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

NHEXAS PHASE I ARIZONA STUDY--STANDARD OPERATING PROCEDURE FOR ANALYSIS OF SOIL OR HOUSE DUST SAMPLES USING CHLORPYRIFOS ELISA SAMPLES (BCO-L-1.0)

EPA Science Inventory

This abstract is included for completeness of documentation, but this SOP was not used in the study.

The purpose of this SOP is to describe the procedures for analyzing both Stage II and Stage III soil and vacuum-cleaner collected house dust samples, and Stage III air samples u...

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.

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.

Principle Findings from Development of a Recirculated Exhaust Gas Intake Sensor (REGIS) Enabling Cost-Effective Fuel Efficiency Improvement

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

Schnabel, Claus

Kick-off of the Bosch scope of work for the REGIS project started in October 2012. The primary work-packages included in the Bosch scope of work were the following: overall project management, development of the EGR sensor (design of sensor element, design of protection tube, and design of mounting orientation), development of EGR system control strategy, build-up of prototype sensors, evaluation of system performance with the new sensor and the new control strategy, long-term durability testing, and development of a 2nd generation sensor concept for continued technology development after the REGIS project. The University of Clemson was a partner with Boschmore » in the REGIS project. The Clemson scope of work for the REGIS project started in June 2013. The primary work-packages included in the Clemson scope of work were the following: development of EGR system control strategy, and evaluation of system performance with the new sensor and new control strategy. This project was split into phase I, phase II and phase III. Phase I work was completed by the end of June 2014 and included the following primary work packages: development of sensor technical requirements, assembly of engine testbench at Clemson, design concept for sensor housing, connector, and mounting orientation, build-up of EGR flow test benches at Bosch, and build-up of first sensor prototypes. Phase II work was completed by the end of June 2015 and included the following primary work pack ages: development of an optimizing function and demonstration of robustness of sensor, system control strategy implementation and initial validation, completion of engine in the loop testing of developed control algorithm, completion of sensor testing including characteristic line, synthetic gas test stand, and pressure dependency characterization, demonstration of benefits of control w/o sensing via simulation, development of 2nd generation sensor concept. Notable technical achievements from phase II were the following: publication of two new technical papers by Clemson detailing the control strategies used for the EGR system control. The two papers was published in the 2016 SAE World Congress in April 2016. The titles of each paper are, “Physics-Based Exhaust Pressure and Temperature Estimation for Low Pressure EGR Control in Turbocharged Gasoline Engines,” by K. Siokos, and “A Control Algorithm for Low Pressure – EGR Systems using a Smith Predictor with Intake Oxygen Sensor Feedback”, by R. Koli. All phase III work packages have been completed. The primary work packages in phase III were the following: completion of long-term sensor durability testing, final demonstration of benefits of EGR control w/o sensing, final decision of the second generation sensor development path.« less

Cadmium Alternatives for High-Strength Steel JTP - Phase 2

DTIC Science & Technology

2008-02-27

Project Overview Objective • Assess DoD- selected Cadmium alternatives in accordance with the DoD-approved Joint Test Protocol (JTP) for both...HE and adhesion testing): NAVAIR (complete) – Phase II (JTP test matrix): AFRL/CTC – Phase III (Testing for Threaded Fasteners): ARL • Selection of...Curry • Hill AFB – Mr. Nate Hughes • Alumiplate – Mr. Gus Vallejo • Marshall Labs – Mr. John Marshall U.S. AIR FORCE Phase I Overview and Selection

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.

Enhanced abiotic reduction of Cr(VI) in a soil slurry system by natural biomaterial addition.

PubMed

Park, Donghee; Ahn, Chi Kyu; Kim, Young Mi; Yun, Yeoung-Sang; Park, Jong Moon

2008-12-30

Among various plant-based natural biomaterials, pine bark was chosen as an efficient biomaterial capable of removing toxic Cr(VI) from aqueous solution. XPS spectra indicated that Cr(VI) was abiotically reduced to Cr(III) in both liquid and solid phases. The Cr(VI)-reducing capacity of pine bark was determined as 545 (+/-1.3)mg-Cr(VI)g(-1) of it, which was 8.7 times higher than that of a common chemical Cr(VI)-reductant, FeSO4 x 7H2O. Because pine bark could completely reduce toxic Cr(VI) to less toxic or nontoxic Cr(III) even at neutral pH, it was used as an organic reductant to remediate Cr(VI)-contaminated soil in this study. Soil slurry system using a bottle roller was applied to ex situ slurry-phase remediation experiments. In the soil slurry system, pine bark completely reduced Cr(VI) to Cr(III) and adsorbed the reduced-Cr(III) on its surface. Abiotic remediation rate of Cr(VI)-contaminated soil increased with the increase of pine bark dosage and with the decreases of Cr(VI) and water contents. In conclusion, pine bark can be used to remediate Cr(VI)-contaminated soil efficiently and environmentally friendly.

International Space Station (ISS)

NASA Image and Video Library

1995-04-17

International Cooperation Phase III: A Space Shuttle docked to the International Space Station (ISS) in this computer generated representation of the ISS in its completed and fully operational state with elements from the U.S., Europe, Canada, Japan, and Russia.

The NATO III 5 MHz Distribution System

NASA Technical Reports Server (NTRS)

Vulcan, A.; Bloch, M.

1981-01-01

A high performance 5 MHz distribution system is described which has extremely low phase noise and jitter characteristics and provides multiple buffered outputs. The system is completely redundant with automatic switchover and is self-testing. Since the 5 MHz reference signals distributed by the NATO III distribution system are used for up-conversion and multiplicative functions, a high degree of phase stability and isolation between outputs is necessary. Unique circuit design and packaging concepts insure that the isolation between outputs is sufficient to quarantee a phase perturbation of less than 0.0016 deg when other outputs are open circuited, short circuited or terminated in 50 ohms. Circuit design techniques include high isolation cascode amplifiers. Negative feedback stabilizes system gain and minimizes circuit phase noise contributions. Balanced lines, in lieu of single ended coaxial transmission media, minimize pickup.

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.

Surrogate endpoints in randomized cardiovascular clinical trials.

PubMed

Domanski, Michael; Pocock, Stuart; Bernaud, Corine; Borer, Jeffrey; Geller, Nancy; Revkin, James; Zannad, Faiez

2011-08-01

Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

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/

Laronidase.

PubMed

2002-01-01

BioMarin Pharmaceutical is developing laronidase, recombinant alpha-L-iduronidase enzyme replacement therapy for the treatment of mucopolysaccharidosis I (MPS-I) [the most severe form of this is called Hurler syndrome]. The company has received US and European orphan drug designation for the enzyme and has fast-track review status with the FDA. In 1998, BioMarin Pharmaceutical and Genzyme General formed a joint venture for development and marketing of laronidase. A Phase I trial in 10 patients with a range of disease severity of MPS-I required for US and European filing was completed at the Harbor-UCLA Medical Center in California. This open label trial involved weekly infusions with laronidase. The two-year follow-up data revealed sustained and, in certain parameters, improved clinical results recorded at the end of 1 year of therapy. BioMarin and Genzyme General have completed a pivotal, Phase III trial in the centres in the USA, Canada and Europe, including patients with Hurler-Scheie and Scheie syndromes. In a multicentre, double-blind, placebo-controlled study, all 45 patients with MPS-I have received at least their initial weekly infusion of laronidase. Patients are being evaluated over a 6-month period. BioMarin Pharmaceutical and Genzyme General have filed on 15 April 2002 the first portion of a 'rolling' BLA with the US FDA for use of laronidase in the treatment of MPS-I. The companies are planning to complete the BLA filing in Q3 2002. The application will include 6-month data from the ongoing open-label Phase III extension study and also the 6-month data from the placebo-controlled part of the Phase III study. In the open-label extension study, patients from both the treatment and placebo arms of the Phase III trial received weekly infusions of laronidase for at least 6 months. The response from the US FDA is anticipated during the H1 of 2003. Both companies plan to initiate two new clinical trials in patients with MPS-I. One study will enrol patients with MPS-I under 5 years old. Another study will investigate laronidase in patients with advanced clinical symptoms of MPS-I. Additionally, patients from the ongoing Phase III study will continue to receive treatment with laronidase. On 1 March 2002, BioMarin and Genzyme filed a marketing approval application with European regulatory authorities for AldurazymeOE for the treatment of MPS-I. Mucopolysaccharidosis I is a rare autosomal recessive lysosomal storage disorder caused by alpha-L-iduronidase deficiency. Its manifestations in children can include growth and developmental delay, enlargement of spleen and liver, skeletal deformity, cardiac and pulmonary impairment, vision or hearing loss and mental dysfunction. At present, bone marrow transplantation is the only available treatment.

Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward.

PubMed

Guy, Bruno; Briand, Olivier; Lang, Jean; Saville, Melanie; Jackson, Nicholas

2015-12-10

Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

An Overview of the Cooperative Effort between the United States Department of Energy and the China Atomic Energy Authority to Enhance MPC&A Inspections for Civil Nuclear Facilities in China

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

Ahern, Keith; Daming, Liu; Hanley, Tim

The United States Department of Energy, National Nuclear Security Administration (DOE/NNSA) and the China Atomic Energy Authority (CAEA) are cooperating to enhance the domestic regulatory inspections capacity for special nuclear material protection, control and accounting (MPC&A) requirements for civil nuclear facilities in China. This cooperation is conducted under the auspices of the Agreement between the Department of Energy of the United States of America and the State Development and Planning Commission of the People s Republic of China on Cooperation Concerning Peaceful Uses of Nuclear Technology. This initial successful effort was conducted in three phases. Phase I focused on introducingmore » CAEA personnel to DOE and U. S. Nuclear Regulatory Commission inspection methods for U. S. facilities. This phase was completed in January 2008 during meetings in Beijing. Phase II focused on developing physical protection and material control and accounting inspection exercises that enforced U. S. inspection methods identified during Phase 1. Hands on inspection activities were conducted in the United States over a two week period in July 2009. Simulated deficiencies were integrated into the inspection exercises. The U. S. and Chinese participants actively identified and discussed deficiencies noted during the two week training course. The material control and accounting inspection exercises were conducted at the Paducah Gaseous Diffusion Plant (PGDP) in Paducah, KY. The physical protection inspection exercises were conducted at the Oak Ridge National Laboratory (ORNL) in Oak Ridge, TN. Phase III leveraged information provided under Phase I and experience gained under Phase II to develop a formal inspection guide that incorporates a systematic approach to training for Chinese MPC&A field inspectors. Additional hands on exercises that are applicable to Chinese regulations were incorporated into the Phase III training material. Phase III was completed in May 2010 at the China Institute of Atomic Energy (CIAE) in Beijing. This paper provides details of the successful cooperation between DOE/NNSA and CAEA for all phases of the cooperative effort to enhance civil domestic MPC&A inspections in China.« less

Canakinumab: in patients with cryopyrin-associated periodic syndromes.

