase led to decreased Cr(iii) oxidation in the presence of carbon and light, whereas no change in reactivity was observed in the absence of carbon and/or in the dark. As only minimal Cr(iii) oxidation was observed in the absence of Mn oxides, these results strongly point to coupled Mn oxide- and photo-induced generation of organic and/or oxygen radicals involved in Cr(iii) oxidation. Based on Mn oxide concentration and structural trends, we postulate that Mn(ii) produced from the oxidation of Cr(iii) by the primary Mn oxide is recycled in the presence of organics and light conditions, (re)generating secondary hexagonal birnessite and thereby allowing for continuous oxidation of Cr(iii). In the absence of this Mn oxide regeneration, Cr(iii) induced structural ripening of the hexagonal birnessite precludes further Cr(iii) oxidation. These results highlight the complexity of reactions involved in Mn oxide mediated Cr(iii) oxidation and suggest that photochemical carbon reactions are requisite for sustained Cr(iii) oxidation and persistence of reactive Mn oxides.

Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

ClinicalTrials.gov

2016-06-27

Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Waldenström Macroglobulinemia

Complexation Enhancement Drives Water-to-Oil Ion Transport: A Simulation Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qiao, Baofu; Ferru, Geoffroy; Ellis, Ross J.

We address the structures and energetics of ion solvation in aqueous and organic solutions to understand liquid-liquid ion transport. Atomistic molecular dynamics (MD) simulations with polarizable force field are performed to study the coordination transformations driving lanthanide (Ln(III)) and nitrate ion transport between aqueous and an alkylamide-oil solution. An enhancement of the coordination behavior in the organic phase is achieved in contrast with the aqueous solution. In particular, the coordination number of Ce3+ increases from 8.9 in the aqueous to 9.9 in the organic solutions (from 8 in the aqueous to 8.8 in the organic systems for Yb3+). Moreover, themore » local coordination environ ment changes dramatically. Potential of mean force calculations show that the Ln(III)-ligand coordination interaction strengths follow the order of Ln(III-)nitrate> Ln(III)-water>Ln(III)-DMDBTDMA. They increase 2-fold in the lipophilic environment in comparison to the aqueous phase, and we attribute this to the shedding of the outer solvation shell. Our findings highlight the importance of outer sphere interactions on the competitive solvation energetics that cause ions to migrate between immiscible phases; an essential ingredient for advancing important applications such as rare earth metal separations. Some open questions in simulating the coordination behavior of heavy metals are also addressed.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hawkins, Cory A.; Bustillos, Christian G.; May, Iain

Conventional solvent extraction of selected f-element cations by bis(2-ethylhexyl)phosphoric acid (HDEHP) yields increased extraction from aqueous to organic solution along the series Np(V) < Cm(III) < Eu(III) < U(VI), with distribution ratios all within two orders of magnitude. However, in the presence of the water-soluble tetradentate Schiff base (N,N'-bis(5-sulfonatosalicylidene)-ethylenediamine or H 2salenSO 3), selective complexation of the two actinyl cations (Np(V) and U(VI)) resulted in an extraction order of Np(V) < U(VI) << Eu(III) < Cm(III). The extraction of neither Cm(III) or Eu(III) by HDEHP are significantly impacted by the presence of the aqueous phase Schiff base. Despite observed hydrolyticmore » decomposition of H 2salenSO 3 in aqueous solutions, the calculated high conditional stability constant (β 11 = 26) for the complex [UO 2(salenSO 3)] 2- demonstrates its capacity for aqueous hold-back of U(VI). UV-visible-NIR spectroscopy of solutions prepared with a Np(VI) stock and H 2salenSO 3 suggest that reduction of Np(VI) to Np(V) by the ligand was rapid, resulting in a pentavalent Np complex that was substantially retained in the aqueous phase. Lastly, results from 1H NMR of aqueous solutions of H 2salenSO 3 with U(VI) and La(III), Eu(III), and Lu(III) provides additional evidence that the ligand readily chelates U(VI), but has only weak interactions with trivalent lanthanide ions.« less

Transferrable monolithic III-nitride photonic circuit for multifunctional optoelectronics

NASA Astrophysics Data System (ADS)

Shi, Zheng; Gao, Xumin; Yuan, Jialei; Zhang, Shuai; Jiang, Yan; Zhang, Fenghua; Jiang, Yuan; Zhu, Hongbo; Wang, Yongjin

2017-12-01

A monolithic III-nitride photonic circuit with integrated functionalities was implemented by integrating multiple components with different functions into a single chip. In particular, the III-nitride-on-silicon platform is used as it integrates a transmitter, a waveguide, and a receiver into a suspended III-nitride membrane via a wafer-level procedure. Here, a 0.8-mm-diameter suspended device architecture is directly transferred from silicon to a foreign substrate by mechanically breaking the support beams. The transferred InGaN/GaN multiple-quantum-well diode (MQW-diode) exhibits a turn-on voltage of 2.8 V with a dominant electroluminescence peak at 453 nm. The transmitter and receiver share an identical InGaN/GaN MQW structure, and the integrated photonic circuit inherently works for on-chip power monitoring and in-plane visible light communication. The wire-bonded monolithic photonic circuit on glass experimentally demonstrates in-plane data transmission at 120 Mb/s, paving the way for diverse applications in intelligent displays, in-plane light communication, flexible optical sensors, and wearable III-nitride optoelectronics.

Constraining the Statistics of Population III Binaries

NASA Technical Reports Server (NTRS)

Stacy, Athena; Bromm, Volker

2012-01-01

We perform a cosmological simulation in order to model the growth and evolution of Population III (Pop III) stellar systems in a range of host minihalo environments. A Pop III multiple system forms in each of the ten minihaloes, and the overall mass function is top-heavy compared to the currently observed initial mass function in the Milky Way. Using a sink particle to represent each growing protostar, we examine the binary characteristics of the multiple systems, resolving orbits on scales as small as 20 AU. We find a binary fraction of approx. 36, with semi-major axes as large as 3000 AU. The distribution of orbital periods is slightly peaked at approx. < 900 yr, while the distribution of mass ratios is relatively flat. Of all sink particles formed within the ten minihaloes, approx. 50 are lost to mergers with larger sinks, and 50 of the remaining sinks are ejected from their star-forming disks. The large binary fraction may have important implications for Pop III evolution and nucleosynthesis, as well as the final fate of the first stars.

Multiplicity in Early Stellar Evolution

NASA Astrophysics Data System (ADS)

Reipurth, B.; Clarke, C. J.; Boss, A. P.; Goodwin, S. P.; Rodríguez, L. F.; Stassun, K. G.; Tokovinin, A.; Zinnecker, H.

Observations from optical to centimeter wavelengths have demonstrated that multiple systems of two or more bodies is the norm at all stellar evolutionary stages. Multiple systems are widely agreed to result from the collapse and fragmentation of cloud cores, despite the inhibiting influence of magnetic fields. Surveys of class 0 protostars with millimeter interferometers have revealed a very high multiplicity frequency of about 2/3, even though there are observational difficulties in resolving close protobinaries, thus supporting the possibility that all stars could be born in multiple systems. Near-infrared adaptive optics observations of class I protostars show a lower binary frequency relative to the class 0 phase, a declining trend that continues through the class II/III stages to the field population. This loss of companions is a natural consequence of dynamical interplay in small multiple systems, leading to ejection of members. We discuss observational consequences of this dynamical evolution, and its influence on circumstellar disks, and we review the evolution of circumbinary disks and their role in defining binary mass ratios. Special attention is paid to eclipsing PMS binaries, which allow for observational tests of evolutionary models of early stellar evolution. Many stars are born in clusters and small groups, and we discuss how interactions in dense stellar environments can significantly alter the distribution of binary separations through dissolution of wider binaries. The binaries and multiples we find in the field are the survivors of these internal and external destructive processes, and we provide a detailed overview of the multiplicity statistics of the field, which form a boundary condition for all models of binary evolution. Finally, we discuss various formation mechanisms for massive binaries, and the properties of massive trapezia.

Cytotoxicity and apoptotic inducibility of Vitex agnus-castus fruit extract in cultured human normal and cancer cells and effect on growth.

PubMed

Ohyama, Kunio; Akaike, Takenori; Hirobe, Chieko; Yamakawa, Toshio

2003-01-01

A crude extract was prepared with ethanol from dried ripened Vitex agnus-castus fruits growing in Israel (Vitex extract). Cytotoxicity of the extract against human uterine cervical canal fibroblast (HCF), human embryo fibroblast (HE-21), ovarian cancer (MCF-7), cervical carcinoma (SKG-3a), breast carcinoma (SKOV-3), gastric signet ring carcinoma (KATO-III), colon carcinoma (COLO 201), and small cell lung carcinoma (Lu-134-A-H) cells was examined. After culture for 24 h (logarithmic growth phase) or 72 h (stationary growth phase), the cells were treated with various concentrations of Vitex extract. In both growth phases, higher growth activity of cells and more cytotoxic activity of Vitex extract were seen. The cytotoxic activity against stationary growth-phase cells was less than that against logarithmic growth-phase cells. DNA fragmentation of Vitex extract-treated cells was seen in SKOV-3, KATO-III, COLO 201, and Lu-134-A-H cells. The DNA fragmentation in Vitex extract-treated KATO-III cells was inhibited by the presence of the antioxidative reagent pyrrolidine dithiocarbamate or N-acetyl-L-cysteine (NAC). Western blotting analysis showed that in Vitex extract-treated KATO-III cells, the presence of NAC also inhibited the expression of heme oxygenase-1 and the active forms of caspases-3, -8 and -9. It is concluded that the cytotoxic activity of Vitex extract may be attributed to the effect on cell growth, that cell death occurs through apoptosis, and that this apoptotic cell death may be attributed to increased intracellular oxidation by Vitex extract treatment.

The impact of RTOG 0614 and RTOG 0933 trials in routine clinical practice: The US Survey of Utilization of Memantine and IMRT planning for hippocampus sparing in patients receiving whole brain radiotherapy for brain metastases.

PubMed

Slade, Alexander N; Stanic, Sinisa

2016-03-01

Two recent clinical trials, phase III RTOG 0614 and phase II RTOG 0933, showed some effectiveness of Memantine and IMRT planning for hippocampus sparing, among patients receiving whole brain radiotherapy (WBRT) for brain metastases; however, their use in routine clinical practice is unknown. A survey was sent to 1933 radiation oncologists in the US. Data collected included utilization of Memantine and hippocampus sparing, reasons for adoption and non-adoption, and demographic variables. A total of 196 radiation oncologists responded to the survey, with 64% reporting using Memantine in almost none of the patients receiving WBRT for brain metastases, and only 11% considering Memantine for <10% of their patients. The most common reason for not using Memantine was a poor patient performance status, and limited life expectancy. Likewise, 56% of radiation oncologists would not change their clinical practice to include hippocampus sparing IMRT in patients receiving WBRT based on the results of RTOG 0933. Further validation of hippocampus sparing in a phase III trial was supported by 71% of radiation oncologists, whereas further exploration of Memantine for this purpose in a phase III trial was supported by 42%. At this time, the majority of surveyed radiation oncologists in the US do not use Memantine, or IMRT planning for hippocampus sparing in patients receiving WBRT. Further validation of the hippocampus sparing concept in a phase III trial was supported, before adopting it in routine clinical practice. Copyright © 2015 Elsevier Inc. All rights reserved.

Persistence of Mixed and Non-intermediate Valence in the High-Pressure Structure of Silver(I,III) Oxide, AgO: A Combined Raman, X-ray Diffraction (XRD), and Density Functional Theory (DFT) Study.

PubMed

Grzelak, Adam; Gawraczyński, Jakub; Jaroń, Tomasz; Somayazulu, Maddury; Derzsi, Mariana; Struzhkin, Viktor; Grochala, Wojciech

2017-05-15

The X-ray diffraction data collected up to ca. 56 GPa and the Raman spectra measured up to 74.8 GPa for AgO, or Ag I Ag III O 2 , which is a prototypical mixed valence (disproportionated) oxide, indicate that two consecutive phase transitions occur: the first-order phase transition occurs between 16.1 GPa and 19.7 GPa, and a second-order phase transition occurs at ca. 40 GPa. All polymorphic forms host the square planar [Ag III O 4 ] units typical of low-spin Ag III . The disproportionated Imma form persists at least up to 74.8 GPa, as indicated by Raman spectra. Theoretical hybrid density functional theory (DFT) calculations show that the first-order transition is phonon-driven. AgO stubbornly remains disproportionated up to at least 100 GPa-in striking contrast to its copper analogue-and the fundamental band gap of AgO is ∼0.3 eV at this pressure and is weakly pressure-dependent. Metallization of AgO is yet to be achieved.