PubMed

Curran, Monique P

2012-02-01

Canakinumab is a recombinant, fully human, monoclonal, anti-human interleukin-1β (IL-1β) antibody that binds with high affinity and specificity to human IL-1β, preventing its interaction with IL-1 receptors. Canakinumab (150 mg in patients weighing >40 kg or 2 mg/kg in those weighing 15-40 kg) administered once every 8 weeks as a single dose via subcutaneous injection provided a rapid and sustained response in patients with cryopyrin-associated periodic syndromes (CAPS). During the initial 8-week phase of a three-part, phase III trial, a complete response to a single dose of canakinumab occurred in 97% of the 35 patients with CAPS, with 71% of responses occurring within 8 days. After 8 weeks, 31 responders entered a 24-week, randomized, double-blind, withdrawal phase; there was a significant between-group difference in this phase in that none of the canakinumab recipients relapsed compared with 81% of placebo recipients. All patients from the second phase of the trial entered a third, 16-week phase of open-label treatment with canakinumab once every 8 weeks; clinical and biochemical remission was maintained in 28 of 29 patients who completed the trial. In a 2-year, open-label, phase III trial, subcutaneous canakinumab once every 8 weeks provided sustained disease control in the majority of patients with CAPS. Canakinumab was generally well tolerated in all trials, with the predominant adverse events being mild to moderate infections that were responsive to standard treatment.

Clinical status of carboplatin.

PubMed

Canetta, R; Franks, C; Smaldone, L; Bragman, K; Rozencweig, M

1987-07-01

Carboplatin, a cisplatin derivative, shows promise of being an effective weapon against ovarian, cervical, and small-cell lung cancer, as well as epidermoid cancer of the head and neck, with fewer toxic effects than cisplatin. It has successfully completed phase III investigation and clinical trials continue.

Long Valley Coring Project

USGS Publications Warehouse

Sass, John; Finger, John; McConnel, Vicki

1998-01-01

In December 1997, the California Energy Commission (CEC) agreed to provide funding for Phase III continued drilling of the Long Valley Exploratory Well (LVEW) near Mammoth Lakes, CA, from its present depth. The CEC contribution of $1 million completes a funding package of $2 million from a variety of sources, which will allow the well to be cored continuously to a depth of between 11,500 and 12,500 feet. The core recovered from Phase III will be crucial to understanding the origin and history of the hydrothermal systems responsible for the filling of fractures in the basement rock. The borehole may penetrate the metamorphic roof of the large magmatic complex that has fed the volcanism responsible for the caldera and subsequent activity.

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.

TRX-4 (TolerRx Inc).

PubMed

Brown, William M

2006-04-01

TolerRx Inc, under license from BTG plc, is developing TRX-4, an anti-CD3 humanized monoclonal antibody for the potential treatment of type 1 diabetes and psoriasis. Phase II trials of the therapeutic antibody in type 1 diabetes have been completed and the company is planning a pivotal phase III trial for this indication. TolerRx is also enrolling psoriasis patients in a phase Ib clinical study of TRX-4. TRX-4 has been awarded Orphan Drug status for recent-onset type 1 diabetes.

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.

South Lake Tahoe Coordinated Transit System project : phase III evaluation report

DOT National Transportation Integrated Search

2000-03-01

Utah's basic highway information system is one of the most complete data base management systems found in any of the Highway Safety Information System (HSIS) States in terms of the number of files included in the system and the flexibility of output....

Development Studies for a Novel Wet Oxidation Process

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

Delphi Research

1999-09-30

DETOX is a catalyzed wet oxidation process that destroys organic materials in an acidic water solution of iron at 373 to 473 K. The solution can be used repeatedly to destroy great amounts of organic materials. Since the process is conducted in a contained vessel, air emissions from the process can be well controlled. The solution is also capable of dissolving and concentrating many heavy and radioactive metals for eventual stabilization and disposal. The Phase III effort for this project is fabrication, assembly, and installation of the DETOX demonstration unit, preparation of documentation and training to meet site requirements formore » operation, followed by system run-in and shakedown testing of the unit prior to demonstration testing. The Title III design was completed and the unit was fabricated according to standards set forth by OSHA, EPA, the American Petroleum Institute (i.e., chemical and petroleum industry standards), and the ASME B-313 Piping Code requirements as agreed to in preliminary design meetings with primary stakeholders. The unit was assembled in three modules and two trailers and then shipped to the TNX facility at the Savannah River Site in September and october of 1996. On-going site integration tasks were address while delays in installation arose due to funding sources and costs. In March of 1997, Delphi was authorized to proceed with the installation of the unit, making electrical and mechanical connections necessary to operate the unit. All installation tasks were completed in August of 1997. Results of an Operational Readiness Review conducted in August 1997 verified that Delphi's procedures and documentation met the necessary requirements to operate the unit at SRS. Completion of the final checklist of WSRC requirements was then addressed including the Owner's Independent Inspection Report, verifying all components of the unit met B-31.3 standards. Final hydraulic and pneumatic tests were completed in November to satisfy the B-31.3 requirement. During the month of December, the control system and heating and cooling systems were then prepared to initiate system startup and conduct the run-in tests. Shakedown tests were combined with the Phase IV tasks due to DOE funding constraints, i.e., tests formerly planned to be conducted with oil and solid materials were deferred to Phase IV and combined with similar testing. Once run-in testing has been completed, the primary objectives of Phase III will have been achieved and the project will be ready to proceed to demonstration testing (Phase IV).« less

JPRS Report, Science and Technology: Europe, German Aerospace Industry Competitiveness.

DTIC Science & Technology

1991-05-31

construction , in which the German aerospace industry is involved (Alpha Jet, Tornado, Jaeger 90), are not directly transferable, since they deal with...INTA 1,500 100 Japan NASDA 938 749 U.S. NASA 23,0003 7,653 1. Planned after completion of construction phase (cun mately 100) 2. Annual average...for five-year construction phase 3. Excluding contractors rently approxi- Source: DLR, DASA III.5 Fiscal Aspects, Subsidies Taxes and duties affect

Anti-MRSA beta-lactams in development.

PubMed

Page, Malcolm G P

2006-10-01

Ceftobiprole medocaril, the most advanced of the anti-MRSA (methicillin-resistant Staphylococcus aureus) beta-lactams in clinical development, has recently completed its first Phase III clinical trial, and has demonstrated non-inferiority to vancomycin. Phase II clinical trials have been initiated with PPI0903, which is, like ceftobiprole medocaril, an injectable pro-drug of a broad-spectrum cephalosporin with anti-MRSA activity, and with RO4908643, a carbapenem with more modest activity against MRSA.

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis

PubMed Central

Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

2013-01-01

Background Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. Objectives To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. Methods The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Results Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. Conclusions The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. PMID:23252768

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

PubMed

Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

2013-04-01

Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. © 2012 Biofrontera Bioscience GmbH BJD © 2012 British Association of Dermatologists.

Thrombopoietic agents.

PubMed

Stasi, Roberto; Bosworth, Jenny; Rhodes, Elizabeth; Shannon, Muriel S; Willis, Fenella; Gordon-Smith, Edward C

2010-01-01

Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the thrombopoietin receptor that is expressed on the surface of platelets, megakaryocytes, and megakaryocytic precursors. First-generation thrombopoietic agents were recombinant forms of human TPO, and their development was discontinued after prolonged thrombocytopenia due to neutralizing auto-antibodies cross-reacting with endogenous TPO was observed. Second-generation thrombopoiesis-stimulating molecules are now available, which have unique pharmacological properties and no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have already completed phase III trials in primary immune thrombocytopenia and have been granted marketing authorization for use in this disease. Phase II and III trials with these novel drugs are ongoing in other conditions characterized by thrombocytopenia, such as chemotherapy, chronic liver disease, and the myelodysplastic syndromes. Most of the other second-generation thrombopoietic growth factors are in early phase clinical development. Copyright 2010 Elsevier Ltd. All rights reserved.

Durable Complete Responses in Some Recurrent High Grade Glioma Patients Treated with Toca 511 & Toca FC.

PubMed

Cloughesy, Timothy F; Landolfi, Joseph; Vogelbaum, Michael A; Ostertag, Derek; Elder, James B; Bloomfield, Stephen; Carter, Bob; Chen, Clark C; Kalkanis, Steven N; Kesari, Santosh; Lai, Albert; Lee, Ian Y; Liau, Linda M; Mikkelsen, Tom; Nghiemphu, Phioanh; Piccioni, David; Accomando, William; Diago, Oscar R; Hogan, Daniel J; Gammon, Dawn; Kasahara, Noriyuki; Kheoh, Thian; Jolly, Douglas J; Gruber, Harry E; Das, Asha; Walbert, Tobias

2018-05-12

Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of anti-tumor immunity. Recurrent high grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection, received Toca 511 injected into resection cavity wall followed by orally administered cycles of Toca FC. Among 56 patients, durable complete responses were observed. A subgroup was identified based on Toca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both IDH1-mutant and -wildtype tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive, 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Multi-year durable responses have been observed in rHGG patients treated with Toca 511 & Toca FC in a phase I trial and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

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

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.

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.

PubMed

Hohloch, Karin; Zeynalova, Samira; Chapuy, Björn; Pfreundschuh, Michael; Loeffler, Markus; Ziepert, Marita; Feller, Alfred C; Trümper, Lorenz; Hasenclever, Dirk; Wulf, Gerald; Schmitz, Norbert

2016-06-01

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

The LOGCAP III to LOGCAP IV Transition in Northern Afghanistan. Contract Services Phase-in and Phase-out on a Grand Scale

DTIC Science & Technology

2011-02-01

Contracting • Engineering and Technology • Logistics • Acquisition Management • Program Management For more information , visit http://clc.dau.mil ...for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data...sources, gathering and maintaining the data needed, and completing and reviewing the collection of information . Send comments regarding this burden

U.S. Air Force Installation Restoration Program. Phase 1. Records Search for Suffolk County Air Force Base (Retired) Landfills 1 and 2. Suffolk County Airport, Westhampton Beach, New York.

DTIC Science & Technology

1987-09-20

of the two study sites (Appendix D). Common species include the herring and ring-billed gull, mourning dove, tree swallow, chimney swift, purple... Species ................... 111-30 III.G ADJACENT LAND USE .................................... 111-31 III.H SUMMARY OF ENVIRONMENTAL FEATURES...methodology, and a list of acronyms/abbreviations used in this report. 1-4 W- x--WW- -- vqwu UV X DECISION TREE Complete List of Locations/Sites I Evaluation

Analysis of phase II studies on targeted agents and subsequent phase III trials: what are the predictors for success?

PubMed

Chan, John K; Ueda, Stefanie M; Sugiyama, Valerie E; Stave, Christopher D; Shin, Jacob Y; Monk, Bradley J; Sikic, Branimir I; Osann, Kathryn; Kapp, Daniel S

2008-03-20

To identify the characteristics of phase II studies that predict for subsequent "positive" phase III trials (those that reached the proposed primary end points of study or those wherein the study drug was superior to the standard regimen investigating targeted agents in advanced tumors. We identified all phase III clinical trials of targeted therapies against advanced cancers published from 1985 to 2005. Characteristics of the preceding phase II studies were reviewed to identify predictive factors for success of the subsequent phase III trial. Data were analyzed using the chi(2) test and logistic regression models. Of 351 phase II studies, 167 (47.6%) subsequent phase III trials were positive and 184 (52.4%) negative. Phase II studies from multiple rather than single institutions were more likely to precede a successful trial (60.4% v 39.4%; P < .001). Positive phase II results were more likely to lead to a successful phase III trial (50.8% v 22.5%; P = .003). The percentage of successful trials from pharmaceutical companies was significantly higher compared with academic, cooperative groups, and research institutes (89.5% v 44.2%, 45.2%, and 46.3%, respectively; P = .002). On multivariate analysis, these factors and shorter time interval between publication of phase II results and III study publication were independent predictive factors for a positive phase III trial. In phase II studies of targeted agents, multiple- versus single-institution participation, positive phase II trial, pharmaceutical company-based trials, and shorter time period between publication of phase II to phase III trial were independent predictive factors of success in a phase III trial. Investigators should be cognizant of these factors in phase II studies before designing phase III trials.

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.