Evidence to Support Peer Tutoring Programs at the Undergraduate Level

ERIC Educational Resources Information Center

Colver, Mitchell; Fry, Trevor

2016-01-01

The present study examined undergraduate peer tutoring in three phases. Phase I qualitatively surveyed students' perceptions about the effectiveness of tutoring. Phase II examined the usefulness of promoting regular use of services through a tutoring contract. Phase III utilized an archival, quasi-experimental approach to estimate the effect of…

40 CFR 72.92 - Phase I unit allowance surrender.

Code of Federal Regulations, 2010 CFR

2010-07-01

... chapter) for all Phase I units in the dispatch system. (iii) Calculating percentage change in dispatch... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Phase I unit allowance surrender. 72... (CONTINUED) PERMITS REGULATION Compliance Certification § 72.92 Phase I unit allowance surrender. (a) Annual...

40 CFR 72.92 - Phase I unit allowance surrender.

Code of Federal Regulations, 2011 CFR

2011-07-01

... chapter) for all Phase I units in the dispatch system. (iii) Calculating percentage change in dispatch... 40 Protection of Environment 16 2011-07-01 2011-07-01 false Phase I unit allowance surrender. 72... (CONTINUED) PERMITS REGULATION Compliance Certification § 72.92 Phase I unit allowance surrender. (a) Annual...

Seeking the Profile of an Elementary Educator: Phase III.

ERIC Educational Resources Information Center

Arth, Alfred A.; And Others

This paper presents the third phase of a student-faculty investigation seeking the profile of the elementary school teacher. Phase I discovered an indication of different personality traits in elementary and secondary teachers. Phase II redesigned the original questionnaire and supported the findings with additional research. This third phase…

Working With Parents to Prevent Childhood Obesity: Protocol for a Primary Care-Based eHealth Study.

PubMed

Avis, Jillian Ls; Cave, Andrew L; Donaldson, Stephanie; Ellendt, Carol; Holt, Nicholas L; Jelinski, Susan; Martz, Patricia; Maximova, Katerina; Padwal, Raj; Wild, T Cameron; Ball, Geoff Dc

2015-03-25

Parents play a central role in preventing childhood obesity. There is a need for innovative, scalable, and evidence-based interventions designed to enhance parents' motivation to support and sustain healthy lifestyle behaviors in their children, which can facilitate obesity prevention. (1) Develop an online screening, brief intervention, and referral to treatment (SBIRT) eHealth tool to enhance parents' concern for, and motivation to, support children's healthy lifestyle behaviors, (2) refine the SBIRT eHealth tool by assessing end-user acceptability, satisfaction, and usability through focus groups, and (3) determine feasibility and preliminary effectiveness of the refined SBIRT eHealth tool through a randomized controlled trial. This is a three-phase, multi-method study that includes SBIRT eHealth tool development (Phase I), refinement (Phase II), and testing (Phase III). Phase I: Theoretical underpinnings of the SBIRT tool, entitled the Resource Information Program for Parents on Lifestyle and Education (RIPPLE), will be informed by concepts applied within existing interventions, and content will be based on literature regarding healthy lifestyle behaviors in children. The SBIRT platform will be developed in partnership between our research team and a third-party intervention development company. Phase II: Focus groups with parents, as well as health care professionals, researchers, and trainees in pediatrics (n=30), will explore intervention-related perceptions and preferences. Qualitative data from the focus groups will inform refinements to the aesthetics, content, structure, and function of the SBIRT. Phase III: Parents (n=200) of children-boys and girls, 5 to 17 years old-will be recruited from a primary care pediatric clinic while they await their children's clinical appointment. Parents will be randomly assigned to one of five groups-four intervention groups and one control group-as they complete the SBIRT. The randomization function is built into the tool. Parents will complete the eHealth SBIRT using a tablet that will be connected to the Internet. Subsequently, parents will be contacted via email at 1-month follow-up to assess (1) change in concern for, and motivation to, support children's dietary and physical activity behaviors (primary outcome), and (2) use of online resources and referrals to health services for obesity prevention (secondary outcome). This research was successfully funded and received ethics approval. Development of the SBIRT started in summer 2012, and we expect all study-related activities to be completed by fall 2016. The proposed research is timely and applies a novel, technology-based application designed to enhance parents concern for, and motivation to, support children's healthy lifestyle behaviors and encourage use of online resources and community services for childhood obesity prevention. Overall, this research builds on a foundation of evidence supporting the application of SBIRTs to encourage or "nudge" individuals to make healthy lifestyle choices. Findings from Phase III of this project will directly inform a cluster randomized controlled trial to study the effectiveness of our intervention across multiple primary care-based settings. ClinicalTrials.gov NCT02330588; http://clinicaltrials.gov/ct2/show/NCT02330588 (Archived by WebCite at http://www.webcitation.org/6WyUOeRlr).

Interim analysis of postoperative chemoradiotherapy with capecitabine and oxaliplatin versus capecitabine alone for pathological stage II and III rectal cancer: a randomized multicenter phase III trial.

PubMed

Feng, Yan-Ru; Zhu, Yuan; Liu, Lu-Ying; Wang, Wei-Hu; Wang, Shu-Lian; Song, Yong-Wen; Wang, Xin; Tang, Yuan; Liu, Yue-Ping; Ren, Hua; Fang, Hui; Zhang, Shi-Ping; Liu, Xin-Fan; Yu, Zi-Hao; Li, Ye-Xiong; Jin, Jing

2016-05-03

The aim of this study is to present an interim analysis of a phase III trial (NCT00714077) of postoperative concurrent capecitabine and radiotherapy with or without oxaliplatin for pathological stage II and III rectal cancer. Patients with pathologically confirmed stage II and III rectal cancer were randomized to either radiotherapy with concurrent capecitabine (Cap-RT group) or with capecitabine and oxaliplatin (Capox-RT group). The primary endpoint was 3-year disease-free survival rate (DFS). The 3-year DFS rate was 73.9% in the Capox-RT group and 71.6% in the Cap-RT group (HR 0.92, p = 0.647), respectively. No significant difference was observed in overall survival, cumulative incidence of local recurrence and distant metastasis between the two groups (p > 0.05). More grade 3-4 acute toxicity was observed in the Capox-RT group than in the Cap-RT group (38.1% vs. 29.2%, p = 0.041). Inclusion of oxaliplatin in the capecitabine-based postoperative regimen did not improve DFS but increased toxicities for pathological stage II and III rectal cancer in this interim analysis.

Monolithic integration of InGaAs/InP multiple quantum wells on SOI substrates for photonic devices

NASA Astrophysics Data System (ADS)

Li, Zhibo; Wang, Mengqi; Fang, Xin; Li, Yajie; Zhou, Xuliang; Yu, Hongyan; Wang, Pengfei; Wang, Wei; Pan, Jiaoqing

2018-02-01

A direct epitaxy of III-V nanowires with InGaAs/InP multiple quantum wells on v-shaped trenches patterned silicon on insulator (SOI) substrates was realized by combining the standard semiconductor fabrication process with the aspect ratio trapping growth technique. Silicon thickness as well as the width and gap of each nanowire were carefully designed to accommodate essential optical properties and appropriate growth conditions. The III-V element ingredient, crystalline quality, and surface topography of the grown nanowires were characterized by X-ray diffraction spectroscopy, photoluminescence, and scanning electron microscope. Geometrical details and chemical information of multiple quantum wells were revealed by transmission electron microscopy and energy dispersive spectroscopy. Numerical simulations confirmed that the optical guided mode supported by one single nanowire was able to propagate 50 μm with ˜30% optical loss. This proposed integration scheme opens up an alternative pathway for future photonic integrations of III-V devices on the SOI platform at nanoscale.

1-(2-Formamidoethyl)-3-phenylurea functionalized activated carbon for selective solid-phase extraction and preconcentration of metal ions.

PubMed

Tu, Zhifeng; He, Qun; Chang, Xijun; Hu, Zheng; Gao, Ru; Zhang, Lina; Li, Zhenhua

2009-09-07

A novel method that utilizes 1-(2-formamidoethyl)-3-phenylurea-modified activated carbon (AC-1-(2-formamidoethyl)-3-phenylurea) as a solid-phase extractant has been developed for simultaneous preconcentration of trace Cr(III), Cu(II), Fe(III) and Pb(II) prior to the measurement by inductively coupled plasma atomic emission spectrometry (ICP-AES). Experimental conditions for effective adsorption of trace levels of Cr(III), Cu(II), Fe(III) and Pb(II) were optimized using batch and column procedures in detail. The optimum pH value for the separation of metal ions simultaneously on the new sorbent was 4. And the adsorbed metal ions could be completely eluted by using 2.0 mL 2.0 mol L(-1) HCl solution. Common coexisting ions did not interfere with the separation and determination of target metal ions. The maximum static adsorption capacity of the sorbent at optimum conditions was found to be 39.8, 39.9, 77.8 and 17.3 mg g(-1) for Cr(III), Cu(II), Fe(III) and Pb(II), respectively. The detection limits of the method were found to be 0.15, 0.41, 0.27 and 0.36 ng mL(-1) for Cr(III), Cu(II), Fe(III) and Pb(II), respectively. The relative standard deviation (RSD) of the method was lower than 4.0% (n=8). The method was successfully applied for the preconcentration of trace Cr(III), Cu(II), Fe(III) and Pb(II) in natural and certified samples with satisfactory results.

Iron dynamics: Transformation of Fe(II)/Fe(III) during injection of natural organic matter in a sandy aquifer

NASA Astrophysics Data System (ADS)

Liang, Liyuan; McCarthy, John F.; Jolley, Louwanda W.; McNabb, J. Andrew; Mehlhorn, Tonia L.

1993-05-01

The dynamics of dissolved, colloidal, and deposited iron phases were examined during a forced-gradient field experiment. The experiment involved the injection of oxygenated water containing high levels of natural organic matter (NOM) into a sandy aquifer. The initial redox potential of the aquifer favored Fe(II) in the groundwater. The changes in the concentrations of Fe(II) and Fe(III) were observed in sampling wells. Under the increased dissolved oxygen (DO) conditions, Fe(II) oxygenation was rapid, resulting in the formation of Fe(III) (hydr) oxide colloids. The oxidation follows the rate law as given in STUMM and MORGAN (1981): d[ Fe(II)] /dt = - k obs[ O2( aq)] /[ H+] 2[ Fe(II)] , with a rate constant, kobs to be 1.9 × 10 -12 M min -1. For an averaged pH and DO of the groundwater, the half time of Fe(II) oxidation is 49 h. The NOM was postulated to stabilize the newly formed colloids, thereby increasing the turbidity in the groundwater. The additional increase in the colloidal fraction of Fe(III) oxide suggested that transport of the colloidal particles was occurring. At those locations where DO remained constantly low, the turbidity increase was moderate, and up to 80% of Fe(III) was in the dissolved phase (< 3000 mol. wt). The latter observation was attributed to the presence of NOM, forming Fe(III)-organic complexes. In addition, NOM may play a role in the oxygen consumption through a Fe(II)/Fe(III) catalyzed oxidation of organic matter as outlined by STUMM and MORGAN (1981, p. 469). In this mechanism, Fe(II) oxidation is slow, maintaining a near constant Fe(II) concentration, in agreement with field data. The overall increase in Fe(III) under low DO conditions was postulated to be a combination of (1) slow oxidation, (2) ligand-promoted and catalytic dissolution of deposited iron phases, and (3) the transport of newly formed iron oxide colloids along flow paths.

Methodology of health-related quality of life analysis in phase III advanced non-small-cell lung cancer clinical trials: a critical review.

PubMed

Fiteni, Frédéric; Anota, Amélie; Westeel, Virginie; Bonnetain, Franck

2016-02-18

Health-related quality of life (HRQoL) is recognized as a component endpoint for cancer therapy approvals. The aim of this review was to evaluate the methodology of HRQoL analysis and reporting in phase III clinical trials of first-line chemotherapy in advanced non-small cell lung cancers (NSCLC). A search in MEDLINE databases identified phase III clinical trials in first-line chemotherapy for advanced NSCLC, published between January 2008 to December 2014. Two authors independently extracted information using predefined data abstraction forms. A total of 55 phase III advanced NSCLC trials were identified. HRQoL was declared as an endpoint in 27 studies (49%). Among these 27 studies, The EORTC questionnaire Quality of Life Questionnaire C30 was used in 13 (48%) of the studies and The Functional Assessment of Cancer Therapy-General was used in 12 (44%) trials. The targeted dimensions of HRQoL, the minimal clinically important difference and the statistical approaches for dealing with missing data were clearly specified in 13 (48.1%), 9 (33.3%) and 5 (18.5%) studies, respectively. The most frequent statistical methods for HRQoL analysis were: the mean change from baseline (33.3%), the linear mixed model for repeated measures (22.2%) and time to HRQoL score deterioration (18.5%). For each targeted dimension, the results for each group, the estimated effect size and its precision were clearly reported in 4 studies (14.8%), not clearly reported in 11 studies (40.7%) and not reported at all in 12 studies (44.4%). This review demonstrated the weakness and the heterogeneity of the measurement, analysis, and reporting of HRQoL in phase III advanced NSCLC trials. Precise and uniform recommendations are needed to compare HRQoL results across publications and to provide understandable messages for patients and clinicians.

A Pilot Study to Evaluate the Co-Infusion of Ex Vivo Expanded Cord Blood Cells With an Unmanipulated Cord Blood Unit in Patients Undergoing Cord Blood Transplant for Hematologic Malignancies

ClinicalTrials.gov

2015-02-10

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

Chemomodulatory effect of Moringa oleifera, Lam, on hepatic carcinogen metabolising enzymes, antioxidant parameters and skin papillomagenesis in mice.

PubMed

Bharali, Rupjyoti; Tabassum, Jawahira; Azad, Mohammed Rekibul Haque

2003-01-01

The modulatory effects of a hydro-alcoholic extract of drumsticks of Moringa oliefera Lam at doses of 125 mg/kg bodyweight and 250 mg/ kg body weight for 7 and 14 days, respectively, were investigated with reference to drug metabolising Phase I (Cytochrome b(5) and Cytochrome p(450) ) and Phase II (Glutathione-S- transferase) enzymes, anti-oxidant enzymes, glutathione content and lipid peroxidation in the liver of 6-8 week old female Swiss albino mice. Further, the chemopreventive efficacy of the extract was evaluated in a two stage model of 7,12 - dimethylbenz(a)anthracene induced skin papillomagenesis. Significant increase (p<0.05 to p<0.01) in the activities of hepatic cytochrome b(5), cytochrome p(450), catalase, glutathione peroxidase ( GPx ), glutathione reductase (GR), acid soluble sulfhydryl content (-SH ) and a significant decrease ( p<0.01 ) in the hepatic MDA level were observed at both dose levels of treatment when compared with the control values. Glutathione-S- transferase ( GST )activity was found to be significantly increased (p<0.01 ) only at the higher dose level. Butylated hydroxyanisol (BHA ) fed at a dose of 0.75% in the diet for 7 and 14 days (positive control ) caused a significant increase (p<0.05 to p<0.01) in the levels of hepatic phase I and phase II enzymes, anti- oxidant enzymes, glutathione content and a decrease in lipid peroxidation. The skin papillomagenesis studies demonstrated a significant decrease (p<0.05 ) in the percentage of mice with papillomas, average number of papillomas per mouse and papillomas per papilloma bearing mouse when the animals received a topical application of the extract at a dose of 5mg/ kg body weight in the peri-initiation phase 7 days before and 7 days after DMBA application, Group II ), promotional phase (from the day of croton oil application and continued till the end of the experiment, Group III ) and both peri and post initiation stages (from 7 days prior to DMBA application and continued till the end of the experiment, Group IV) compared to the control group (Group I ). The percentage inhibition of tumor multiplicity has been recorded to be 27, 72, and 81 in Groups II, III, and IV, respectively. These findings are suggestive of a possible chemopreventive potential of Moringa oliefera drumstick extract against chemical carcinogenesis.

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

PubMed

Oki, E; Murata, A; Yoshida, K; Maeda, K; Ikejiri, K; Munemoto, Y; Sasaki, K; Matsuda, C; Kotake, M; Suenaga, T; Matsuda, H; Emi, Y; Kakeji, Y; Baba, H; Hamada, C; Saji, S; Maehara, Y

2016-07-01

Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Safinamide for the treatment of Parkinson's disease.

PubMed

Kandadai, Rukmini Mridula; Jabeen, Shaik Afshan; Kanikannan, Meena A; Borgohain, Rupam

2014-11-01

Parkinson's disease (PD) is a neurodegenerative disease caused by a complex interaction of loss of dopaminergic and non-dopaminergic neurotransmitter systems. Drugs acting on the dopaminergic pathways are the mainstay of treatment for motor symptoms today. Safinamide (NW-1015) is a novel drug with multiple actions. It is a monoamine oxidase B inhibitor and improves dopaminergic transmission. In addition, it has antiglutamatergic effects and can thus reduce dyskinesias, which is a side effect limiting most dopaminergic therapy. In Phase III trials, safinamide has been found to be a useful adjunctive to dopamine agonists in early PD and has been shown to increase time without increasing troublesome dyskinesias when used as an adjunct to levodopa in patients with advanced PD. A possible neuroprotective role in inhibiting PD disease progression is envisaged and warrants future studies.

Will dapivirine redeem the promises of anti-HIV microbicides? Overview of product design and clinical testing.

PubMed

das Neves, José; Martins, João Pedro; Sarmento, Bruno

2016-08-01

Microbicides are being developed in order to prevent sexual transmission of HIV. Dapivirine, a non-nucleoside reverse transcriptase inhibitor, is one of the leading drug candidates in the field, currently being tested in various dosage forms, namely vaginal rings, gels, and films. In particular, a ring allowing sustained drug release for 1month is in an advanced stage of clinical testing. Two parallel phase III clinical trials are underway in sub-Saharan Africa and results are expected to be released in early 2016. This article overviews the development of dapivirine and its multiple products as potential microbicides, with particular emphasis being placed on clinical evaluation. Also, critical aspects regarding regulatory approval, manufacturing, distribution, and access are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of Protein Incorporation on the Nanostructure of the Bicontinuous Microemulsion Phase of Winsor-III Systems: A Small-Angle Neutron Scattering Study

DOE PAGES

Hayes, Douglas G.; Gomez del Rio, Javier A.; Ye, Ran; ...

2015-01-20

Small-angle neutron scattering (SANS) analysis using the Teubner₋Strey model has been employed to evaluate the effect of protein incorporation into the middle, bicontinuous microemulsion (BμE) phase of Winsor-III (W III) systems formed by an aerosol-OT (AOT)/alkyl ethoxylate mixed surfactant system to understand better the extraction of proteins into and out of BμEs and to study the effect of proteins on a system that serves as a biomimetic analog of cell membranes. Under conditions of high salinity, the incorporation of positively charged proteins cytochrome c, lysozyme, and α-chymotrypsin, near their solubilization limit in the BμEs promoted the release of water andmore » oil from the BμEs, a decrease in the quasi-periodic repeat distance (d), an increase in ordering (a decrease in the amphiphilicity factor, f a) for the surfactant monolayers, and a decrease in the surface area per surfactant headgroup, suggesting that the proteins affected the self-assembly of components in the BμE phase and produced Debye shielding of AOTs sulfonate headgroup. For W III systems possessing lower salinity, cytochrome c reduced the efficiency of surfactant in the BμE phase, noted by increases in d and f a, suggesting that the enzyme and AOT underwent ion pairing. We find that the results of this study demonstrate the importance of ionic strength to modulate proteinsurfactant interactions, which in turn will control the release of proteins encapsulated in the BμEs, relevant to W III-based protein extraction and controlled release from BμE delivery systems, and demonstrate the utility of BμEs as a model system to understand the effect of proteins on biomembranes.« less

Organic and Aqueous Redox Speciation of Cu(III) Periodate Oxidized Transuranium Actinides

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCann, Kevin; Sinkov, Sergey I.; Lumetta, Gregg J.

A hexavalent group actinide separation process could streamline used nuclear fuel recycle and waste management. The limiting factor to such a process compatible with current fuel dissolution practices is obtaining and maintaining hexavalent Am, in molar nitric acid due to the high reduction potential of the Am(VI)/Am(III) couple (1.68 V vs SCE). Two strong oxidants, sodium bismuthate and Cu(III) periodate, have demonstrated quantitative oxidation of Am under molar acid conditions and better than 50% recovery by diamyl amylphosphonate (DAAP) is possible under these same conditions. This work considers the use of Cu(III) periodate to oxidize Np(V) to Np(VI) and Pu(IV)more » to Pu(VI) and recover these elements by extraction with DAAP. A metal:oxidant ratio of 1:1.2 and 1:3 was necessary to quantitatively oxidize Np(V) and Pu(IV), respectively, to the hexavalent state. Extraction of hexavalent Np, Pu, and Am by 1 M DAAP in n-dodecane was measured using UV-Vis [Pu(VI), Am (VI)] and NIR [Np(VI)]. Distribution values of Am(VI) were found to match previous tracer level studies. The organic phase spectra of Np, Pu, and Am are presented and molar absorptivities are calculated for characteristic peaks. Hexavalent Pu was found to be stable in the organic phase while Np(VI) showed some reduction to Np(V) and Am was present as Am(III), Am(V), and Am(VI) species in aqueous and organic phases during the extraction experiments. These results demonstrate, for the first time, the ability to recover macroscopic amounts of americium that would be present during fuel reprocessing and are the first characterization of Am organic phase oxidation state speciation relevant to a hexavalent group actinide separation process under acidic conditions.« less

New treatments for the motor symptoms of Parkinson's disease.

PubMed

Vijverman, Anne-Catherine; Fox, Susan H

2014-11-01

Levodopa remains the most potent drug to treat motor symptoms in Parkinson's disease (PD); however, motor fluctuations and levodopa-induced dyskinesia that occur with long-term use restrict some of its therapeutic value. Despite these limitations, the medical treatment of PD strives for continuous relief of symptoms using different strategies throughout the course of the illness: increasing the half-life of levodopa, using 'levodopa-sparing agents' and adding non-dopaminergic drugs. New options to 'improve' delivery of levodopa are under investigation, including long-acting levodopa, nasal inhalation and continuous subcutaneous or intrajejunal administration of levodopa. Long-acting dopamine agonists were recently developed and are undergoing further comparative studies to investigate potential superiority over the immediate-release formulations. Non-dopaminergic drugs acting on adenosine receptors, cholinergic, adrenergic, serotoninergic and glutamatergic pathways are newly developed and many are being evaluated in Phase II and Phase III trials. This article focuses on promising novel therapeutic approaches for the management of PD motor symptoms and motor complications. We will provide an update since 2011 on new formulations of current drugs, new drugs with promising results in Phase II and Phase III clinical trials, old drugs with new possibilities and some new potential strategies that are currently in Phase I and II of development (study start date may precede 2011 but are included as study is still ongoing or full data have not yet been published). Negative Phase II and Phase III clinical trials published since 2011 will also be briefly mentioned.

Decision-theoretic designs for a series of trials with correlated treatment effects using the Sarmanov multivariate beta-binomial distribution.

PubMed

Hee, Siew Wan; Parsons, Nicholas; Stallard, Nigel

2018-03-01

The motivation for the work in this article is the setting in which a number of treatments are available for evaluation in phase II clinical trials and where it may be infeasible to try them concurrently because the intended population is small. This paper introduces an extension of previous work on decision-theoretic designs for a series of phase II trials. The program encompasses a series of sequential phase II trials with interim decision making and a single two-arm phase III trial. The design is based on a hybrid approach where the final analysis of the phase III data is based on a classical frequentist hypothesis test, whereas the trials are designed using a Bayesian decision-theoretic approach in which the unknown treatment effect is assumed to follow a known prior distribution. In addition, as treatments are intended for the same population it is not unrealistic to consider treatment effects to be correlated. Thus, the prior distribution will reflect this. Data from a randomized trial of severe arthritis of the hip are used to test the application of the design. We show that the design on average requires fewer patients in phase II than when the correlation is ignored. Correspondingly, the time required to recommend an efficacious treatment for phase III is quicker. © 2017 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Metal-Organic Framework-Polymer Composite as a Highly Efficient Sorbent for Sulfonamide Adsorption and Desorption: Effect of Coordinatively Unsaturated Metal Site and Topology.

PubMed

Shih, Yung-Han; Wang, Kuen-Yun; Singco, Brenda; Lin, Chia-Her; Huang, Hsi-Ya

2016-11-08

In this study, we first demonstrated the effect of two types of metal-organic framework-polymer (MOF-polymer) monoliths on in-tube solid-phase microextraction (IT-SPME) of sulfonamides. Sulfonamides were successfully adsorbed onto MIL-101(Cr)-polymer but were difficult to elute due to these sulfonamides could interact via Lewis acid-base interaction with the presence of Cr(III) coordinatively unsaturated metal sites (CUS). Moreover, the cage-type topology of MIL-101(Cr) that could produce multiple pathways thus complicates the desorption of the test analytes from the sorbent. Contrastingly, MIL-53(Al)-polymer provided weaker Al(III) CUS, and its one-dimensional channel pore structure could provide an unhindered pathway for sulfonamides transfer during elution. After optimizing the IT-SPME condition such as MOF content, pH of sample matrix, column length, extraction flow rate, and elution volume, the calculated extraction recovery of sulfonamides in MIL-53(Al)-polymer as analyzed by microemulsion electrokinetic chromatography (MEEKC) were in the range of 40%-90% with relative standard deviations (RSDs) below 5% and a reusability of at least 30 times.