Research and Operational Support for the Study of Military Relevant Infectious Diseases of Interest to United States and Royal Thai Government

DTIC Science & Technology

2006-01-01

in progress 8 PvDBP Polymorphisms Study completed; publication in progress 9 Tafenoquine Cure /Radical Cure Dose Ranging NIH In life completed Jan...and II, as possibly phase III testing. We will continue efforts for tafenoquine development, especially towards an indication of radical cure for...disease (prophylaxis) and to cure the infection (therapeutic). Antimalarial drug screening in the rhesus monkey model is very effective for making

GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months.

PubMed

Ludvigsson, Johnny; Chéramy, Mikael; Axelsson, Stina; Pihl, Mikael; Akerman, Linda; Casas, Rosaura

2014-07-01

This study aimed to analyse data from two different studies (phase II and phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum) at 30 months after administration to children and adolescents with type 1 diabetes. The phase II trial was a double-blind, randomised placebo-controlled study, including 70 children and adolescents who were followed for 30  months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and 1 month later. During a subsequent larger European phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9  months. The phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up, and 45 patients completed the trial at 30 months. Both studies included GAD65 auto-antibodies-positive patients with fasting C-peptide ≥ 0.10 nmol/l. We have now combined the results of these two trials. There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide area under the curve had decreased significantly less (9  m: p  <  0.037; 15 m: p  <  0.032; 21 m: p  <  0.003 and 30  m: p <  0.004), and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide > 0.2  nmol/L (p  <  0.05), as compared with placebo. Treatment with two doses of GAD-alum in children and adolescents with recent-onset type 1 diabetes shows no adverse events and preserves residual insulin secretion. Copyright © 2013 John Wiley & Sons, Ltd.

Reversed Phase Column HPLC-ICP-MS Conditions for Arsenic Speciation Analysis of Rice Flour.

PubMed

Narukawa, Tomohiro; Matsumoto, Eri; Nishimura, Tsutomu; Hioki, Akiharu

2015-01-01

New measurement conditions for arsenic speciation analysis of rice flour were developed using HPLC-ICP-MS equipped with a reversed phase ODS column. Eight arsenic species, namely, arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMAA), dimethylarsinic acid (DMAA), trimethylarsine oxide (TMAO), tetramethylarsonium (TeMA), arsenobetaine (AsB) and arsenocholine (AsC), were separated and determined under the proposed conditions. In particular, As(III) and MMAA and DMAA and AsB were completely separated using a newly proposed eluent containing ammonium dihydrogen phosphate. Importantly, the sensitivity changes, in particular those of As(V) and As(III) caused by coexisting elements and by complex matrix composition, which had been problematical in previously reported methods, were eliminated. The new eluent can be applied to C8, C18 and C30 ODS columns with the same effectiveness and with excellent repeatability. The proposed analytical method was successfully applied to extracts of rice flour certified reference materials.

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

BTS randomised feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma: ISRCTN 54469112.

PubMed

Muers, M F; Rudd, R M; O'Brien, M E R; Qian, W; Hodson, A; Parmar, M K B; Girling, D J

2004-02-01

The incidence of mesothelioma is rising rapidly in the UK. There is no generally accepted standard treatment. The BTS recommends active symptom control (ASC). It is not known whether chemotherapy in addition prolongs survival or provides worthwhile palliation with acceptable toxicity. Palliation as recorded by patients has been fully reported for only two regimens: mitomycin, vinblastine, and cisplatin (MVP), and vinorelbine (N). The BTS and collaborators planned to conduct a phase III randomised trial comparing ASC only, ASC+MVP, and ASC+N in 840 patients with survival as the primary outcome measure. The aim of the present study was to assess the acceptability of the trial design to patients and the suitability of two standard quality of life (QL) questionnaires for mesothelioma. Collaborating centres registered all new patients with mesothelioma. Those eligible and giving informed consent completed EORTC QLQ-C30+LC13 and FACT-L QL questionnaires and were randomised between all three or any two of (1) ASC only, (2) ASC+4 cycles of MVP, and (3) ASC+12 weekly doses of N. During 1 year, 242 patients were registered of whom 109 (45%) were randomised (55% of the 197 eligible patients). Fifty two patients from 20 centres were randomised to an option including ASC only. This translates into a rate of 312 per year from 60 centres interested in collaborating in the phase III trial. The EORTC QL questionnaire was superior to FACT-L in terms of completeness of data and patient preference. Clinically relevant palliation was achieved with ASC. The planned phase III trial is feasible.

Repetitively Pulsed Backward-Wave Oscillator Investigations

DTIC Science & Technology

1994-03-31

Sinus-6 High Power BWO Experiments and Theory .................. 6 A . B W O physics .............................................................. 6...B. Experiments with high power output of BWO .............................. 8 Section III. Long Pulse Vacuum BWO Experiments...UNM) has completed its initial phase of research on repetitively pulsed high power backward-wave oscillators (BWOs). The aggressive program that we had

International Space Station (ISS)

NASA Image and Video Library

1995-07-11

Artist's concept for Phase III of the International Space Station (ISS) as shown here in its completed and fully operational state with elements from the United States, Europe, Canada, Japan, and Russia. Sixteen countries are cooperating to provide a multidisciplinary laboratory, technology test bed, and observatory that will provide an unprecedented undertaking in scientific, technological, and international experimentation.

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.

Mechanisms and efficiency of the simultaneous removal of metals and cyanides by using ferrate(VI): crucial roles of nanocrystalline iron(III) oxyhydroxides and metal carbonates.

PubMed

Filip, Jan; Yngard, Ria A; Siskova, Karolina; Marusak, Zdenek; Ettler, Vojtech; Sajdl, Petr; Sharma, Virender K; Zboril, Radek

2011-08-29

The reaction of potassium ferrate(VI), K(2)FeO(4), with weak-acid dissociable cyanides--namely, K(2)[Zn(CN)(4)], K(2)[Cd(CN)(4)], K(2)[Ni(CN)(4)], and K(3)[Cu(CN)(4)]--results in the formation of iron(III) oxyhydroxide nanoparticles that differ in size, crystal structure, and surface area. During cyanide oxidation and the simultaneous reduction of iron(VI), zinc(II), copper(II), and cadmium(II), metallic ions are almost completely removed from solution due to their coprecipitation with the iron(III) oxyhydroxides including 2-line ferrihydrite, 7-line ferrihydrite, and/or goethite. Based on the results of XRD, Mössbauer and IR spectroscopies, as well as TEM, X-ray photoelectron emission spectroscopy, and Brunauer-Emmett-Teller measurements, we suggest three scavenging mechanisms for the removal of metals including their incorporation into the ferrihydrite crystal structure, the formation of a separate phase, and their adsorption onto the precipitate surface. Zn and Cu are preferentially and almost completely incorporated into the crystal structure of the iron(III) oxyhydroxides; the formation of the Cd-bearing, X-ray amorphous phase, together with Cd carbonate is the principal mechanism of Cd removal. Interestingly, Ni remains predominantly in solution due to the key role of nickel(II) carbonate, which exhibits a solubility product constant several orders of magnitude higher than the carbonates of the other metals. Traces of Ni, identified in the iron(III) precipitate, are exclusively adsorbed onto the large surface area of nanoparticles. We discuss the relationship between the crystal structure of iron(III) oxyhydroxides and the mechanism of metal removal, as well as the linear relationship observed between the rate constant and the surface area of precipitates. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Virulizin.

PubMed

2002-01-01

Virulizin, a biological response modifier, is a mixture of proteins and peptides that have been extracted from bovine reticuloendothelial tissue that activates macrophages. It is being developed by Lorus Therapeutics (formerly Imutec Pharma) for the treatment of various cancers and had completed phase II clinical trials in Canada for the treatment of pancreatic cancer and advanced malignant melanoma. The commencement of phase III clinical trials in Canada, for the treatment of pancreatic cancer, was delayed due to quality control problems with batches of virulizin and all clinical trials of virulizin were suspended as Lorus underwent a major restructuring programme. However, phase I/II clinical trials are now underway again in Canada in HIV-positive patients with Kaposi's sarcoma and for the treatment of pancreatic cancer. A phase I/II clinical trial is also underway in patients with pancreatic cancer in the USA. Lorus announced in June 2000 that it had completed a meta analysis of three phase I/II studies of virulizin that showed the drug increased survival and improved quality of life for pancreatic cancer patients. Based on these positive results, Lorus initiated a phase III trial to be conducted at 40 sites in North America in November 2001. The study aims to enrol 350 patients with advanced pancreatic cancer and will test the effectiveness of virulizin as first- and second-line treatment of pancreatic cancer. The study will compare virulizin + gemcitabine with gemcitabine alone as first-line therapy, while second-line treatment will involve patients who have failed to respond to gemcitabine. Some of these patients will receive virulizin + fluorouracil while another group will receive only fluorouracil. The study is scheduled to complete in 2004 or early 2005. Virulizin received orphan drug status for this indication from the US FDA in February 2001. Lorus received fast track designation from the FDA in June 2002 for virulizin for the treatment of pancreatic cancer. Virulizin is registered for the treatment of malignant melanoma in Mexico and is due to be launched there in 2002. Lorus has entered into an exclusive 7-year distribution agreement with Faulding Canada Inc., giving Faulding (now part of Mayne Group) the right to market and sell virulizin in Mexico for the treatment of melanoma. Lorus will receive royalties from sales of the product and will be responsible for its manufacture. In April 2002, Mayne exercised its option to acquire the distribution rights for virulizin in Brazil. Lorus Therapeutics has signed a collaborative agreement with NaPro BioTherapeutics, USA, to study the efficacy of virulizin in combination with paclitaxel for the treatment of lung adenocarcinoma. Lorus is conducting preclinical studies of virulizin in human breast cancer, lung, ovarian and prostate cancer, and has reported successful activity of the agent in these indications. Lorus was awarded a patent by the US Patent and Trademark Office to protect the only known process used to create virulizin. This patent, in conjunction with the patents issued in Australia, South Africa, New Zealand, Korea and Singapore, broadens and strengthens the protection of Lorus' intellectual property rights regarding the process, composition and use of virulizin.

Evaluating Protocol Lifecycle Time Intervals in HIV/AIDS Clinical Trials

PubMed Central

Schouten, Jeffrey T.; Dixon, Dennis; Varghese, Suresh; Cope, Marie T.; Marci, Joe; Kagan, Jonathan M.

2014-01-01

Background Identifying efficacious interventions for the prevention and treatment of human diseases depends on the efficient development and implementation of controlled clinical trials. Essential to reducing the time and burden of completing the clinical trial lifecycle is determining which aspects take the longest, delay other stages, and may lead to better resource utilization without diminishing scientific quality, safety, or the protection of human subjects. Purpose In this study we modeled time-to-event data to explore relationships between clinical trial protocol development and implementation times, as well as identify potential correlates of prolonged development and implementation. Methods We obtained time interval and participant accrual data from 111 interventional clinical trials initiated between 2006 and 2011 by NIH’s HIV/AIDS Clinical Trials Networks. We determined the time (in days) required to complete defined phases of clinical trial protocol development and implementation. Kaplan-Meier estimates were used to assess the rates at which protocols reached specified terminal events, stratified by study purpose (therapeutic, prevention) and phase group (pilot/phase I, phase II, and phase III/ IV). We also examined several potential correlates to prolonged development and implementation intervals. Results Even though phase grouping did not determine development or implementation times of either therapeutic or prevention studies, overall we observed wide variation in protocol development times. Moreover, we detected a trend toward phase III/IV therapeutic protocols exhibiting longer developmental (median 2 ½ years) and implementation times (>3years). We also found that protocols exceeding the median number of days for completing the development interval had significantly longer implementation. Limitations The use of a relatively small set of protocols may have limited our ability to detect differences across phase groupings. Some timing effects present for a specific study phase may have been masked by combining protocols into phase groupings. Presence of informative censoring, such as withdrawal of some protocols from development if they began showing signs of lost interest among investigators, complicates interpretation of Kaplan-Meier estimates. Because this study constitutes a retrospective examination over an extended period of time, it does not allow for the precise identification of relative factors impacting timing. Conclusions Delays not only increase the time and cost to complete clinical trials, but they also diminish their usefulness by failing to answer research questions in time. We believe that research analyzing the time spent traversing defined intervals across the clinical trial protocol development and implementation continuum can stimulate business process analyses and reengineering efforts that could lead to reductions in the time from clinical trial concept to results, thereby accelerating progress in clinical research. PMID:24980279

Ultrastructural study on the retinal pigment epithelium of human embryos, with special reference to quantitative study on the development of melanin granules.