Use of column V alkyls in organometallic vapor phase epitaxy (OMVPE)

NASA Technical Reports Server (NTRS)

Ludowise, M. J.; Cooper, C. B., III

1982-01-01

The use of the column V-trialkyls trimethylarsenic (TMAs) and trimethylantimony (TMSb) for the organometallic vapor phase epitaxy (OM-VPE) of III-V compound semiconductors is reviewed. A general discussion of the interaction chemistry of common Group III and Group V reactants is presented. The practical application of TMSb and TMAs for OM-VPE is demonstrated using the growth of GaSb, GaAs(1-y)Sb(y), Al(x)Ga(1-x)Sb, and Ga(1-x)In(x)As as examples.

A seamless phase IIB/III adaptive outcome trial: design rationale and implementation challenges.

PubMed

Chen, Y H Joshua; Gesser, Richard; Luxembourg, Alain

2015-02-01

The licensed four-valent prophylactic human papillomavirus vaccine is highly efficacious in preventing cervical, vulvar, vaginal, and anal cancers and related precancers caused by human papillomavirus types 6, 11, 16, and 18. These four types account for approximately 70% of cervical cancers. A nine-valent human papillomavirus vaccine, including the four original types (6, 11, 16, and 18) plus the next five most prevalent types in cervical cancer (31, 33, 45, 52, and 58) could provide approximately 90% overall cervical cancer coverage. To expedite the nine-valent human papillomavirus vaccine clinical development, an adaptive, seamless Phase IIB/III outcome trial with ∼ 15,000 subjects was conducted to facilitate dose formulation selection and provide pivotal evidence of safety and efficacy for regulatory registrations. We discuss the design rationale and implementation challenges of the outcome trial, focusing on the adaptive feature of the seamless Phase IIB/III design. Subjects were enrolled in two parts (Part A and Part B). Approximately 1240 women, 16-26 years of age, were enrolled in Part A for Phase IIB evaluation and equally randomized to one of three dose formulations of the nine-valent human papillomavirus vaccine or the four-valent human papillomavirus vaccine (active control). Based on an interim analysis of immunogenicity and safety, one dose formulation of the nine-valent human papillomavirus vaccine was selected for evaluation in the Phase III part of the study. Subjects enrolled in Part A who received the selected dose formulation of the nine-valent human papillomavirus vaccine or four-valent human papillomavirus vaccine continued to be followed up and contributed to the final efficacy and safety analyses. In addition, ∼ 13,400 women 16-26 years of age were enrolled in Part B, randomized to nine-valent human papillomavirus vaccine at the selected dose formulation or four-valent human papillomavirus vaccine, and followed for immunogenicity, efficacy, and safety. A seamless Phase IIB/III design was justified by the extensive pre-existing knowledge of the licensed four-valent human papillomavirus vaccine and the development objectives for the nine-valent human papillomavirus vaccine. Subjects enrolled in Part A who received either the selected nine-valent human papillomavirus formulation or four-valent human papillomavirus vaccine contributed ∼ 10% of person-years of follow-up due to its earlier start-thereby maximizing the overall efficiency of the trial. Some of the challenges encountered in the implementation of the adaptive design included practical considerations during Phase IIB formulation selection by internal and external committees, End-of-Phase II discussion with health authorities and managing changes in the assay for immunological endpoints. Application of the experience and lesson learned from this seamless adaptive design to other clinical programs may depend on case-by-case consideration. A seamless Phase IIB/III adaptive design was successfully implemented in this large outcome study. The development time of the second-generation nine-valent human papillomavirus vaccine was shortened due to improved statistical efficiency. © The Author(s) 2014.

Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice.

PubMed

Fazio, N; Scarpa, A; Falconi, M

2014-01-01

Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy: somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, research has moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically binding to the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several molecular targeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. The mTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA and EMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), on the basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has been studied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological and clinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigation are addressed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beeston, Michael Philip; University of Exeter in Cornwall; Tuen van Elteren, Johannes

A methodology is presented to study the physico-chemical processes in old tailings ponds using an array of analytical-physical chemistry approaches. A case study was conducted on the sorption/desorption behaviour of arsenic in tailings pond 2406, at the King Edward Mine (KEM) in Cornwall, UK. The tailings pond was in operation from approximately 1907 to 1921. The methodology involves two principal stages: (1) sequential extraction followed by subsequent arsenic species determination to characterise the material with regards to the association of arsenic with soil phases and identification of As (III/V) in the easily accessible soil phase; (2) batch contacting/equilibrating the tailingsmore » pond material with As(III/V), followed by a similar procedure as in stage 1 to establish the material's As(III/V) phase distribution kinetics/thermodynamics. By extrapolating the data from present day samples we infer past and future elemental mobility. From this study it is concluded that adsorption and desorption from tailings material is a rapid process for the most unstable soil phases (non-specific and specific) and a slow process for the more stable phases (poorly crystalline and well crystalline). The hypothetical application of this conclusion to the tailings from dam 2406 is that, during the initial phases of the dam's creation (ca. 100 years ago), when arsenic was both in solution and bound to mineralogical components, arsenic must have dispersed into the environment as a result of slow As(V) adsorption/phase distribution processes. Aging of the tailings material sees the movement of the arsenic to the more stable soil phases, producing a situation that is seen at present day.« less

Improving Participants' Retention in a Smoking Cessation Intervention Using a Community-based Participatory Research Approach.

PubMed

Estreet, Anthony; Apata, Jummai; Kamangar, Farin; Schutzman, Christine; Buccheri, Jane; O'Keefe, Anne-Marie; Wagner, Fernando; Sheikhattari, Payam

2017-01-01

This study compares participant' sretention in three phases of smoking cessation interventions, one provided in a health clinic and the subsequent two in community-based settings. Smoking cessation interventions were conducted in three phases from 2008 to 2015 in two underserved urban communities with low socioeconomic profiles and high rates of smoking ( n = 951). Phase I was conducted in a clinic; Phases II and III were conducted in community venues. In Phases II and III, incremental changes were made based on lessons learned from the previous phases. Retention (attending six or more sessions) was the primary predictor of cessation and was analyzed while controlling for associated factors including age, gender, race, employment, education, and nicotine dependence. Retention increased substantially over the three phases, with rates for attending six or more sessions of 13.8%, 51.9%, and 67.9% in Phases I, II, and III, respectively. Retention was significantly higher in community settings than in the clinic setting (adjusted odds ratio [OR] = 6.7; 95% confidence intervals [CI] = 4.6, 9.8). In addition to the intervention in community venues, predictors of retention included age and unemployment. Higher retention was significantly associated with higher quit rates (adjusted OR = 2.4; 95% CI = 1.5, 3.8). Conducting the intervention in community settings using trained peer motivators rather than health-care providers resulted in significantly higher retention and smoking cessation rates. This was due in part to the ability to tailor cessation classes in the community for specific populations and improving the quality of the intervention based on feedback from participants and community partners.

Determination of thallium at ultra-trace levels in water and biological samples using solid phase spectrophotometry

NASA Astrophysics Data System (ADS)

Amin, Alaa S.; El-Sharjawy, Abdel-Azeem M.; Kassem, Mohammed A.

2013-06-01

A new simple, very sensitive, selective and accurate procedure for the determination of trace amounts of thallium(III) by solid-phase spectrophotometry (SPS) has been developed. The procedure is based on fixation of Tl(III) as quinalizarin ion associate on a styrene-divinylbenzene anion-exchange resin. The absorbance of resin sorbed Tl(III) ion associate is measured directly at 636 and 830 nm. Thallium(I) was determined by difference measurements after oxidation of Tl(I) to Tl(III) with bromine. Calibration is linear over the range 0.5-12.0 μg L-1 of Tl(III) with relative standard deviation (RSD) of 1.40% (n = 10). The detection and quantification limits are 150 and 495 ng L-1 using 0.6 g of the exchanger. The molar absorptivity and Sandell sensitivity are also calculated and found to be 1.31 × 107 L mol-1 cm-1 and 0.00156 ng cm-2, respectively. The proposed procedure has been successfully applied to determine thallium in water, urine and serum samples.

Determination of thallium at ultra-trace levels in water and biological samples using solid phase spectrophotometry.

PubMed

Amin, Alaa S; El-Sharjawy, Abdel-Azeem M; Kassem, Mohammed A

2013-06-01

A new simple, very sensitive, selective and accurate procedure for the determination of trace amounts of thallium(III) by solid-phase spectrophotometry (SPS) has been developed. The procedure is based on fixation of Tl(III) as quinalizarin ion associate on a styrene-divinylbenzene anion-exchange resin. The absorbance of resin sorbed Tl(III) ion associate is measured directly at 636 and 830 nm. Thallium(I) was determined by difference measurements after oxidation of Tl(I) to Tl(III) with bromine. Calibration is linear over the range 0.5-12.0 μg L(-1) of Tl(III) with relative standard deviation (RSD) of 1.40% (n=10). The detection and quantification limits are 150 and 495 ng L(-1) using 0.6 g of the exchanger. The molar absorptivity and Sandell sensitivity are also calculated and found to be 1.31×10(7) L mol(-1)cm(-1) and 0.00156 ng cm(-2), respectively. The proposed procedure has been successfully applied to determine thallium in water, urine and serum samples. Copyright © 2013 Elsevier B.V. All rights reserved.

The development of Drink Less: an alcohol reduction smartphone app for excessive drinkers.

PubMed

Garnett, Claire; Crane, David; West, Robert; Brown, Jamie; Michie, Susan

2018-05-04

Excessive alcohol consumption poses a serious problem for public health. Digital behavior change interventions have the potential to help users reduce their drinking. In accordance with Open Science principles, this paper describes the development of a smartphone app to help individuals who drink excessively to reduce their alcohol consumption. Following the UK Medical Research Council's guidance and the Multiphase Optimization Strategy, development consisted of two phases: (i) selection of intervention components and (ii) design and development work to implement the chosen components into modules to be evaluated further for inclusion in the app. Phase 1 involved a scoping literature review, expert consensus study and content analysis of existing alcohol apps. Findings were integrated within a broad model of behavior change (Capability, Opportunity, Motivation-Behavior). Phase 2 involved a highly iterative process and used the "Person-Based" approach to promote engagement. From Phase 1, five intervention components were selected: (i) Normative Feedback, (ii) Cognitive Bias Re-training, (iii) Self-monitoring and Feedback, (iv) Action Planning, and (v) Identity Change. Phase 2 indicated that each of these components presented different challenges for implementation as app modules; all required multiple iterations and design changes to arrive at versions that would be suitable for inclusion in a subsequent evaluation study. The development of the Drink Less app involved a thorough process of component identification with a scoping literature review, expert consensus, and review of other apps. Translation of the components into app modules required a highly iterative process involving user testing and design modification.

Carbonate-Bridged Lanthanoid Triangles: Single-Molecule Magnet Behavior, Inelastic Neutron Scattering, and Ab Initio Studies.

PubMed

Giansiracusa, Marcus J; Vonci, Michele; Van den Heuvel, Willem; Gable, Robert W; Moubaraki, Boujemaa; Murray, Keith S; Yu, Dehong; Mole, Richard A; Soncini, Alessandro; Boskovic, Colette

2016-06-06

Optimization of literature synthetic procedures has afforded, in moderate yield, homogeneous and crystalline samples of the five analogues Na11[{RE(OH2)}3CO3(PW9O34)2] (1-RE; RE = Y, Tb, Dy, Ho, and Er). Phase-transfer methods have allowed isolation of the mixed salts (Et4N)9Na2[{RE(OH2)}3CO3(PW9O34)2] (2-RE; RE = Y and Er). The isostructural polyanions in these compounds are comprised of a triangular arrangement of trivalent rare-earth ions bridged by a μ3-carbonate ligand and sandwiched between two trilacunary Keggin {PW9O34} polyoxometalate ligands. Alternating-current (ac) magnetic susceptibility studies of 1-Dy, 1-Er, and 2-Er reveal the onset of frequency dependence for the out-of-phase susceptibility in the presence of an applied magnetic field at the lowest measured temperatures. Inelastic neutron scattering (INS) spectra of 1-Ho and 1-Er exhibit transitions between the lowest-lying crystal-field (CF) split states of the respective J = 8 and (15)/2 ground-state spin-orbit multiplets of the Ho(III) and Er(III) ions. Complementary ab initio calculations performed for these two analogues allow excellent reproduction of the experimental magnetic susceptibility and low-temperature magnetization data and are in reasonable agreement with the experimental INS data. The ab initio calculations reveal that the slight difference in coordination environments of the three Ln(III) ions in each complex gives rise to differences in the CF splitting that are not insignificant. This theoretical result is consistent with the observation of multiple relaxation processes by ac magnetic susceptibility and the broadness of the measured INS peaks. The ab initio calculations also indicate substantial mixing of the MJ contributions to the CF split energy levels of each Ln(III) ion. Calculations indicate that the CF ground states of the Ho(III) centers in 1-Ho are predominantly comprised of contributions from small MJ, while those of the Er(III) centers in 1-Er are predominantly comprised of contributions from large MJ, giving rise to slow magnetic relaxation. Although no direct evidence for intramolecular RE···RE magnetic coupling is observed in either magnetic or INS studies, on the basis of the ab initio calculations, we find noncollinear magnetic axes in 1-Er that are coplanar with the erbium triangle and radially arranged with respect to the triangle's centroid; thus, we argue that the absence of magnetic coupling in this system arises from dipolar and antiferromagnetic superexchange interactions that cancel each other out.