PubMed

Oguni, M; Tanaka, O; Shinohara, H; Yoshioka, T; Setogawa, T

1991-01-01

The development of the retinal pigment epithelium (RPE) was studied ultrastructurally, using 13 externally normal human embryos, Carnegie stages ranging from 13 to 23 (4-8 week of gestation). Melanosomes in the peripheral and posterior RPE were classified according to Fitzpatrick et al. The melanosome of phase I is formed from the Golgi complex and parcelled off into small vesicles. The vesicle enlarges and elongates to form an oval organelle with membranous structures in it (phase II melanosome). Subsequently, melanin deposits on the membranous structures of the melanosomes (phase III melanosomes), and the completion of this process produces a uniformly electrondense granule without discernible internal structures (phase IV melanosome). Melanosomes of phases III and IV appeared in the RPE at stage 15. As the embryonic stage advanced, the ratio of phase II melanosomes decreased and that of phase IV melanosomes increased. The number of phase III melanosomes reached a peak in the peripheral and posterior RPE at stages 15 and 18, respectively. After stage 17, the increase in melanosomes and intracellular organelles was more prominent in the posterior than in the peripheral RPE. During stages 13 and 15, gap junctions were present not only in the apical but also basal plasma membranes of the RPE. At stage 20, gap junctions in the basal plasma membrane disappeared except for the transitional areas from the RPE to the neural retina (NR). In addition, gap junctions were observed between NR and RPE only in the peripheral region at stage 20. The morphological and quantitative differences in the peripheral and posterior RPE in the embryonic period are discussed.

Phase III trial comparing 3-6 months of adjuvant FOLFOX4/XELOX in stage II-III colon cancer: safety and compliance in the TOSCA trial.

PubMed

Lonardi, S; Sobrero, A; Rosati, G; Di Bartolomeo, M; Ronzoni, M; Aprile, G; Massida, B; Scartozzi, M; Banzi, M; Zampino, M G; Pasini, F; Marchetti, P; Cantore, M; Zaniboni, A; Rimassa, L; Ciuffreda, L; Ferrari, D; Barni, S; Zagonel, V; Maiello, E; Rulli, E; Labianca, R

2016-11-01

Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems. TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data. From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34). TOSCA is the first trial comparing 3 versus 6 months of adjuvant chemotherapy completing accrual within the international initiative of treatment duration evaluation (International Duration Evaluation of Adjuvant, IDEA). High compliance to treatment in control arm will allow a correct assessment of potential differences between the two treatment durations. NCT00646607. © The Author 2016. 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.

Structure of Bordetella pertussis peptidoglycan

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

Folkening, W.J.; Nogami, W.; Martin, S.A.

1987-09-01

Bordetella pertussis Tohama phases I and III were grown to the late-exponential phase in liquid medium containing (/sup 3/H)diaminopimelic acid and treated by a hot (96/sup 0/C) sodium dodecyl sulfate extraction procedure. Washed sodium dodecyl sulfate-insoluble residue from phases I and III consisted of complexes containing protein (ca. 40%) and peptidoglycan (60/sup 6/). Subsequent treatment with proteinase K yielded purified peptidoglycan which contained N-acetylglucosamine, N-acetylmuramic acid, alanine, glutamic acid, and diaminopimelic acid in molar ratios of 1:1:2:1:1 and <2% protein. Radiochemical analyses indicated that /sup 3/H added in diaminopimelic acid was present in peptidoglycan-protein complexes and purified peptidoglycan as diaminopimelicmore » acid exclusively and that pertussis peptidoglycan was not O acetylated, consistent with it being degraded completely by hen egg white lysozyme. Muramidase-derived disaccharide peptide monomers and peptide-cross-linked dimers and higher oligomers were isolated by molecular-sieve chromatography; from the distribution of these peptidoglycan fragments, the extent of peptide cross-linking of both phase I and III peptidoglycan was calculated to be ca. 48%. Unambiguous determination of the structure of muramidase-derived pepidoglycan fragments by fast atom bombardment-mass spectrometry and tandem mass spectrometry indicated that the pertussis peptidoglycan monomer fraction was surprisingly homogeneous, consisting of >95% N-acetylglucosaminyl-N-acetylmuramyl-alanyl-glutamyl-diaminopimelyl-alanine.« less

A randomized phase II/III trial of perioperative chemotherapy with adriamycin plus ifosfamide versus gemcitabine plus docetaxel for high-grade soft tissue sarcoma: Japan Clinical Oncology Group Study JCOG1306.

PubMed

Kataoka, Kozo; Tanaka, Kazuhiro; Mizusawa, Junki; Kimura, Aya; Hiraga, Hiroaki; Kawai, Akira; Matsunobu, Tomoya; Matsumine, Akihiko; Araki, Nobuhito; Oda, Yoshinao; Fukuda, Haruhiko; Iwamoto, Yukihide

2014-08-01

A randomized Phase II/III trial was planned to commence in March 2014. Perioperative chemotherapy with adriamycin plus ifosfamide is the current standard treatment for T2bN0M0 high-grade non-round cell soft tissue sarcoma. The purpose of this study is to confirm the non-inferiority of perioperative chemotherapy with gemcitabine and docetaxel to adriamycin plus ifosfamide for patients with T2bN0M0 or any TN1M0 non-round cell soft tissue sarcoma in the extremities and body wall. A total of 140 patients will be accrued from 28 Japanese institutions over 6 years. The primary endpoint in the Phase II part is the proportion of completion of pre-operative chemotherapy without progressive disease and overall survival in the Phase III part. The secondary endpoints are progression-free survival, response rate of pre-operative chemotherapy, pathological response rate, proportion of preservation of diseased limbs, disease control rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000013175 [http://www.umin.ac.jp/ctr/index.htm]. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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.

Photodynamic therapy--1994: treatment of benign and malignant upper aerodigestive tract disease

NASA Astrophysics Data System (ADS)

Schweitzer, Vanessa G.

1995-03-01

From 1983 to 1994 Phase II and III clinical studies at Henry Ford Hospital demonstrated complete or partial responses in 46 of 47 patients treated with hematoporphyrin-derivative photodynamic therapy (HPD-PDT) for a variety of benign and malignant upper aerodigestive tract disease: (1) superficial `condemned mucosa' or `field cancerization' of the oral cavity; (2) stage III/IV head and neck cancer; (3) mucocutaneous AIDS-related Kaposi's sarcoma of the upper aerodigestive tract; (4) recurrent laryngotracheal papillomatosis; (5) severe dysplasia/adenocarcinoma in situ in Barrett's esophagus; (6) partial or completely obstructing terminal esophageal cancer. HPD-PDT produced complete responses in 19 patients (follow up 6 months to 8 years) with `field cancerization' (CIS, T1) of the oral cavity and larynx (6), adenocarcinoma in situ in Barrett's esophagus (2), mucocutaneous Kaposi's sarcoma (9), obstructing esophageal carcinoma (1), and stage IV squamous cell carcinoma of the nasopharynx (1). PDT treatment protocols, results, complications, and application as adjunct or primary oncologic therapy for head and neck disease are reviewed.

Preconcentration of trace lead and iron on activated carbon functionalized by o-Anisic acid derivatives prior to their determination in environmental samples.

PubMed

Tian, Hua; Hu, Zheng; He, Qun; Liu, Xueliang; Zhang, Li; Chang, Xijun

2012-07-01

Two solid-phase adsorbents (phase I and phase II) were synthesized successfully that o-Anisic acid derivatives were evenly functionalized on the surface of activated carbon. It was certified that the two adsorbents were applied to preconcentrate and separate trace levels of Pb(II) and Fe(III) from natural liquid samples with satisfactory results. It can be found that the adsorption capacity of the ions adsorbed on phase I and phase II was 48.3 and 85.7 mg g(-1) for Pb(II), 39.5 and 72.5 mg g(-1) for Fe(III), respectively. The detection limit (3σ) of the method separated on phase I and phase II was 0.12 and 0.09 ng mL(-1) for Pb(II), 0.23 and 0.17 ng mL(-1) for Fe(III), respectively. The relative standard deviation (R.S.D.) of the method was lower than 3.0%. The adsorption and desorption property of two kinds of adsorbents was comparatively studied, respectively. The adsorption selectivity of heavy metal ions at certain pH, the adsorption kinetics, the condition of complete elution, the effect of coexisting ions, the adsorption capacity and adsorption isotherm modes were examined. Based on the experimental datum determined by inductively coupled plasma optical emission spectrometry (ICP-OES), it was certified that the adsorption on the surface of adsorbents was in strict accordance with the monolayer adsorption principle. The structural features of series of multidentate ligand modified on adsorption matrix had been obtained. These conclusions can provide reference for synthesizing an efficient adsorbent which is specific to remove a particular kind of contaminant. Copyright © 2012 Elsevier B.V. All rights reserved.

Design, analysis, and test verification of advanced encapsulation systems

NASA Technical Reports Server (NTRS)

Mardesich, N.; Minning, C.

1982-01-01

Design sensitivities are established for the development of photovoltaic module criteria and the definition of needed research tasks. The program consists of three phases. In Phase I, analytical models were developed to perform optical, thermal, electrical, and structural analyses on candidate encapsulation systems. From these analyses several candidate systems will be selected for qualification testing during Phase II. Additionally, during Phase II, test specimens of various types will be constructed and tested to determine the validity of the analysis methodology developed in Phase I. In Phse III, a finalized optimum design based on knowledge gained in Phase I and II will be developed. All verification testing was completed during this period. Preliminary results and observations are discussed. Descriptions of the thermal, thermal structural, and structural deflection test setups are included.

Phase III development of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire module for women undergoing breast reconstruction.