Association of metallothionein-III with oligodendroglial cytoplasmic inclusions in multiple system atrophy.

PubMed

Pountney, D L; Dickson, T C; Power, J H T; Vickers, J C; West, A J; Gai, W P

2011-01-01

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterised by Parkinsonian and autonomic symptoms and by widespread intracytoplasmic inclusion bodies in oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are comprised of 9-10 nm filaments rich in the protein alpha-synuclein, also found in neuronal inclusion bodies associated with Parkinson's disease. Metallothioneins (MTs) are a class of low-molecular weight (6-7 kDa), cysteine-rich metal-binding proteins the expression of which is induced by heavy metals, glucocorticoids, cytokines and oxidative stress. Recent studies have shown a role for the ubiquitously expressed MT-I/II isoforms in the brain following a variety of stresses, whereas, the function of the brain-specific MT isoform, MT-III, is less clear. MT-III and MT-I/II immunostaining of post-mortem tissue in MSA and normal control human brains showed that the number of MT-III-positive cells is significantly increased in MSA in visual cortex, whereas MT-I/II isoforms showed no significant difference in the distribution of immunopositive cells in MSA compared to normal tissue. GCIs were immunopositive for MT-III, but were immunonegative for the MT-I/II isoforms. Immunofluorescence double labelling showed the co-localisation of alpha-synuclein and MT-III in GCIs in MSA tissue. In isolated GCIs, transmission electron microscopy demonstrated MT-III immunogold labelling of the amorphous material surrounding alpha-synuclein filaments in GCIs. High-molecular weight MT-III species in addition to MT-III monomer were detected in GCIs by Western analysis of the detergent-solubilised proteins of purified GCIs. These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments.

Analysis of Wake VAS Benefits Using ACES Build 3.2.1: VAMS Type 1 Assessment

NASA Technical Reports Server (NTRS)

Smith, Jeremy C.

2005-01-01

The FAA and NASA are currently engaged in a Wake Turbulence Research Program to revise wake turbulence separation standards, procedures, and criteria to increase airport capacity while maintaining or increasing safety. The research program is divided into three phases: Phase I near term procedural enhancements; Phase II wind dependent Wake Vortex Advisory System (WakeVAS) Concepts of Operations (ConOps); and Phase III farther term ConOps based on wake prediction and sensing. The Phase III Wake VAS ConOps is one element of the Virtual Airspace Modelling and Simulation (VAMS) program blended concepts for enhancing the total system wide capacity of the National Airspace System (NAS). This report contains a VAMS Program Type 1 (stand-alone) assessment of the expected capacity benefits of Wake VAS at the 35 FAA Benchmark Airports and determines the consequent reduction in delay using the Airspace Concepts Evaluation System (ACES) Build 3.2.1 simulator.

Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials.

PubMed

Manzi, Susan; Sánchez-Guerrero, Jorge; Merrill, Joan T; Furie, Richard; Gladman, Dafna; Navarra, Sandra V; Ginzler, Ellen M; D'Cruz, David P; Doria, Andrea; Cooper, Simon; Zhong, Z John; Hough, Douglas; Freimuth, William; Petri, Michelle A

2012-11-01

To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) organ domain scores. At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA-SLEDAI, and immunological by SELENA-SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA-SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (≤16%) at baseline, including the SELENA-SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA-SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.

Magnetic resonance-guided focused ultrasound surgery for treatment of painful osseous metastases

NASA Astrophysics Data System (ADS)

Hurwitz, Mark; Machtinger, Ronit; Fennessy, Fiona

2011-03-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is an emerging technology that can non-invasively heat and ablate targeted tissue utilizing ultrasound energy. Use of MR imaging for treatment guidance provides several key advantages over more widely used ultrasound guidance for focused ultrasound ablation. MR allows for precise targeting, detailed beam path visualization, real time non-invasive temperature measurement, and treatment feedback to ensure therapeutic goals are achieved. In the realm of oncology, management of painful bone metastases is a common and daunting clinical problem. The Insightec ExAblate System has been shown in phase I/II trials for treatment of bone metastases to have an excellent safety profile and high rates of pain response. An international multi-center phase III trial for patients with painful bone metastases or multiple myeloma who are not candidates for radiation therapy is currently open. Patients are randomized 3:1 to MRgFUS or sham treatment with crossover to study treatment allowed for sham failures. The primary study endpoint is assessment of pain control over 3 months following treatment. In addition safety, quality of life, cost effectiveness analysis, and patient perceived clinical benefit are also being assessed. Details of the MRgFUS system, technical and clinical therapeutic parameters, use of real time non-invasive MR thermometry, and examples of patient treatments with use of MRgFUS to treat bone metastases will be discussed. New directions in use of MRgFUS including an update on development of a new mobile applicator and integration of MRgFUS in multimodality oncologic care will also be presented.

Phase I-II study of multiple daily fractions for palliation of advanced head and neck malignancies.

PubMed

Paris, K J; Spanos, W J; Lindberg, R D; Jose, B; Albrink, F

1993-03-15

To assess palliation of advance head and neck malignancies with the use of rapid hyper fractionation studies similar to the RTOG 85-02. 37 patients with 39 lesions were entered into the non-randomized Phase I-II protocol, between 1984 and 1991. Previously untreated malignancies were present in 24 lesions, primary recurrent diseases in six patients, metastasis to the head and neck in five patients and skin primaries in the remaining two cases. At presentation 15 of 37 patients (or 17 of 39 lesions) were in operable due to poor medical status, eight patients were considered technically in operable due to extent of disease, 10 patients had distant metastasis and four patients refused surgery. The protocol uses twice a day fraction (370 cGy per fraction) for 2 consecutive days totalling 1,480 cGy per course. Three courses were given at 3-week intervals for a final tumor dose of 4,440 cGy in twelve fraction over 8-9 weeks. Eleven of 39 lesions had complete response; 19 lesions had partial response; 4 lesions had no response; 3 lesions progressed under treatment. Response could not be assessed in two patients. The average survival after completion of therapy was 4.5 months ranging from 2 weeks to 31 months. Palliation was achieved in 33 of 39 lesions. The acute reactions were minimal and no late or long term complications were noted. The absence of significant complications with reasonable response in the high rate of palliation suggests that this rapid hyper fractionation palliation study should be studied for further evaluation.

Sunny hours and variations in the prevalence of asthma in schoolchildren according to the International Study of Asthma and Allergies (ISAAC) Phase III in Spain

NASA Astrophysics Data System (ADS)

Arnedo-Pena, Alberto; García-Marcos, Luis; Fernández-Espinar, Jorge Fuertes; Bercedo-Sanz, Alberto; Aguinaga-Ontoso, Ines; González-Díaz, Carlos; Carvajal-Urueña, Ignacio; Busquet-Monge, Rosa; Suárez-Varela, Maria Morales; de Andoin, Nagore García; Batlles-Garrido, Juan; Blanco-Quirós, Alfredo; Varela, Angel López-Silvarrey; García-Hernández, Gloria

2011-05-01

The objective of this study was to estimate the relationship between the prevalence of asthma in schoolchildren aged 6-7 years and 13-14 years and the mean annual sunny hours (MASH) in Spain, and to explore predictive models for asthma prevalence. The prevalence of asthma was obtained from the International Study of Asthma and Allergies (ISAAC) Phase III 2002-2003, and climate and socio-economic variables from official sources. Nine centres were studied and a further four centres, two of which are in ISAAC, to test the predictive models. Logistic regression was used to estimate adjusted prevalence rates of asthma for each centre, and multiple regression models to study the effects of MASH and other meteorological and socio-economic variables. The adjusted prevalence rate of asthma decreased 0.6% [95% confidence interval (CI) 0.4-0.8%] for the 6-7 years group and 1.1% (95% CI 0.8-1.3%) for the 13-14 years group with an increase in the MASH of 100 h. Relative humidity was negatively associated with asthma in the older age group, and gross province product per capita (GPP) was positively associated with asthma in the younger age group. The predictive models, which included MASH, gender, relative humidity, and GPP, anticipated prevalence rates of asthma without significant differences between the levels observed and those expected in 9 of the11 measurements carried out. The results indicate that sunny hours have a protective effect on the prevalence of asthma in schoolchildren.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

PubMed Central

2012-01-01

Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies. PMID:22340283

Phases of Feminist Re-Vision in the Psychology of Personality.

ERIC Educational Resources Information Center

Torrey, Jane W.

1987-01-01

Reviews McIntosh's 1983 theory on the five-phase evolution of scholarship required by increasing feminism. Documents the sequence of the five phases using references to scholarly literature on the psychology of personality. Elaborates on Phase III in which investigators study women as inherently different from men and urges further study and…

Early Restoration | NOAA Gulf Spill Restoration

Science.gov Websites

Early Restoration Plan. On April 20, 2011 we reached an agreement with BP to start restoration planning draft plan for the third phase of early restoration in December 2013. We are considering your comments : All Phase III information and documents Phase II Useful Links: Phase II Early Restoration Plan &

New pharmacotherapy options for multiple myeloma.

PubMed

Mina, Roberto; Cerrato, Chiara; Bernardini, Annalisa; Aghemo, Elena; Palumbo, Antonio

2016-01-01

Novel agents and the availability of autologous stem-cell transplantation have revolutionized the treatment of patients with multiple myeloma. First-generation novel agents namely thalidomide, lenalidomide, and bortezomib have significantly improved response and survival of patients. Second-generation novel agents such as pomalidomide, carfilzomib, and monoclonal antibodies are being tested both in the newly diagnosed and relapse settings, and results are promising. In this review article, the main results derived from Phase III trials with thalidomide, lenalidomide, and bortezomib for the treatment of myeloma patients, both at diagnosis and at relapse, are summarized. Data about second-generation novel agents such as pomalidomide and carfilzomib are also reported. Newer effective drugs currently under investigation and the promising results with monoclonal antibodies are described. The availability of new effective drugs has considerably increased the treatment options for myeloma patients. A sequential approach including induction, transplantation (when possible), consolidation, and maintenance is an optimal strategy to achieve disease control and prolong survival. Despite these improvements, the best combination, the optimal sequence, and the proper target of newer drugs need to be defined.

Monoclonal antibodies and recombinant immunoglobulins for the treatment of multiple sclerosis.

PubMed

Gensicke, Henrik; Leppert, David; Yaldizli, Özgür; Lindberg, Raija L P; Mehling, Matthias; Kappos, Ludwig; Kuhle, Jens

2012-01-01

Multiple sclerosis (MS) is an inflammatory and degenerative disease leading to demyelination and axonal damage in the CNS. Autoimmunity plays a central role in MS pathogenesis. Per definition, monoclonal antibodies are recombinant biological compounds with a well defined target, thus carrying the promise of targeting pathogenic cells or molecules with high specificity, avoiding undesired off-target effects. Natalizumab was the first monoclonal antibody to be approved for the treatment of MS. Several other monoclonal antibodies are in development and have demonstrated promising efficacy in phase II studies. They can be categorized according to their mode of action into compounds targeting (i) leukocyte migration into the CNS (natalizumab); (ii) cytolytic antibodies (rituximab, ocrelizumab, ofatumumab, alemtuzumab); or (iii) antibodies and recombinant proteins targeting cytokines and chemokines and their receptors (daclizumab, ustekinumab, atacicept, tabalumab [Ly-2127399], secukinumab [AIN457]). In this review, we discuss the specific molecular targets, clinical efficacy and safety of these compounds and discuss criteria to anticipate the position of monoclonal antibodies in the diversifying armamentarium of MS therapy in the coming years.

The challenge of comorbidity in clinical trials for multiple sclerosis.

PubMed

Marrie, Ruth Ann; Miller, Aaron; Sormani, Maria Pia; Thompson, Alan; Waubant, Emmanuelle; Trojano, Maria; O'Connor, Paul; Reingold, Stephen; Cohen, Jeffrey A

2016-04-12

We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS). We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS. We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies. Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to "real world" settings where the MS population commonly has comorbid conditions. © 2016 American Academy of Neurology.

The challenge of comorbidity in clinical trials for multiple sclerosis

PubMed Central

Miller, Aaron; Sormani, Maria Pia; Thompson, Alan; Waubant, Emmanuelle; Trojano, Maria; O'Connor, Paul; Reingold, Stephen; Cohen, Jeffrey A.

2016-01-01

Objective: We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS). Methods: We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS. Results: We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies. Conclusion: Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to “real world” settings where the MS population commonly has comorbid conditions. PMID:26888986

β-Ga2O3 versus ε-Ga2O3: Control of the crystal phase composition of gallium oxide thin film prepared by metal-organic chemical vapor deposition

NASA Astrophysics Data System (ADS)

Zhuo, Yi; Chen, Zimin; Tu, Wenbin; Ma, Xuejin; Pei, Yanli; Wang, Gang

2017-10-01

Gallium oxide thin films of β and ε phase were grown on c-plane sapphire using metal-organic chemical vapor deposition and the phase compositions were analyzed using X-ray diffraction. The epitaxial phase diagram was constructed as a function of the growth temperature and VI/III ratio. A low growth temperature and low VI/III ratio were beneficial for the formation of hexagonal-type ε-Ga2O3. Further structure analysis revealed that the epitaxial relationship between ε-Ga2O3 and c-plane sapphire is ε-Ga2O3 (0001) || Al2O3 (0001) and ε-Ga2O3 || Al2O3 . The structural evolution of the mixed-phase sample during film thickening was investigated. By reducing the growth rate, the film evolved from a mixed phase to the energetically favored ε phase. Based on these results, a Ga2O3 thin film with a phase-pure ε-Ga2O3 upper layer was successfully obtained.

X-ray Raman spectroscopic study of benzene at high pressure.

PubMed

Pravica, Michael; Grubor-Urosevic, Ognjen; Hu, Michael; Chow, Paul; Yulga, Brian; Liermann, Peter

2007-10-11

We have used X-ray Raman spectroscopy (XRS) to study benzene up to approximately 20 GPa in a diamond anvil cell at ambient temperature. The experiments were performed at the High-Pressure Collaborative Access Team's 16 ID-D undulator beamline at the Advanced Photon Source. Scanned monochromatic X-rays near 10 keV were used to probe the carbon X-ray edge near 284 eV via inelastic scattering. The diamond cell axis was oriented perpendicular to the X-ray beam axis to prevent carbon signal contamination from the diamonds. Beryllium gaskets confined the sample because of their high transmission throughput in this geometry. Spectral alterations with pressure indicate bonding changes that occur with pressure because of phase changes (liquid: phase I, II, III, and III') and possibly due to changes in the hybridization of the bonds. Changes in the XRS spectra were especially evident in the data taken when the sample was in phase III', which may be related to a rate process observed in earlier shock wave studies.

Mono- and polynucleation, atomistic growth, and crystal phase of III-V nanowires under varying group V flow

NASA Astrophysics Data System (ADS)

Dubrovskii, V. G.

2015-05-01

We present a refined model for the vapor-liquid-solid growth and crystal structure of Au-catalyzed III-V nanowires, which revisits several assumptions used so far and is capable of describing the transition from mononuclear to polynuclear regime and ultimately to regular atomistic growth. We construct the crystal phase diagrams and calculate the wurtzite percentages, elongation rates, critical sizes, and polynucleation thresholds of Au-catalyzed GaAs nanowires depending on the As flow. We find a non-monotonic dependence of the crystal phase on the group V flow, with the zincblende structure being preferred at low and high group V flows and the wurtzite structure forming at intermediate group V flows. This correlates with most of the available experimental data. Finally, we discuss the atomistic growth picture which yields zincblende crystal structure and should be very advantageous for fabrication of ternary III-V nanowires with well-controlled composition and heterointerfaces.

Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis.

PubMed

Mills, Edward; Wilson, Kumanan; Clarke, Mike; Foster, Brian; Walker, Scott; Rachlis, Beth; DeGroot, Nick; Montori, Victor M; Gold, Wayne; Phillips, Elizabeth; Myers, Stephen; Gallicano, Keith

2005-03-01

To determine whether ingestion of milk thistle affects the pharmacokinetics of indinavir. We conducted a three-period, randomized controlled trial with 16 healthy participants. We randomized participants to milk thistle or control. All participants received initial dosing of indinavir, and baseline indinavir levels were obtained (AUC(0-8)) (phase I). The active group were then given 450 mg milk-thistle extract capsules to be taken t.i.d. from day 2 to day 30. The control group received no plant extract. On day 29 and day 30, indinavir dosing and sampling was repeated in both groups as before (phase II). After a wash-out period of 7 days, indinavir dosing and sampling were repeated as before (phase III). All participants completed the trial, but two were excluded from analysis due to protocol violation. There were no significant between-group differences. Active group mean AUC(0-8) indinavir decreased by 4.4% (90% CI, -27.5% to -26%, P=0.78) from phase I to phase II in the active group, and by 17.3% (90% CI, -37.3% to +9%, P=0.25) in phase III. Control group mean AUC(0-8) decreased by 21.5% (90% CI, -43% to +8%, P=0.2) from phase I to phase II and by 38.5% (90% CI, -55.3% to -15.3%, P=0.01) of baseline at phase III. To place our findings in context, milk thistle-indinavir trials were identified through systematic searches of the literature. A meta-analysis of three milk thistle-indinavir trials revealed a non-significant pooled mean difference of 1% in AUC(0-8) (95% CI, -53% to 55%, P=0.97). Indinavir levels were not reduced significantly in the presence of milk thistle.

An ab initio study on the structural, electronic and mechanical properties of quaternary full-Heusler alloys FeMnCrSn and FeMnCrSb

NASA Astrophysics Data System (ADS)

Erkişi, Aytaç

2018-06-01

The quaternary full Heusler alloys FeMnCrSn and FeMnCrSb, which have face-centred cubic (FCC) crystal structure and conform to ? space group with 216 space number, have been investigated using Generalised Gradient Approximation (GGA) in the Density Functional Theory (DFT) as implemented in VASP (Vienna Ab initio Simulation Package) software. These alloys are considered in ferromagnetic (FM) order. After the investigation of structural stability of these alloys, their mechanical and thermal properties and also electronic band structures have been examined. The calculated spin-polarised electronic band structures and total electronic density of states (DOS) within GGA approximation show that these alloys can exhibit both metallic and half-metallic characters in different structural phases. The calculated formation enthalpies and the plotted energy-volume graphs show that Type-III phase is most stable structural phase for these materials. Also, FeMnCrSb alloy in Type-I/Type-III phases and FeMnCrSn alloy in Type-III phase show half-metallic behaviour with integer total magnetic moments almost 2 and 1 μB per formula unit, respectively, since there are band gaps observed in spin-down states, whereas they have metallic behaviour in majority bands. Other structural phases of both systems are also metallic. Moreover, the calculated elastic constants and the estimated anisotropy shear factors indicate that these materials are stable mechanically in all of three phases except FeMnCrSn in Type-I phase that does not satisfy Born stability criteria in this phase and have high anisotropic behaviour.

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

PubMed

Ziemssen, Tjalf; Kern, Raimar; Cornelissen, Christian

2015-06-18

Fingolimod (Gilenya) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS). Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile. Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland. However, less is known about the safety of long-term fingolimod use in daily practice. Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany. PANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase. A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase. Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted. PANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials. The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions.

One-year outcomes with the Taxus Liberté stent in the real world: the Taxus Olympia registry (phase I).

PubMed

Ahmed, Waqar Habib; Zambahari, Robaayah; Al-Rashdan, Ibrahim; Al Naeemi, Abdullah; Saeed, Fuad A; Mascioli, Stephen

2008-12-01

The Taxus Olympia registry is a prospective, postapproval registry collecting clinical outcomes data on patients receiving the Taxus Liberté paclitaxel-eluting stent during routine interventional cardiology practice. Between February and July 2005, 529 patients receiving the Taxus Liberté stent at 16 centers in the Middle East, South/Central America, and Asia/Pacific regions were enrolled in Phase I of Olympia. The primary end-point was Taxus Liberté stent-related cardiac events (cardiac death, MI, and revascularization) at 30 days postimplant. Additional clinical assessment was conducted at 6 and 12 months. Olympia phases II and III are in clinical follow-up and will be reported separately. One-year clinical follow-up is available for 98% of patients. Complex patients and lesions were prevalent, including: 50% diabetes mellitus, 49% multivessel disease, 30% multiple stenting, 48% AHA/ACC type B2/C lesions, 19% long lesions (>26 mm), and 40% small vessels (30 days postprocedure. One-year cardiac event rates among complex subpopulations (diabetics 5.0%, multiple stents 3.8%, long lesions 3.1%, and small vessels 2.9%) were comparable to the overall study population. In conclusion, this first report of real-world experience with the Taxus Liberté stent demonstrates the safety and clinical utility of this stent in the broader spectrum of coronary disease treated in everyday practice.

30 CFR 57.22205 - Doors on main fans (I-A, II-A, III, and V-A mines).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Doors on main fans (I-A, II-A, III, and V-A mines). 57.22205 Section 57.22205 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF... main fans (I-A, II-A, III, and V-A mines). In mines ventilated by multiple main fans, each main fan...

Searching for a neurologic injury's Wechsler Adult Intelligence Scale-Third Edition profile.

PubMed

Gonçalves, Marta A; Moura, Octávio; Castro-Caldas, Alexandre; Simões, Mário R

2017-01-01

This study aimed to investigate the presence of a Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) cognitive profile in a Portuguese neurologic injured sample. The Portuguese WAIS-III was administered to 81 mixed neurologic patients and 81 healthy matched controls selected from the Portuguese standardization sample. Although the mixed neurologic injury group performed significantly lower than the healthy controls for the majority of the WAIS-III scores (i.e., composite measures, discrepancies, and subtests), the mean scores were within the normal range and, therefore, at risk of being unobserved in a clinical evaluation. ROC curves analysis showed poor to acceptable diagnostic accuracy for the WAIS-III composite measures and subtests (Working Memory Index and Digit Span revealed the highest accuracy for discriminating between participants, respectively). Multiple regression analysis showed that both literacy and the presence of brain injury were significant predictors for all of the composite measures. In addition, multiple regression analysis also showed that literacy, age of injury onset, and years of survival predicted all seven composite measures for the mixed neurologic injured group. Despite the failure to find a WAIS-III cognitive profile for mixed neurologic patients, the results showed a significant influence of brain lesion and literacy in the performance of the WAIS-III.

Cyanide binding to human plasma heme-hemopexin: A comparative study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ascenzi, Paolo, E-mail: ascenzi@uniroma3.it; Istituto Nazionale di Biostrutture e Biosistemi, Roma; Leboffe, Loris

Highlights: Black-Right-Pointing-Pointer Cyanide binding to ferric HHPX-heme-Fe. Black-Right-Pointing-Pointer Cyanide binding to ferrous HHPX-heme-Fe. Black-Right-Pointing-Pointer Dithionite-mediated reduction of ferric HHPX-heme-Fe-cyanide. Black-Right-Pointing-Pointer Cyanide binding to HHPX-heme-Fe is limited by ligand deprotonation. Black-Right-Pointing-Pointer Cyanide dissociation from HHPX-heme-Fe-cyanide is limited by ligand protonation. -- Abstract: Hemopexin (HPX) displays a pivotal role in heme scavenging and delivery to the liver. In turn, heme-Fe-hemopexin (HPX-heme-Fe) displays heme-based spectroscopic and reactivity properties. Here, kinetics and thermodynamics of cyanide binding to ferric and ferrous hexa-coordinate human plasma HPX-heme-Fe (HHPX-heme-Fe(III) and HHPX-heme-Fe(II), respectively), and for the dithionite-mediated reduction of the HHPX-heme-Fe(III)-cyanide complex, at pH 7.4 and 20.0 Degree-Sign C,more » are reported. Values of thermodynamic and kinetic parameters for cyanide binding to HHPX-heme-Fe(III) and HHPX-heme-Fe(II) are K = (4.1 {+-} 0.4) Multiplication-Sign 10{sup -6} M, k{sub on} = (6.9 {+-} 0.5) Multiplication-Sign 10{sup 1} M{sup -1} s{sup -1}, and k{sub off} = 2.8 Multiplication-Sign 10{sup -4} s{sup -1}; and H = (6 {+-} 1) Multiplication-Sign 10{sup -1} M, h{sub on} = 1.2 Multiplication-Sign 10{sup -1} M{sup -1} s{sup -1}, and h{sub off} = (7.1 {+-} 0.8) Multiplication-Sign 10{sup -2} s{sup -1}, respectively. The value of the rate constant for the dithionite-mediated reduction of the HHPX-heme-Fe(III)-cyanide complex is l = 8.9 {+-} 0.8 M{sup -1/2} s{sup -1}. HHPX-heme-Fe reactivity is modulated by proton acceptor/donor amino acid residue(s) (e.g., His236) assisting the deprotonation and protonation of the incoming and outgoing ligand, respectively.« less

Safinamide.