PubMed

Winters, Z E; Balta, V; Thomson, H J; Brandberg, Y; Oberguggenberger, A; Sinove, Y; Unukovych, D; Nava, M; Sandelin, K; Johansson, H; Dobbeleir, J; Blondeel, P; Bruno, N; Catanuto, G; Llewellyn-Bennett, R

2014-03-01

Comprehensive outcome assessments after breast reconstruction (BRR) require surgery-specific patient-reported outcome measures. The aims of this study were to assess the relevance, acceptability and redundancy of questions/items (phase III pretesting) of a new BRR questionnaire evaluating patients' health-related quality of life before and after BRR. Phase III occurred in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) following earlier development phases that identified 31 items. The EORTC BRR subgroup applied decision-making rules to each question according to eight EORTC criteria. A total of 197 patients (from the UK, Austria, Belgium, Italy and Sweden) were recruited. Forty-seven patients completed pre- and post-BRR questionnaires prospectively, and 150 reported post-BRR questionnaires only retrospectively. Qualitative debriefing interviews were undertaken in 189 patients. Preliminary psychometric analyses were performed. Thirty-one items fulfilled 'relevance', with none producing 'difficulties'. Ten items were not a priority for 10 per cent of respondents. Of these, two questions concerning muscle twitching in the affected breast and problem with donor-site swelling were deleted. Three redundant items were deleted: weakness in arm, which correlated significantly to the Quality of Life Questionnaire (QLQ) BR23 breast questionnaire, and shape and colour of the affected nipple. Descriptive statistics reduced the module to 26 items conceptualized into three provisional scales (disease treatment/surgery-related symptoms, sexuality and cosmetic outcome) within the newly completed questionnaire, EORTC QLQ-BRR26. The QLQ-BRR26 is available for psychometric validation in a large-field international sample. The intended use for QLQ-BRR26 is alongside EORTC QLQ-C30 and QLQ-BR23, in women treated by mastectomy for breast cancer and undergoing all types of BRR. © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

Facilitating the implementation of the American College of Surgeons/Association of Program Directors in Surgery phase III skills curriculum: training faculty in the assessment of team skills.

PubMed

Hull, Louise; Arora, Sonal; Stefanidis, Dimitrios; Sevdalis, Nick

2015-11-01

Effective teamwork is critical to safety in the operating room; however, implementation of phase III of the American College of Surgeons (ACS) and Association of Program Directors in Surgery (APDS) Curriculum that focuses on team-based skills remains worryingly low. Training and assessing the complexities of teamwork is challenging. The objective of this study was to establish guidelines and recommendations for training faculty in assessing/debriefing team skills. A multistage survey-based consensus study was completed by 108 experts responsible for training and assessing surgical residents from the ACS Accredited Educational Institutes. Experts agreed that a program to teach faculty to assess team-based skills should include training in the recognition of teamwork skills, practice rating these skills, and training in the provision of feedback/debriefing. Agreement was reached that faculty responsible for conducting team-based skills assessment should be revalidated every 2 years and stringent proficiency criteria should be met. Faculty development is critical to ensure high-quality, standardized training and assessment. Training faculty to assess team-based skills has the potential to facilitate the effective implementation of phase III of the ACS and APDS Curriculum. Copyright © 2015 Elsevier Inc. All rights reserved.

A call for more transparency of registered clinical trials on endometriosis

PubMed Central

Guo, Sun-Wei; Hummelshoj, Lone; Olive, David L.; Bulun, Serdar E.; D'Hooghe, Thomas M.; Evers, Johannes L.H.

2009-01-01

In response to the pressing need for more efficacious and safer therapeutics for endometriosis, there have been numerous reports in the last decade of positive results from animal and in vitro studies of various compounds as potential therapeutics for endometriosis. A handful of these have undergone phase II/III clinical trials. Since the announcement of the International Committee of Medical Journal Editors that mandated registration as a prerequisite for publication, 57 endometriosis-related clinical trials have been registered at ClinicalTrials.gov, an Internet-based public depository for information on drug studies. Among them, 25 are listed as completed, and 2 as suspended. There are 15 completed phase II/III trials, which evaluated the efficacy of various promising compounds. Yet only three of the 15 trials (20%) have published their results. The remaining 12 (80%) studies so far have not published their findings. We argue that this apparent lack of transparency will actually not benefit the trial sponsors or the public, and will ultimately prove detrimental to research efforts attempting to develop more efficacious and safer therapeutics for endometriosis. Thus we call for more transparency of clinical trials on endometriosis. PMID:19264712

Material growth and characterization for solid state devices

NASA Technical Reports Server (NTRS)

Collis, Ward J.; Abul-Fadl, Ali; Iyer, Shanthi

1988-01-01

During the period of this research grant, the process of liquid phase electroepitaxy (LPEE) was used to grow ternary and quaternary alloy III-V semiconductor thin films. Selective area growth of InGaAs was performed on InP substrates using a patterned sputtered quartz or spin-on glass layer. The etch back and growth characteristics with respect to substrate orientation were investigated. The etch back behavior is somewhat different from wet chemical etching with respect to the sidewall profiles which are observed. LPEE was also employed to grow epitaxial layers of InGaAsP alloys on InP substrates. The behavior of Mn as an acceptor dopant was investigated with low temperature Hall coefficient and photoluminescence measurements. A metal-organic vapor phase epitaxy system was partially complete within the grant period. This atmospheric pressure system will be used to deposit III-V compound and alloy semiconductor layers in future research efforts.

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.

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

Phase III study of the European Organisation for Research and Treatment of Cancer satisfaction with cancer care core questionnaire (EORTC PATSAT-C33) and specific complementary outpatient module (EORTC OUT-PATSAT7).

PubMed

Brédart, A; Anota, A; Young, T; Tomaszewski, K A; Arraras, J I; Moura De Albuquerque Melo, H; Schmidt, H; Friend, E; Bergenmar, M; Costantini, A; Vassiliou, V; Hureaux, J; Marchal, F; Tomaszewska, I M; Chie, W-C; Ramage, J; Beaudeau, A; Conroy, T; Bleiker, E; Kulis, D; Bonnetain, F; Aaronson, N K

2018-01-01

Advances in cancer care delivery require revision and further development of questionnaires assessing patients' perceived quality of care. This study pre-tested the revised EORTC satisfaction with cancer care core questionnaire applicable in both the cancer inpatient and outpatient settings, and its new, outpatient-specific complementary module. The process of revision, development of the extended application, and pre-testing of these questionnaires was based on phases I to III of the "EORTC Quality of Life Group Module Development Guidelines." In phase III, patients in 11 countries in four European regions, South America and Asia completed provisional versions of the questionnaires. Fifty-seven relevant issues selected from literature reviews and input from experts were operationalized into provisional items, and subsequently translated into ten languages. Assessment of understanding, acceptability, redundancy and relevance by patients (n = 151) from oncology inpatient wards, and outpatient chemotherapy, radiotherapy and consultation settings, led to retention of, deletion of and merging of 40, 14 and 6 items respectively. Cronbach's alpha coefficients for hypothesized questionnaire scales were above 0.80. Our results provide preliminary support for the 33-item EORTC Satisfaction with cancer care core questionnaire and the 7-item complementary module specific for the outpatient care setting. A large scale phase IV cross-cultural psychometric study is now underway. © 2017 John Wiley & Sons Ltd.

Enhancement of arsenite removal using manganese oxide coupled with iron (III) trimesic

NASA Astrophysics Data System (ADS)

Phanthasri, Jakkapop; Khamdahsag, Pummarin; Jutaporn, Panitan; Sorachoti, Kwannapat; Wantala, Kitirote; Tanboonchuy, Visanu

2018-01-01

A simultaneous removal of As(III) was investigated on a mixture of manganese oxide based octahedral molecular sieves (K-OMS2) and iron-benzenetricarboxylate (Fe-BTC). As(III) removal was stimulated by an oxidation cooperated with adsorption process. K-OMS2 and Fe-BTC were separately synthesized and characterized by X-ray diffraction (XRD), Transmission Electron Microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). K-OMS2 showed characters of pure cryptomelane phase, nanorod structure, and a mixed-valent manganese framework with the coexistence of Mn(IV) and Mn(III). As(III) was successfully oxidized to As(V) by K-OMS2 in a temperature range of 303-333 K. An intermediate adsorption of As(V) was carried out with Fe-BTC in the same batch. A maximum adsorption capacity, described by Langmuir isotherm model, was observed at 76.34 mg/g. With an As(III) initial concentration of 5 mg/L, when K-OMS2 and Fe-BTC were simultaneously introduced into the solution, the As(III) removal process was completed within 60 min. Thus, it shortened the process time compared to the case where K-OMS2 was added first, followed by the addition of Fe-BTC.

[Development of an orphan drug to treat a genetic disease: the paradigm of agalsidase beta].

PubMed

Germain, Dominique P; Benistan, Karelle

2007-03-01

Preclinical and phase I/II studies gave the proof of principle of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A through the demonstration of the clearance of the accumulated subtrate from plasma and tissues. In a multicenter, randomized, placebo-controlled, double-blind phase Ill study, the biological efficacy of recombinant alpha-galactosidose A (agalsidase beta 1 mg/kg/714 days) was demonstrated on the basis of complete clearance of accumulated globotriaosylceramide from the endothelia of the kidney, heart and skin. The phase III extension study data gives additional results: kidney function appears to be stabilized after 54 to 60 months of treatment with agolsidase beta in most patients. Intent-to-treat analysis of a double-blind, randomized, placebo-controlled, phase IV study, showed that, adjusted for on imbalance in baseline proteinuria, agalsidase beta significantly reduces by 53% the risk of a first clinical event (renal, cardiac and cerebrovascular), compared with placebo. Clinical benefits of ERT depend on patients' clinical status at baseline, therefore prompting for onset of ERT before irreversible damage occur and underlying the need to stratify patients' populations to better understand the outcome of ERT.

Feeding fat from distillers dried grains with solubles to dairy heifers: III. Effects on long-term reproductive and lactation performance

USDA-ARS?s Scientific Manuscript database

During the prepubertal growth phase, 33 Holstein heifers (133 ± 18 d old) were used in a 24-week randomized complete block design. Treatments included: 1) a control diet (CON) containing ground corn (15.9% of DM) and soybean products (17.9%); 2) a low-fat diet (LFDG) formulated with 21.9% fat-extrac...

Research development of a new GnRH antagonist (Elagolix) for the treatment of endometriosis: a review of the literature.

PubMed

Alessandro, Pontis; Luigi, Nappi; Felice, Sorrentino; Maria, Paoletti Anna; Benedetto, Melis Gian; Stefano, Angioni

2017-04-01

Limitated studies have reported the efficacy of GnRH antagonist on endometriosis symptoms. The aim of our study was to review all available trials to investigate the medical treatment of endometriosis with only GnRH antagonists, with special attention to pharmacodynamic activity, safety, and efficacy. Pub Med and Sciencedirect database were searched using terms of "endometriosis treatment", "GnRH antagonist", and "Elagolix". The search was limited to clinical studies published in English. Title and abstract were screened to identify relevant articles. Five studies covering use of GnRH antagonist were found. A phase 1 study evaluated the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single dose and 7 day elagolix administration to healthy premenopausal women; two phase II studies evaluated efficacy in patient with endometriosis. Moreover, there are two Phase III clinical trials just completed. GnRH antagonists may have the advantage of oral administration and lower incidence of adverse events. Currently, only Phase II studies have been published demonstrating promising results in terms of efficacy, safety, and tolerability. From the results of the phase III studies, elagolix may become a valuable addition to the armamentarium of pharmacological agents to treat endometriosis-related pain.

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.

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

PHP-HT (VitaResc Biotech).

PubMed

Baldwin, A; Wiley, E

2001-04-01

VitaResc (formerly Apex) is developing PHP-HT, pyridoxalated hemoglobin polyoxyethylene conjugate, for the potential treatment of nitric oxide-induced shock (characterized by hypotension), associated with various etiologies, initially in septic shock. A phase I safety study and an initial phase I/II patient trial for NO-induced shock have been completed, and VitaResc has enrolled patients in three of five planned cohorts in a continuation of these trials to include a protocol of continuous infusion and dose escalation [330680,349187,390918]. The results from the dose escalation trials are expected to provide the basis for a randomized, controlled phase II/III pivotal trial of PHP-HT [390918]. VitaResc has licensed PHP-HT exclusively from Ajinomoto for all indications, worldwide, except Japan [275263]. Ajinomoto originally developed the human derived and chemically modified hemoglobin preparation as a blood substitute, but no development has been reported by the company since 1997 [275277,303577]. The other potential indications of PHP-HT include shock associated with burns, pancreatitis, hemodialysis and cytokine therapies [275277]. VitaResc expects the annual market potential of PHP-HT to exceed 1 billion dollars [330680].