PubMed

Fariello, Ruggero G

2007-01-01

Safinamide (SAF) ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino)propanamide) was initially synthetized by Farmitalia Carlo Erba (Italy). Following initial anticonvulsant screening, safinamide was selected for its potency, broad spectrum of action, and good safety margin. Pharmacodynamic properties probably relevant to its antiepileptic activity are use- and frequency-dependent block of voltage sensitive Na+ channels, block of Ca++ channels, and glutamate release inhibition. Possibly contributing mechanism are also selective and reversible monoamide oxidase B inhibition and dopamine and noradrenaline uptake inhibition. The high selectivity for the sigma-1 receptor site does not entail psychotomimetic or behavioral changes. In several experimental in vitro and in vivo conditions, SAF exerts neurorescuing and neuroprotectant effects. Safinamide is water soluble and suitable for 1 times a day oral administration in humans. In a pilot phase II study in 38 refractory epilepsy patients affected by multiple types of seizures, 41% of subjects obtained > or =50% seizure reduction during a 12-week escalating dose up to 300 mg 1 times day compared with perspective baseline. Safinamide is being developed in phase III for treatment of Parkinson's disease, whereas the development in epilepsy relates to the industrial strategy of the company.

Mechanistic modelling of the inhibitory effect of pH on microbial growth.

PubMed

Akkermans, Simen; Van Impe, Jan F

2018-06-01

Modelling and simulation of microbial dynamics as a function of processing, transportation and storage conditions is a useful tool to improve microbial food safety and quality. The goal of this research is to improve an existing methodology for building mechanistic predictive models based on the environmental conditions. The effect of environmental conditions on microbial dynamics is often described by combining the separate effects in a multiplicative way (gamma concept). This idea was extended further in this work by including the effects of the lag and stationary growth phases on microbial growth rate as independent gamma factors. A mechanistic description of the stationary phase as a function of pH was included, based on a novel class of models that consider product inhibition. Experimental results on Escherichia coli growth dynamics indicated that also the parameters of the product inhibition equations can be modelled with the gamma approach. This work has extended a modelling methodology, resulting in predictive models that are (i) mechanistically inspired, (ii) easily identifiable with a limited work load and (iii) easily extended to additional environmental conditions. Copyright © 2017. Published by Elsevier Ltd.

[Pharmaconutrition with parenteral selenium in sepsis].

PubMed

Langlois, P L; de Oliveira Figliolino, L F; Hardy, G; Manzanares, W

2014-04-01

Critical illness is characterized by oxidative stress which leads to multiple organ failure, and sepsis-related organ dysfunction remains the most common cause of death in the intensive care unit. Over the last 2 decades, different antioxidant therapies have been developed to improve outcomes in septic patients. According to recent evidence, selenium therapy should be considered the cornerstone of the antioxidant strategies. Selenium given as selenious acid or sodium selenite should be considered as a drug or pharmaconutrient with prooxidant and cytotoxic effects when a loading dose in intravenous bolus form is administered, particularly in the early stage of severe sepsis/septic shock. To date, several phase ii trials have demonstrated that selenium therapy may be able to decrease mortality, improve organ dysfunction and reduce infections in critically ill septic patients. The effect of selenium therapy in sepsis syndrome must be confirmed by large, well designed phase iii clinical trials. The purpose of this review is to discuss current evidence on selenium pharmaconutrition in sepsis syndrome. Copyright © 2013 Elsevier España, S.L. and SEMICYUC. All rights reserved.

Involvement of peripheral III nerve in multiple sclerosis patient: Report of a new case and discussion of the underlying mechanism.

PubMed

Shor, Natalia; Amador, Maria Del Mar; Dormont, Didier; Lubetzki, Catherine; Bertrand, Anne

2017-04-01

Multiple sclerosis (MS) is a chronic disorder that affects the central nervous system myelin. However, a few radiological cases have documented an involvement of peripheral cranial nerves, within the subarachnoid space, in MS patients. We report the case of a 36-year-old female with a history of relapsing-remitting (RR) MS who consulted for a subacute complete paralysis of the right III nerve. Magnetic resonance imaging (MRI) examination showed enhancement and thickening of the cisternal right III nerve, in continuity with a linear, mesencephalic, acute demyelinating lesion. Radiological involvement of the cisternal part of III nerve has been reported only once in MS patients. Radiological involvement of the cisternal part of V nerve occurs more frequently, in almost 3% of MS patients. In both situations, the presence of a central demyelinating lesion, in continuity with the enhancement of the peripheral nerve, suggests that peripheral nerve damage is a secondary process, rather than a primary target of demyelination.

Amino group in Leptothrix sheath skeleton is responsible for direct deposition of Fe(III) minerals onto the sheaths.

PubMed

Kunoh, Tatsuki; Matsumoto, Syuji; Nagaoka, Noriyuki; Kanashima, Shoko; Hino, Katsuhiko; Uchida, Tetsuya; Tamura, Katsunori; Kunoh, Hitoshi; Takada, Jun

2017-07-26

Leptothrix species produce microtubular organic-inorganic materials that encase the bacterial cells. The skeleton of an immature sheath, consisting of organic exopolymer fibrils of bacterial origin, is formed first, then the sheath becomes encrusted with inorganic material. Functional carboxyl groups of polysaccharides in these fibrils are considered to attract and bind metal cations, including Fe(III) and Fe(III)-mineral phases onto the fibrils, but the detailed mechanism remains elusive. Here we show that NH 2 of the amino-sugar-enriched exopolymer fibrils is involved in interactions with abiotically generated Fe(III) minerals. NH 2 -specific staining of L. cholodnii OUMS1 detected a terminal NH 2 on its sheath skeleton. Masking NH 2 with specific reagents abrogated deposition of Fe(III) minerals onto fibrils. Fe(III) minerals were adsorbed on chitosan and NH 2 -coated polystyrene beads but not on cellulose and beads coated with an acetamide group. X-ray photoelectron spectroscopy at the N1s edge revealed that the terminal NH 2 of OUMS1 sheaths, chitosan and NH 2 -coated beads binds to Fe(III)-mineral phases, indicating interaction between the Fe(III) minerals and terminal NH 2 . Thus, the terminal NH 2 in the exopolymer fibrils seems critical for Fe encrustation of Leptothrix sheaths. These insights should inform artificial synthesis of highly reactive NH 2 -rich polymers for use as absorbents, catalysts and so on.

Exploratory double-blind, parallel-group, placebo-controlled extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis.

PubMed

2017-10-01

Following the first phase III study of edaravone for amyotrophic lateral sclerosis (ALS), this extension study was performed to evaluate longer-term efficacy and safety. Patients given edaravone in the first 24-week phase III study (Cycles 1-6) were randomised to edaravone (E-E) or placebo (E-P) in the subsequent 24-week double-blind period (Cycles 7-12). Patients given placebo in phase III were switched to edaravone (P-E). Subsequently, all patients received edaravone for 12 weeks (Cycles 13-15). Efficacy endpoints included revised ALS Functional Rating Scale (ALSFRS-R) score. Analysis populations were the full analysis set (FAS) and the efficacy-expected subpopulation (EESP) defined by post-hoc analysis of the first phase III study. The least-squares mean and standard error of the intergroup difference (E-E vs. E-P) of change in the ALSFRS-R score from Cycles 7-12 was 1.16 ± 0.93 (p = 0.2176) in the FAS, and 1.85 ± 1.14 (p = 0.1127) in the EESP. The ALSFRS-R score changed almost linearly in the E-E group throughout Cycles 1-15 (60 weeks). The incidence of serious adverse events associated with ALS progression was higher in E-E than in E-P. Edaravone might have potential efficacy for up to 15 cycles when used to treat patients in the EESP with careful safety monitoring.

Arsenic removal with iron(II) and iron(III) in waters with high silicate and phosphate concentrations.

PubMed

Roberts, Linda C; Hug, Stephan J; Ruettimann, Thomas; Billah, Morsaline; Khan, Abdul Wahab; Rahman, Mohammad Tariqur

2004-01-01

Arsenic removal by passive treatment, in which naturally present Fe(II) is oxidized by aeration and the forming iron(III) (hydr)oxides precipitate with adsorbed arsenic, is the simplest conceivable water treatment option. However, competing anions and low iron concentrations often require additional iron. Application of Fe(II) instead of the usually applied Fe(III) is shown to be advantageous, as oxidation of Fe(II) by dissolved oxygen causes partial oxidation of As(III) and iron(III) (hydr)oxides formed from Fe(II) have higher sorption capacities. In simulated groundwater (8.2 mM HCO3(-), 2.5 mM Ca2+, 1.6 mM Mg2+, 30 mg/L Si, 3 mg/L P, 500 ppb As(III), or As(V), pH 7.0 +/- 0.1), addition of Fe(II) clearly leads to better As removal than Fe(III). Multiple additions of Fe(II) further improved the removal of As(II). A competitive coprecipitation model that considers As(III) oxidation explains the observed results and allows the estimation of arsenic removal under different conditions. Lowering 500 microg/L As(III) to below 50 microg/L As(tot) in filtered water required > 80 mg/L Fe(III), 50-55 mg/L Fe(II) in one single addition, and 20-25 mg/L in multiple additions. With As(V), 10-12 mg/L Fe(II) and 15-18 mg/L Fe(III) was required. In the absence of Si and P, removal efficiencies for Fe(II) and Fe(III) were similar: 30-40 mg/L was required for As(II), and 2.0-2.5 mg/L was required for As(V). In a field study with 22 tubewells in Bangladesh, passive treatment efficiently removed phosphate, but iron contents were generally too low for efficient arsenic removal.

Water-soluble Schiff base-actinyl complexes and their effect on the solvent extraction of f-elements

DOE PAGES

Hawkins, Cory A.; Bustillos, Christian G.; May, Iain; ...

2016-09-07

Conventional solvent extraction of selected f-element cations by bis(2-ethylhexyl)phosphoric acid (HDEHP) yields increased extraction from aqueous to organic solution along the series Np(V) < Cm(III) < Eu(III) < U(VI), with distribution ratios all within two orders of magnitude. However, in the presence of the water-soluble tetradentate Schiff base (N,N'-bis(5-sulfonatosalicylidene)-ethylenediamine or H 2salenSO 3), selective complexation of the two actinyl cations (Np(V) and U(VI)) resulted in an extraction order of Np(V) < U(VI) << Eu(III) < Cm(III). The extraction of neither Cm(III) or Eu(III) by HDEHP are significantly impacted by the presence of the aqueous phase Schiff base. Despite observed hydrolyticmore » decomposition of H 2salenSO 3 in aqueous solutions, the calculated high conditional stability constant (β 11 = 26) for the complex [UO 2(salenSO 3)] 2- demonstrates its capacity for aqueous hold-back of U(VI). UV-visible-NIR spectroscopy of solutions prepared with a Np(VI) stock and H 2salenSO 3 suggest that reduction of Np(VI) to Np(V) by the ligand was rapid, resulting in a pentavalent Np complex that was substantially retained in the aqueous phase. Lastly, results from 1H NMR of aqueous solutions of H 2salenSO 3 with U(VI) and La(III), Eu(III), and Lu(III) provides additional evidence that the ligand readily chelates U(VI), but has only weak interactions with trivalent lanthanide ions.« less

Suppression of nanoindentation-induced phase transformation in crystalline silicon implanted with hydrogen

NASA Astrophysics Data System (ADS)

Jelenković, Emil V.; To, Suet

2017-09-01

In this paper the effect of hydrogen implantation in silicon on nanoindentation-induced phase transformation is investigated. Hydrogen ions were implanted in silicon through 300 nm thick oxide with double energy implantation (75 and 40 keV). For both energies implantation dose was 4 × 1016 cm-2. Some samples were thermally annealed at 400 °C. The micro-Raman spectroscopy was applied on nanoindentation imprints and the obtained results were related to the pop out/elbow appearances in nanoindentatioin unloading-displacement curves. The Raman spectroscopy revealed a suppression of Si-XII and Si-III phases and formation of a-Si in the indents of hydrogen implanted Si. The high-resolution x-ray diffraction measurements were taken to support the analysis of silicon phase formation during nanoindentation. Implantation induced strain, high hydrogen concentration, and platelets generation were found to be the factors that control suppression of c-Si phases Si-XII and Si-III, as well as a-Si phase enhancement during nanoindentation. [Figure not available: see fulltext.

Predicted Growth of Two-Dimensional Topological Insulator Thin Films of III-V Compounds on Si(111) Substrate

DOE PAGES

Yao, Liang-Zi; Crisostomo, Christian P.; Yeh, Chun-Chen; ...

2015-11-05

We have carried out systematic first-principles electronic structure computations of growth of ultrathin films of compounds of group III (B, Al, In, Ga, and Tl) with group V (N, P, As, Sb, and Bi) elements on Si(111) substrate, including effects of hydrogenation. Two bilayers (BLs) of AlBi, InBi, GaBi, TlAs, and TlSb are found to support a topological phase over a wide range of strains, in addition to BBi, TlN, and TlBi which can be driven into the nontrivial phase via strain. A large band gap of 134 meV is identified in hydrogenated 2 BL film of InBi. One andmore » two BL films of GaBi and 2 BL films of InBi and TlAs on Si(111) surface possess nontrivial phases with a band gap as large as 121 meV in the case of 2 BL film of GaBi. Persistence of the nontrivial phase upon hydrogenations in the III-V thin films suggests that these films are suitable for growing on various substrates.« less

Outcomes of Patients With Relapsed Hepatoblastoma Enrolled on Children's Oncology Group (COG) Phase I and II Studies.

PubMed

Trobaugh-Lotrario, Angela D; Meyers, Rebecka L; Feusner, James H

2016-04-01

Data are limited regarding outcomes of patients treated for relapsed hepatoblastoma. We reviewed enrollment patterns and outcomes of patients with hepatoblastoma on Children's Oncology Group (COG) phase I/II studies. The medical literature was searched for reports of COG phase I/II studies using PUBMED as well as an inventory from the COG publications office searching manuscripts published from 2000 to 2014. Seventy-one patients with relapsed hepatoblastoma were enrolled on 23 separate COG phase I/II studies. Four studies collected α-fetoprotein (AFP) data, but none utilized AFP decline in assessing response. Most studies enrolled few patients with relapsed hepatoblastoma: 7 studies enrolled 1 patient, and another 7 studies enrolled 2 patients each. Only 9 studies enrolled 3 or more patients with relapsed hepatoblastoma. Four responses were reported. Dedicated strata and/or focus on 1 or 2 studies with compelling biological or clinical rationale for hepatoblastoma may improve accrual (and statistical significance of response data) of patients with relapsed hepatoblastoma. Prospective study of AFP decline versus RECIST response could help determine the optimal method of assessing response to identify potentially beneficial treatments in hepatoblastoma.

On-line determination of Sb(III) and total Sb using baker's yeast immobilized on polyurethane foam and hydride generation inductively coupled plasma optical emission spectrometry

NASA Astrophysics Data System (ADS)

Menegário, Amauri A.; Silva, Ariovaldo José; Pozzi, Eloísa; Durrant, Steven F.; Abreu, Cassio H.

2006-09-01

The yeast Saccharomyces cerevisiae was immobilized in cubes of polyurethane foam and the ability of this immobilized material to separate Sb(III) and Sb(V) was investigated. A method based on sequential determination of total Sb (after on-line reduction of Sb(V) to Sb(III) with thiourea) and Sb(III) (after on-line solid-liquid phase extraction) by hydride generation inductively coupled plasma optical emission spectrometry is proposed. A flow system assembled with solenoid valves was used to manage all stages of the process. The effects of pH, sample loading and elution flow rates on solid-liquid phase extraction of Sb(III) were evaluated. Also, the parameters related to on-line pre-reduction (reaction coil and flow rates) were optimized. Detection limits of 0.8 and 0.15 μg L - 1 were obtained for total Sb and Sb(III), respectively. The proposed method was applied to the analysis of river water and effluent samples. The results obtained for the determination of total Sb were in agreement with expected values, including the river water Standard Reference Material 1640 certified by the National Institute of Standards and Technology (NIST). Recoveries of Sb(III) and Sb(V) in spiked samples were between 81 ± 19 and 111 ±15% when 120 s of sample loading were used.

SR-90107 (Sanofi-Synthélabo).

PubMed

Liu, F; Bagley, W P; Carroll, R C

2000-09-01

SR-90107 is a synthetic pentasaccharide heparinoid Factor Xa antagonist and thrombokinase inhibitor in joint development by Sanofi-Synthelabo (formerly Sanofi) and Organon as a potential treatment and prophylaxis for deep vein thrombosis (DVT) and symptomatic pulmonary embolism following hip or knee surgery and as a potential treatment for coronary artery diseases [330073,359231]. The compound is in phase III clinical trials for the prevention of DVT and pulmonary embolism; phase III trials for the treatment of DVT and pulmonary embolism were expected to start in the first quarter of 2000 and phase IIb trials in cardiology indications are also underway. NDAs are planned to be submitted in Europe and the US in the third quarter of 2000 for the prevention of DVT and symptomatic pulmonary embolism, in 2002 for the treatment of DVT and pulmonary embolism and in 2004 for the treatment of coronary artery diseases [359231]. DVT AND PULMONARY EMBOLISM: The compound had entered phase III clinical trials by December 1998 for the prevention of thrombosis [320585]. By February 2000, four phase III trials in the prevention of DVT and pulmonary embolism following orthopaedic surgery were underway: the European PENTHIFRA trial, which involves 1707 patients with hip fracture; the US PENTATHLON trial, which involves 2200 patients undergoing hip replacements; the European EPHESUS trial, which involves 2200 patients undergoing hip replacements; and the US PENTAMAKS trial, which involves 1000 patients undergoing major knee surgery [359231]. Clinical data from these trials are expected to be available by June 2000 [359793]. By February 2000, preparations were also being made for two phase III trials of SR-90107 for the treatment of DVT and pulmonary embolism, both expected to be initiated in the first quarter of 2000; the MATISSE DVT trial, a double-blind trial of SR-90107 versus enoxaparin sodium in 2200 patients; and the MATISSE PE trial, an open study of SR-90107 versus unfractionated heparin in 2200 patients [359231]. CORONARY ARTERY DISEASES: By February 2000, SR-90107 was also under development for unstable angina, percutaneous transluminal coronary angioplasty, and acute myocardial infarction. At this time, the phase IIb PENTALYSE trial in thrombolyzed acute myocardial infarction patients had been completed, demonstrating a good safety/efficacy ratio, and the phase IIb PENTUA trial in unstable angina was ongoing [359231]. In October 1999, Merrill Lynch forecast sales of EUR 180 million in 2003, planning a review of this figure once clinical data were available [346209]. Also in October 1999, Lehman Brothers predicted that the product had a 70% chance of reaching the market with potential peak sales of US 700 million dollars in 2008 [346267].

Sequential and simultaneous adsorption of Sb(III) and Sb(V) on ferrihydrite: Implications for oxidation and competition.

PubMed

Qi, Pengfei; Pichler, Thomas

2016-02-01

Antimony (Sb) is a naturally occurring element of growing environmental concern whose toxicity, adsorption behavior and other chemical properties are similar to that of arsenic (As). However, less is known about Sb compared to As. Individual and simultaneous adsorption experiments with Sb(III) and Sb(V) were conducted in batch mode with focus on the Sb speciation of the remaining liquid phase during individual Sb(III) adsorption experiments. The simultaneous adsorption and oxidation of Sb(III) was confirmed by the appearance of Sb(V) in the solution at varying Fe/Sb ratios (500, 100 and 8) and varying pH values (3.8, 7 and 9). This newly formed Sb(V) was subsequently removed from solution at a Fe/Sb ratio of 500 or at a pH of 3.8. However, more or less only Sb(V) was observed in the liquid phase at the end of the experiments at lower Fe/Sb ratios and higher pH, indicating that competition took place between the newly formed Sb(V) and Sb(III), and that Sb(III) outcompeted Sb(V). This was independently confirmed by simultaneous adsorption experiments of Sb(III) and Sb(V) in binary systems. Under such conditions, the presence of Sb(V) had no influence on the adsorption of Sb(III) while Sb(V) adsorption was significantly inhibited by Sb(III) over a wide pH range (4-10). Thus, in the presence of ferrihydrite and under redox conditions, which allow the presence of both Sb species, Sb(V) should be the dominant species in aquatic environments, since Sb(III) is adsorbed preferentially and at the same time oxidized to Sb(V). Copyright © 2015 Elsevier Ltd. All rights reserved.

Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design.

PubMed

Richert, Laura; Doussau, Adélaïde; Lelièvre, Jean-Daniel; Arnold, Vincent; Rieux, Véronique; Bouakane, Amel; Lévy, Yves; Chêne, Geneviève; Thiébaut, Rodolphe

2014-02-26

Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative. By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.

The public health impact of malaria vaccine RTS,S in malaria endemic Africa: country-specific predictions using 18 month follow-up Phase III data and simulation models.

PubMed

Penny, Melissa A; Galactionova, Katya; Tarantino, Michael; Tanner, Marcel; Smith, Thomas A

2015-07-29

The RTS,S/AS01 malaria vaccine candidate recently completed Phase III trials in 11 African sites. Recommendations for its deployment will partly depend on predictions of public health impact in endemic countries. Previous predictions of these used only limited information on underlying vaccine properties and have not considered country-specific contextual data. Each Phase III trial cohort was simulated explicitly using an ensemble of individual-based stochastic models, and many hypothetical vaccine profiles. The true profile was estimated by Bayesian fitting of these models to the site- and time-specific incidence of clinical malaria in both trial arms over 18 months of follow-up. Health impacts of implementation via two vaccine schedules in 43 endemic sub-Saharan African countries, using country-specific prevalence, access to care, immunisation coverage and demography data, were predicted via weighted averaging over many simulations. The efficacy against infection of three doses of vaccine was initially approximately 65 % (when immunising 6-12 week old infants) and 80 % (children 5-17 months old), with a 1 year half-life (exponential decay). Either schedule will avert substantial disease, but predicted impact strongly depends on the decay rate of vaccine effects and average transmission intensity. For the first time Phase III site- and time-specific data were available to estimate both the underlying profile of RTS,S/AS01 and likely country-specific health impacts. Initial efficacy will probably be high, but decay rapidly. Adding RTS,S to existing control programs, assuming continuation of current levels of malaria exposure and of health system performance, will potentially avert 100-580 malaria deaths and 45,000 to 80,000 clinical episodes per 100,000 fully vaccinated children over an initial 10-year phase.

Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial.

PubMed

Schmitt, Thomas; Goldschmidt, Hartmut; Neben, Kai; Freiberger, Anja; Hüsing, Johannes; Gronkowski, Martina; Thalheimer, Markus; Pelzl, Le Hang; Mikus, Gerd; Burhenne, Jürgen; Ho, Anthony D; Egerer, Gerlinde

2014-10-20

The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m(2) was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index-Emesis (FLIE) questionnaire on days -1 and 6. Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001). The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life. © 2014 by American Society of Clinical Oncology.

A Bayesian Hybrid Adaptive Randomisation Design for Clinical Trials with Survival Outcomes.

PubMed

Moatti, M; Chevret, S; Zohar, S; Rosenberger, W F

2016-01-01

Response-adaptive randomisation designs have been proposed to improve the efficiency of phase III randomised clinical trials and improve the outcomes of the clinical trial population. In the setting of failure time outcomes, Zhang and Rosenberger (2007) developed a response-adaptive randomisation approach that targets an optimal allocation, based on a fixed sample size. The aim of this research is to propose a response-adaptive randomisation procedure for survival trials with an interim monitoring plan, based on the following optimal criterion: for fixed variance of the estimated log hazard ratio, what allocation minimizes the expected hazard of failure? We demonstrate the utility of the design by redesigning a clinical trial on multiple myeloma. To handle continuous monitoring of data, we propose a Bayesian response-adaptive randomisation procedure, where the log hazard ratio is the effect measure of interest. Combining the prior with the normal likelihood, the mean posterior estimate of the log hazard ratio allows derivation of the optimal target allocation. We perform a simulation study to assess and compare the performance of this proposed Bayesian hybrid adaptive design to those of fixed, sequential or adaptive - either frequentist or fully Bayesian - designs. Non informative normal priors of the log hazard ratio were used, as well as mixture of enthusiastic and skeptical priors. Stopping rules based on the posterior distribution of the log hazard ratio were computed. The method is then illustrated by redesigning a phase III randomised clinical trial of chemotherapy in patients with multiple myeloma, with mixture of normal priors elicited from experts. As expected, there was a reduction in the proportion of observed deaths in the adaptive vs. non-adaptive designs; this reduction was maximized using a Bayes mixture prior, with no clear-cut improvement by using a fully Bayesian procedure. The use of stopping rules allows a slight decrease in the observed proportion of deaths under the alternate hypothesis compared with the adaptive designs with no stopping rules. Such Bayesian hybrid adaptive survival trials may be promising alternatives to traditional designs, reducing the duration of survival trials, as well as optimizing the ethical concerns for patients enrolled in the trial.

34 CFR 350.5 - What definitions apply?

Code of Federal Regulations, 2011 CFR

2011-07-01

... expected to require multiple vocational rehabilitation services over an extended period of time; and (iii..., hemiplegia, hemophilia, respiratory or pulmonary dysfunction, mental retardation, mental illness, multiple sclerosis, muscular dystrophy, musculoskeletal disorders, neurological disorders (including stroke and...

34 CFR 350.5 - What definitions apply?

Code of Federal Regulations, 2012 CFR

2012-07-01

... expected to require multiple vocational rehabilitation services over an extended period of time; and (iii..., hemiplegia, hemophilia, respiratory or pulmonary dysfunction, mental retardation, mental illness, multiple sclerosis, muscular dystrophy, musculoskeletal disorders, neurological disorders (including stroke and...