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.

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].

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.

Interferon in chronic myeloid leukaemia: past and future.

PubMed

Guilhot, François; Roy, Lydia; Saulnier, Pierre-Jean; Guilhot, Joëlle

2009-09-01

Imatinib has revolutionized the therapy of chronic myeloid leukaemia. However the complete eradication of leukaemic stem cells is still a matter of discussion. Interferon (IFN) has been used in the past with success. However the proportion of patients who achieved sustained complete cytogenetic response was small. Recently, in addition to its direct antineoplastic effect and immunomodulatory activity, IFN has been shown to stimulate the quiescent leukaemic stem cells. Thus there is now a rational for combining Imatinib and IFN. Large prospective phase III trials are in good progress to demonstrate in humans the usefullness of a combination therapy using Imatinib and IFN.

Photometric geodesy of main-belt asteroids. III - Additional lightcurves

NASA Technical Reports Server (NTRS)

Weidenschilling, S. J.; Chapman, C. R.; Davis, D. R.; Greenberg, R.; Levy, D. H.

1990-01-01

A total of 107 complete or partial lightcurves are presented for 59 different asteroids over the 1982-1989 period. Unusual lightcurves with unequal minima and maxima at large amplitudes are preferentially seen for M-type asteroids. Some asteroids, such as 16 Psyche and 201 Penelope, exhibit lightcurves combining large amplitude with very unequal brightness for both maxima and both minima, even at small phase angles. An M-type asteroid is believed to consist of a metal core of a differentiated parent body that has had its rocky mantle completely removed by one or more large impacts.

Photometric geodesy of main-belt asteroids. III. Additional lightcurves

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

Weidenschilling, S.J.; Chapman, C.R.; Davis, D.R.

1990-08-01

A total of 107 complete or partial lightcurves are presented for 59 different asteroids over the 1982-1989 period. Unusual lightcurves with unequal minima and maxima at large amplitudes are preferentially seen for M-type asteroids. Some asteroids, such as 16 Psyche and 201 Penelope, exhibit lightcurves combining large amplitude with very unequal brightness for both maxima and both minima, even at small phase angles. An M-type asteroid is believed to consist of a metal core of a differentiated parent body that has had its rocky mantle completely removed by one or more large impacts. 39 refs.

Phase I/II Clinical Trial of Hyaluronan-Cisplatin Nanoconjugate for the Treatment of Spontaneous Canine Cancers

PubMed Central

Cai, Shuang; Zhang, Ti; Forrest, W.C.; Yang, Qiuhong; Groer, Chad; Mohr, Eva; Aires, Daniel J.; Axiak-Bechtel, Sandra M.; Flesner, Brian K.; Henry, Carolyn J.; Selting, Kimberly A.; Tate, Deborah; Swarz, Jeffrey A.; Bryan, Jeffrey N.; Forrest, M. Laird

2015-01-01

Objective To conduct an open label, multi-dose Phase I/II clinical study in spontaneous canine cancers and evaluate the pharmacokinetics, safety, and efficacy of the hyaluronan-based cisplatin formulation (HA-Pt). Animals 13 dogs with heterogeneous, naturally occurring cancers. Procedures The dogs received up to four injections of 10-30 mg/m2 HA-Pt into the tumor or peritumoral sub-mucosa at three-week intervals. Blood sample (2 mL) was collected from the jugular catheter at 0.5, 1, 2, 4, and 24 hours following drug administration. A complete blood count and renal profile with urinalysis were conducted prior to and one week after each treatment. Tumor measurements were collected three weeks following each administration to assess response. Results Of the 13 dogs with heterogeneous, naturally occurring cancers, 23% had complete response and 15% had partial response or stable disease. Among the dogs that received drug with low diaquated content, the complete response rate for SCC was 3/7 (43%). Myelosuppression and cardiac toxicity were observed for 38% and 19% of the dogs, respectively. The formulation did not cause nephrotoxicity, the dose-limiting toxicity of standard cisplatin, in any dogs. Conclusions and Clinical Relevance The HA-Pt formulation demonstrated positive response in spontaneous canine squamous cell carcinomas. It did not cause nephrotoxicity in any patients. Canine oral SCC is very homogenous in progression and drug response to human HNSCC, and these results could be useful in developing human treatments. PMID:27580113

Columbia River Basin Fish and Wildlife Program Annual Implementation Work Plan for Fiscal Year 1994.

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

United States. Bonneville Power Administration; Northwest Power Planning Council; Columbia Basin Fish and Wildlife Authority

1994-02-01

This document is part of Bonneville Power Administration`s program to protect, mitigate, and enhance fish and wildlife affected by the development and operation of hydroelectric facilities on the Columbia River and its tributaries. The Fiscal Year 1994 (FY 1994) Annual Implementation Work Plan (AIWP) presents Bonneville Power Administration`s (BPA`s) plan for implementation of the Columbia River Basin Fish and Wildlife Program (Program). The purpose of the Program is to guide BPA and other federal agencies in carrying out their responsibilities to protect, mitigate, and enhance fish and wildlife in the Columbia River Basin. Phase I began the work of salmonmore » recovery with certain fast-track measures completed in August 1991. Phase II dealt with Snake and Columbia river flow and salmon harvest and was completed in December 1991. Phase III dealt with system-wide habitat and salmon production issues and was completed in September 1992. Phase IV planning, focusing on resident fish and wildlife, began in August 1993, and was finished and adopted in November 1993. This report provides summaries of the ongoing and new projects for FY 1994 within the areas of juvenile migration, adult migration, salmon harvest, production and habitat, coordinated implementation, monitoring and evaluation, resident fish, and wildlife.« less

Differential repression of arylsulphatase synthesis in Aspergillus oryzae.

PubMed

Burns, G R; Wynn, C H

1977-09-15

1. The activities of the three arylsulphatases (arylsulphate sulphohydrolase, EC 3.1.6.1) of Aspergillus oryzae produced under a variety of repressing and non-repressing conditions were determined. 2. These enzymes exhibit different sensitivities to repression by inorganic sulphate. 3. Arylsulphatase I, but not arylsulphatases II and III, exhibits a transient de-repression in the early growth phase in sulphate media. 4. When the fungus is cultured in repressing media and subsequently transferred to non-repressing media, the synthesis of the three enzymes is non-co-ordinate. 5. Growth of the fungus in media containing choline O-sulphate or tyrosine O-sulphate as the sole source of sulphur results in complete de-repression of arylsulphatase I, But the synthesis of arylsulphatases II and III is essentially fully repressed. 6. The marked similarities between the repression characteristics of arylsulphatases II and III, contrasted with those of arylsulphatase I, indicate that the genetic locus of arylsulphatase I is distinct from that of arylsulphatases II and III, suggesting that there are distinct physiological roles for the enzyme.

Phase II study of the tetrahydropyranyl adriamycin-cyclophosphamide, vincristine, and prednisolone regimen combined with rituximab as first-line treatment for elderly patients with diffuse large B-cell lymphoma.

PubMed

Kasahara, Senji; Hara, Takeshi; Tsurumi, Hisashi; Goto, Naoe; Kitagawa, Jun-Ichi; Kanemura, Nobuhiro; Yoshikawa, Takeshi; Goto, Hideko; Fukuno, Kenji; Yamada, Toshiki; Sawada, Michio; Takahashi, Takeshi; Takami, Tsuyoshi; Moriwaki, Hisataka

2011-04-01

The anthracycline drug pirarubicin (tetrahydropyranyl adriamycin; THP) apparently has fewer cardiotoxic effects than doxorubicin. We previously described the benefit of the THP-COP regimen comprising cyclophosphamide, THP, vincristine, and prednisolone for elderly patients with diffuse large B-cell lymphoma (DLBCL). However, that study was completed before rituximab (R) was introduced into clinical practice. Here we report a phase II study of the THP-COP regimen combined with R (R-THP-COP) every 3 weeks. The complete response and 3-year overall survival rates was 63% and 53%, respectively, and no deaths were related to the regimen. We conclude that the R-THP-COP regimen is safe and effective for patients with DLBCL. Based on these results, a randomized controlled trial of rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and R-THP-COP as a phase III study is ongoing.

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

Numerical Simulation of High-Speed Turbulent Reacting Flows

NASA Technical Reports Server (NTRS)

Givi, P.; Taulbee, D. B.; Madnia, C. K.; Jaberi, F. A.; Colucci, P. J.; Gicquel, L. Y. M.; Adumitroaie, V.; James, S.

1999-01-01

The objectives of this research are: (1) to develop and implement a new methodology for large eddy simulation of (LES) of high-speed reacting turbulent flows. (2) To develop algebraic turbulence closures for statistical description of chemically reacting turbulent flows. We have just completed the third year of Phase III of this research. This is the Final Report of our activities on this research sponsored by the NASA LaRC.

Technology evaluation: adalimumab, Abbott laboratories.

PubMed

Lorenz, Hanns M

2002-04-01

Adalimumab (D2E7), a human monoclonal antibody that binds to and neutralizes TNFa, is being developed by Abbott (formerly Knoll), under license from Cambridge Antibody Technology (CAT), for the potential treatment of inflammatory disorders such as rheumatoid arthritis (RA) and Crohn's disease. It is also being investigated for the potential treatment of coronary heart disease. Phase II studies for Crohn's disease and phase III for RA were ongoing throughout 2001. Limited data are only available for RA. In January 2002, it was reported that phase III trials of adalimumab for RA had been completed, but details have not been published in the primary literature so far. At this time CAT and Abbott expected to file for US approval in the second quarter of 2002 with a launch date anticipated for 2003. Phase III data are expected to be presented at the European League Against Rheumatism meeting in June 2002. In November 2000, Lehman Brothers predicted a US launch in June 2002 with peak US sales of $600 million in 2007 and a launch in non-US markets in 2003 with peak sales in these markets of $300 million in 2008. In December 2000, Merrill Lynch predicted regulatory clearance in the second half of 2003. The probability of adalimumab reaching the market is estimated to be 70%. In December 2000, Merrill Lynch predicted a 2003 launch, with estimated sales of pounds sterling 3.65 million in that year rising to pounds sterling 30.14 million in 2010. In March 2001, ABN AMRO predicted sales of $73 million in 2003 rising to $392 million in 2007.

The Novel Antipsychotic Cariprazine (RGH-188): State-of-the-Art in the Treatment of Psychiatric Disorders.

PubMed

De Berardis, Domenico; Orsolini, Laura; Iasevoli, Felice; Prinzivalli, Emiliano; de Bartolomeis, Andrea; Serroni, Nicola; Mazza, Monica; Valchera, Alessandro; Fornaro, Michele; Vecchiotti, Roberta; Carano, Alessandro; Sepede, Gianna; Vellante, Federica; Matarazzo, Ilaria; Pompili, Maurizio; Perna, Giampaolo; Conti, Chiara; Segura-García, Cristina; Martinotti, Giovanni; Di Giannantonio, Massimo

2016-01-01

Cariprazine (RGH-188) is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3 receptors with preferential binding to D3 receptor, antagonism of 5HT2B receptors and partial agonism of 5HT1A. Currently, cariprazine is in late-stage clinical development (phase III clinical trials) in patients with schizophrenia (S) and in patients with bipolar disorder (BD), as well as an adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. Cariprazine has completed phase III trials for the acute treatment of schizophrenia and bipolar mania, phase II trials for the bipolar depression and MDD whilst it is undergoing phase III trials as an adjunct to antidepressants. The present review aims at proving a comprehensive summary of the current evidence on the safety, tolerability and efficacy of cariprazine in the treatment of schizophrenia, BD (manic/mixed/ depressive episode) and MDD. A systematic search was conducted on PubMed/Medline/ Scopus and the database on Clinical Trials from inception until April 2015 by typing a set of specified keywords. Available evidence seems to support cariprazine efficacy in the treatment of cognitive and negative symptoms of schizophrenia. Preliminary findings suggest its antimanic activity whilst it is still under investigation its efficacy in the treatment of bipolar depression and MDD. Furthermore, the available data seems not to allow judgements about its antipsychotic potential in comparison with currently prescribed antipsychotics. Further studies should be carried out to better investigate its pharmacodynamic and clinical potential, particularly as alternative to current antipsychotic drugs.

A Phase I Trial of Samarium-153-Lexidronam Complex for Treatment of Clinically Nonmetastatic High-Risk Prostate Cancer: First Report of a Completed Study

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

Valicenti, Richard K., E-mail: richard.valicenti@ucdmc.ucdavis.ed; Trabulsi, Edouard; Intenzo, Charles

Purpose: We completed a Phase I trial to determine the maximum tolerated dose of samarium-153 EDTMP ({sup 153}Sm) with hormonal therapy (HT) and radiation therapy (RT) in high-risk clinically nonmetastatic prostate cancer. Methods and Materials: High-risk M0 prostate cancer patients (prostate-specific antigen >20 ng/mL, Gleason score >7, or >T3) were eligible for this prospective trial of dose-escalated radioactive {sup 153}Sm-EDTMP (.25-2.0 mCi/kg) as primary or postoperative therapy. After 1 month of HT, we administered {sup 153}Sm-EDTMP followed by 4 more months of HT, 46.8 Gy to the pelvic region and 23.4 Gy to the prostate target (TD = 70.2 Gy).more » The primary endpoint was Grade III toxicity or higher by the National Cancer Institute Common Toxicity Criteria. Results: Twenty-nine patients enrolled (median prostate-specific antigen = 8.2 ng/mL, 27/29 (93%) T stage {>=}T2b, 24/29 (83%) had Gleason >7) and received {sup 153}Sm-EDTMP (.25 mCi/kg, 4 patients; 0.5 mCi/kg, 4 patients; 0.75 mCi/kg, 6 patients; 1.0 mCi/kg, 6 patients; 1.5 mCi/kg, 5 patients; 2.0mCi/kg, 4 patients). Twenty-eight patients underwent all planned therapy without delays (1 patient required surgery before the start of RT). With a median follow-up time of 23 months, there were 2 patients (7 %) experiencing Grade III hematologic toxicity. There were no other Grade III or IV side effects. Conclusions: Our trial demonstrates that 2 mCi/kg {sup 153}Sm -EDTMP with HT and RT was safe and feasible in men with high-risk M0 prostate cancer. A Phase II study to test this treatment is currently underway by the Radiation Therapy Oncology Group.« less

Is clarithromycin a potential treatment for cachexia in people with lung cancer? A feasibility study.

PubMed

Awan, Sarah; Crosby, Vincent; Potter, Vanessa; Hennig, Ivo; Baldwin, David; Ndlovu, Mehluli; Paradine, Sharon; Wilcock, Andrew

2017-02-01

Clarithromycin may improve cachexia and survival in non-small cell lung cancer (NSCLC), but adequately controlled data are lacking. This study was undertaken primarily to inform the feasibility and scale of a phase III trial. Eligible consenting patients with stage IV NSCLC and cachexia were to be randomized to receive either clarithromycin 250mg twice daily or placebo for eight weeks. Aspects of trial feasibility recorded included numbers eligible, approached and recruited, together with adherence and completion of treatment and assessments. Over 6 months, none of 125 patients identified fulfilled the entry criteria. The commonest reasons for ineligibility were the use of an excluded concurrent drug (45, 36%), brain metastases (22, 18%), poor performance status (21, 17%) and current chemotherapy (15, 12%). A phase III trial of clarithromycin using these entry criteria is not feasible in this setting. Other macrolides that have a lower risk of a drug-drug interaction may be more practical to pursue. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Can Supported Reduced Vanadium Oxides form H2 from CH3OH? A Computational Gas-Phase Mechanistic Study.

PubMed

González-Navarrete, Patricio; Andrés, Juan; Calatayud, Monica

2018-02-01

A detailed density functional theory study is presented to clarify the mechanistic aspects of the methanol (CH 3 OH) dehydrogenation process to yield hydrogen (H 2 ) and formaldehyde (CH 2 O). A gas-phase vanadium oxide cluster is used as a model system to represent reduced V(III) oxides supported on TiO 2 catalyst. The theoretical results provide a complete scenario, involving several reaction pathways in which different methanol adsorption sites are considered, with presence of hydride and methoxide intermediates. Methanol dissociative adsorption process is both kinetically and thermodynamically feasible on V-O-Ti and V═O sites, and it might lead to form hydride species with interesting catalytic reactivity. The formation of H 2 and CH 2 O on reduced vanadium sites, V(III), is found to be more favorable than for oxidized vanadium species, V(V), taking place along energy barriers of 29.9 and 41.0 kcal/mol, respectively.

San Marco D/L Explorer

NASA Technical Reports Server (NTRS)

1988-01-01

ti March 26, 1964, Centro Ricerche Aerospaziali (CRA) successfully launched a two-stage Nike sounding rocket from the Santa Rita launch platform off the Kenya coast, concluding Phase I. It carried basic elements of the San Marco science instrumentation and served further to flight qualify these canponents as well as provide a means of check-out of range instrumentation and equipment. The second phase culminated in the launch of the San Marco-I Spacecraft fran Wallops Island on a Scout vehicle on December 15, 1964. This launch derronstrated the readiness of the CRA launch crews for Phase III operations and qualified the basic spacecraft design. In addition it confirmed the usefulness and reliability of the drag balance device for accurate determinations of air density values and satellite attitude. phase III was completed with the launching of San Marco-11 frcm the San Marco platform off the coast of Kenya on April 26, 1967. ?he San Marco-II carried the same instrunentation as the San Marco-I, but the equatorial orbit permitted a more detailed study to be made of density variations versus altitude in the equatorial region. Ihe successful launch also served to qualify the San Marco Range as a reliable facility for future satellite launches. The successful culmination of the first San Marco endeavor paved the way for still closer collaboration in future space explorations.

The Clinical Development of Molecularly Targeted Agents in Combination With Radiation Therapy: A Pharmaceutical Perspective

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

Ataman, Ozlem U., E-mail: ouataman@hotmail.com; Sambrook, Sally J.; Wilks, Chris

2012-11-15

Summary: This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the (clinicaltrials.gov) Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, andmore » PubMed databases and then cross-correlated with (clinicaltrials.gov) protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such trials are not given priority by pharmaceutical companies. The potential reasons for this and some challenges and possible solutions are discussed.« less

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...

Future Perspectives on Baryon Form Factor Measurements with BES III

NASA Astrophysics Data System (ADS)

Schönning, Karin; Li, Cui

2017-03-01

The electromagnetic structure of hadrons, parameterised in terms of electromagnetic form factors, EMFF's, provide a key to the strong interaction. Nucleon EMFF's have been studied rigorously for more than 60 years but the new techniques and larger data samples available at modern facilities have given rise to a renewed interest for the field. Recently, the access to hyperon structure by hyperon time-like EMFF provides an additional dimension. The BEijing Spectrometer (BES III) at the Beijing Electron Positron Collider (BEPC-II) in China is the only running experiment where time-like baryon EMFF's can be studied in the e+e- → BB̅ reaction. The BES III detector is an excellent tool for baryon form factor measurements thanks to its near 4π coverage, precise tracking, PID and calorimetry. All hyperons in the SU(3) spin 1/2 octet and spin 3/2 decuplet are energetically accessible within the BEPC-II energy range. Recent data on proton and Λ hyperon form factors will be presented. Furthermore, a world-leading data sample was collected in 2014-2015 for precision measurements of baryon form factors. In particular, the data will enable a measurement of the relative phase between the electric and the magnetic form factors for Λ and Λc+ and hyperons. The modulus of the phase can be extracted from the hyperon polarisation, which in turn is experimentally accessible via the weak, parity violating decay. Furthermore, from the spin correlation between the outgoing hyperon and antihyperon, the sign of the phase can be extracted. This means that the time-like form factors can be completely determined for the first time. The methods will be outlined and the prospects of the BES III form factor measurements will be given. We will also present a planned upgrade of the BES III detector which is expected to improve future form factor measurements.

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).

The effects of stimulated star formation on the evolution of the galaxy. III - The chemical evolution of nonlinear systems

NASA Technical Reports Server (NTRS)

Shore, Steven N.; Ferrini, Federico; Palla, Francesco

1987-01-01

The evolution of models for star formation in galaxies with disk and halo components is discussed. Two phases for the halo (gas and stars) and three for the disk (including clouds) are used in these calculations. The star-formation history is followed using nonlinear phase-coupling models which completely determine the populations of the phases as a function of time. It is shown that for a wide range of parameters, including the effects of both spontaneous and stimulated star formation and mass exchange between the spatial components of the system, the observed chemical history of the galaxy can easily be obtained. The most sensitive parameter in the detailed metallicity and star-formation history for the system is the rate of return of gas to the diffuse phase upon stellar death.

An international study to revise the EORTC questionnaire for assessing quality of life in lung cancer patients.

PubMed

Koller, M; Hjermstad, M J; Tomaszewski, K A; Tomaszewska, I M; Hornslien, K; Harle, A; Arraras, J I; Morag, O; Pompili, C; Ioannidis, G; Georgiou, M; Navarra, C; Chie, W-C; Johnson, C D; Himpel, A; Schulz, C; Bohrer, T; Janssens, A; Kulis, D; Bottomley, A

2017-11-01

The European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 was the first module to be used in conjunction with the core questionnaire, the QLQ-C30. Since the publication of the LC13 in 1994, major advances have occurred in the treatment of lung cancer. Given this, an update of the EORTC QLQ-LC13 was undertaken. The study followed phases I to III of the EORTC Module Development Guidelines. Phase I generated relevant quality-of-life issues using a mix of sources including the involvement of 108 lung cancer patients. Phase II transformed issues into questionnaire items. In an international multicenter study (phase III), patients completed both the EORTC QLQ-C30 and the 48-item provisional lung cancer module generated in phases I and II. Patients rated each of the items regarding relevance, comprehensibility, and acceptance. Patient ratings were assessed against a set of prespecified statistical criteria. Descriptive statistics and basic psychometric analyses were carried out. The phase III study enrolled 200 patients with histologically confirmed lung cancer from 12 centers in nine countries (Cyprus, Germany, Italy, Israel, Spain, Norway, Poland, Taiwan, and the UK). Mean age was 64 years (39 - 91), 59% of the patients were male, 82% had non-small-cell lung cancer, and 56% were treated with palliative intent. Twenty-nine of the 48 questions met the criteria for inclusion. The resulting module with 29 questions, thus currently named EORTC QLQ-LC29, retained 12 of the 13 original items, supplemented with 17 items that primarily assess treatment side-effects of traditional and newer therapies. © 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.

Comparison of futility monitoring guidelines using completed phase III oncology trials.

PubMed

Zhang, Qiang; Freidlin, Boris; Korn, Edward L; Halabi, Susan; Mandrekar, Sumithra; Dignam, James J

2017-02-01

Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study. We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group. We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales. For negative studies, our results show that the futility approaches based on testing the alternative hypothesis and repeated confidence interval rules yielded less savings (compared to the other two rules). These boundaries are too conservative, especially during the first half of the study (<50% of information). The conditional power rules are too aggressive during the second half of the study (>50% of information) and may stop a trial even when there is a clinically meaningful treatment effect. The linear inefficacy boundary with three or more interim analyses provided the best results. For positive studies, we demonstrated that none of the futility rules would have stopped the trials. The linear inefficacy boundary futility approach is attractive from statistical, clinical, and logistical standpoints in clinical trials evaluating new anti-cancer agents.

A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations.

PubMed

Fiedler, Walter; Kayser, Sabine; Kebenko, Maxim; Janning, Melanie; Krauter, Jürgen; Schittenhelm, Marcus; Götze, Katharina; Weber, Daniela; Göhring, Gudrun; Teleanu, Veronica; Thol, Felicitas; Heuser, Michael; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut; Schlenk, Richard F

2015-06-01

Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara-C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara-C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity (DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level -1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones. © 2015 John Wiley & Sons Ltd.

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

PubMed

Richardson, Paul G; Soiffer, Robert J; Antin, Joseph H; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L; Steinbach, Gideon; Murray, Karen F; Vogelsang, Georgia B; Chen, Allen R; Krishnan, Amrita; Kernan, Nancy A; Avigan, David E; Spitzer, Thomas R; Shulman, Howard M; Di Salvo, Donald N; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L J; Iacobelli, Massimo; McDonald, George B; Guinan, Eva C

2010-07-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

APF530 versus ondansetron, each in a guideline-recommended three-drug regimen, for the prevention of chemotherapy-induced nausea and vomiting due to anthracycline plus cyclophosphamide–based highly emetogenic chemotherapy regimens: a post hoc subgroup analysis of the Phase III randomized MAGIC trial

PubMed Central

Schnadig, Ian D; Agajanian, Richy; Dakhil, Christopher; Gabrail, Nashat; Vacirca, Jeffrey; Taylor, Charles; Wilks, Sharon; Braun, Eduardo; Mosier, Michael C; Geller, Robert B; Schwartzberg, Lee; Vogelzang, Nicholas

2017-01-01

Background APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial. Patients and methods This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (≤16 mg); stratification was by planned cisplatin ≥50 mg/m2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24–120 hours) complete response (CR). Results APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0–120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population. Conclusion APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging. PMID:28579832

International field testing of the psychometric properties of an EORTC quality of life module for oral health: the EORTC QLQ-OH15.

PubMed

Hjermstad, Marianne J; Bergenmar, Mia; Bjordal, Kristin; Fisher, Sheila E; Hofmeister, Dirk; Montel, Sébastien; Nicolatou-Galitis, Ourania; Pinto, Monica; Raber-Durlacher, Judith; Singer, Susanne; Tomaszewska, Iwona M; Tomaszewski, Krzysztof A; Verdonck-de Leeuw, Irma; Yarom, Noam; Winstanley, Julie B; Herlofson, Bente B

2016-09-01

This international EORTC validation study (phase IV) is aimed at testing the psychometric properties of a quality of life (QoL) module related to oral health problems in cancer patients. The phase III module comprised 17 items with four hypothesized multi-item scales and three single items. In phase IV, patients with mixed cancers, in different treatment phases from 10 countries completed the EORTC QLQ-C30, the QLQ-OH module, and a debriefing interview. The hypothesized structure was tested using combinations of classical test theory and item response theory, following EORTC guidelines. Test-retest assessments and responsiveness to change analysis (RCA) were performed after 2 weeks. Five hundred seventy-two patients (median age 60.3, 54 % females) were analyzed. Completion took <10 min for 84 %, 40 % expressed satisfaction that these issues were addressed. Analyses suggested a revision of the phase III hypothesized scale structure. Two items were deleted based on a high degree of item misfit, together with negative patient feedback. The remaining 15 items formed one eight-item scale named OH-QoL score, a two-item information scale, a two-item scale regarding dentures, and three single items (sticky saliva/mouth soreness/sensitivity to food/drink). Face and convergent validity and internal consistency were confirmed. Test-retest reliability (n = 60) was demonstrated as was RCA for patients undergoing chemotherapy (n = 117; p = 0.06). The resulting QLQ-OH15 discriminated between clinically distinct patient groups, e.g., low performance status vs. higher (p < 000.1), and head-and-neck cancer versus other cancers (p < 0.03). The EORTC module QLQ-OH15 is a short, well-accepted assessment tool focusing on oral problems and QoL to improve clinical management. ClinicalTrials.gov Identifier: NCT01724333.

Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma

PubMed Central

Ogura, Michinori; Tobinai, Kensei; Hatake, Kiyohiko; Ishizawa, Kenichi; Uike, Naokuni; Uchida, Toshiki; Suzuki, Tatsuya; Aoki, Tomohiro; Watanabe, Takashi; Maruyama, Dai; Yokoyama, Masahiro; Takubo, Takatoshi; Kagehara, Hideaki; Matsushima, Takafumi

2014-01-01

Brentuximab vedotin is an antibody–drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21-day cycle up to 16 cycles. In the phase I part of a dose-escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large-cell lymphoma). The median number of treatment cycles was 16 (range, 4–16). In the phase I part, no dose-limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large-cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111650). This phase I/II study was to investigate the tolerability, safety and efficacy of brentuximab vedotin. This study indicates that 1.8 mg/kg brentuximab vedotin given every 3 weeks has a manageable safety profile and has high overall tumor response rate in Japanese patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. PMID:24814862

Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications.

PubMed

Shepshelovich, D; Goldvaser, H; Wang, L; Abdul Razak, A R; Bedard, P L

2017-12-01

Background Data on completeness of reporting of phase I cancer clinical trials in publications are lacking. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with the ClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications and ClinicalTrials.gov were recorded. Linear regression was used to identify factors associated with incomplete reporting. Results After a review of 583 trials in ClinicalTrials.gov , 163 matching primary publications were identified. Publications reported outcomes that did not appear in ClinicalTrials.gov in 25% of trials. Outcomes were upgraded, downgraded or omitted in publications in 47% of trials. The overall median reporting score was 23/28 (interquartile range 21-25). Incompletely reported items in >25% publications were: inclusion criteria (29%), primary outcome definition (26%), secondary outcome definitions (53%), adverse events (71%), serious adverse events (80%) and dates of study start and database lock (91%). Higher reporting scores were associated with phase I (vs phase I/II) trials (p<0.001), multicenter trials (p<0.001) and publication in journals with lower impact factor (p=0.004). Conclusions Reported results in primary publications for early phase cancer trials are frequently inconsistent or incomplete compared with ClinicalTrials.gov entries. ClinicalTrials.gov may provide more comprehensive data from new cancer drug trials.

Phase I/II Study of Erlotinib Combined With Cisplatin and Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

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

Herchenhorn, Daniel, E-mail: herchenhorn@hotmail.co; Dias, Fernando L.; Viegas, Celia M.P.

Purpose: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials: In this Phase I/II trial 100 mg/m{sup 2} of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuingmore » during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase II was initiated 8 weeks after the last Phase I enrollment. Results: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase II dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months' follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC.« less

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.

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.

Advanced Microwave Ferrite Research (AMFeR): Phase Two

DTIC Science & Technology

2006-12-31

motion for the single crystal LPE films were a qualitative success, but a complete set of parameters for these films has not yet been achieved. Key...biasing field. In order to address these issues, we investigated and optimized a new LPE flux system to grow high quality thick films and bulk single...self-biased circulators. III. Methodology: BaM thick film and bulk single crystal growth by LPE process BaFe 120 19 flux melt was prepared from a

Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study.

PubMed

Boccia, Ralph V; Gordan, Lucio N; Clark, Gemma; Howell, Julian D; Grunberg, Steven M

2011-10-01

A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV). Six hundred forty-one patients were randomized to oral (2 mg/day, 3-5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi-day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%. Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, -5%; 95% confidence interval, -13-3). Both treatments were well tolerated, the most common adverse event being constipation. The GTDS provides effective, well-tolerated control of CINV associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron.

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...

A single-blinded, randomized, parallel group superiority trial investigating the effects of footwear and custom foot orthoses versus footwear alone in individuals with patellofemoral joint osteoarthritis: a phase II pilot trial protocol.

PubMed

Wyndow, Narelle; Crossley, Kay M; Vicenzino, Bill; Tucker, Kylie; Collins, Natalie J

2017-01-01

Patellofemoral joint osteoarthritis is a common condition, yet information regarding conservative management is lacking. Foot orthoses are an effective intervention for improving pain and function in younger individuals with patellofemoral pain and may be effective in those with patellofemoral osteoarthritis. This pilot study will seek to establish the feasibility of a phase III randomised controlled trial to investigate whether foot orthoses worn in prescribed motion controlled footwear are superior to prescribed motion control footwear alone in the management of patellofemoral osteoarthritis. This phase II pilot clinical trial is designed as a randomized, single-blind, parallel group, two arm, superiority trial. The trial will recruit 44 participants from Queensland and Tasmania, Australia. Volunteers aged 40 years and over must have clinical symptoms and radiographic evidence of patellofemoral osteoarthritis to be eligible for inclusion. Those eligible will be randomized to receive either foot orthoses and prescribed motion control shoes, or prescribed motion control shoes alone, to be worn for a period of 4 months. The feasibility of a phase III clinical trial will be evaluated by assessing factors such as recruitment rate, number of eligible participants, participant compliance with the study protocol, adverse events, and drop-out rate. A secondary aim of the study will be to determine completion rates and calculate effect sizes for patient reported outcome measures such as knee-related symptoms, function, quality of life, kinesiophobia, self-efficacy, general and mental health, and physical activity at 2 and 4 months. Primary outcomes will be reported descriptively while effect sizes and 95% confidence intervals will be calculated for the secondary outcome measures. Data will be analysed using an intention-to-treat principle. The results of this pilot trial will help determine the feasibility of a phase III clinical trial investigating whether foot orthoses plus motion control footwear are superior to motion control footwear alone in individuals with patellofemoral osteoarthritis. A Phase III clinical trial will help guide footwear and foot orthoses recommendations in the clinical management of this disorder. Retrospectively registered with the Australian New Zealand Clinical Trials Registry: ACTRN12615000002583. Date registered: 07/01/15.

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.

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.

Reactive sputter deposition of metal oxide nanolaminates

NASA Astrophysics Data System (ADS)

Rubin Aita, Carolyn

2008-07-01

We discuss the reactive sputter deposition of metal oxide nanolaminates on unheated substrates using four archetypical examples: ZrO2 Al2O3, HfO2 Al2O3, ZrO2 Y2O3, and ZrO2 TiO2. The pseudobinary bulk phase diagrams corresponding to these nanolaminates represent three types of interfaces. I. Complete immiscibility (ZrO2 Al2O3 and HfO2 Al2O3). II. Complete miscibility (ZrO2 Y2O3). III. Limited miscibility without a common end-member lattice (ZrO2 TiO2). We found that, although reactive sputter deposition is a far-from-equilibrium process, thermodynamic considerations strongly influence both phase formation within layers and at interfaces. We show that pseudobinary phase diagrams can be used to predict interfacial cation mixing in the nanolaminates. However, size effects must be considered to predict specific structures. In the absence of pseudoepitaxy, size effects play a significant role in determining the nanocrystalline phases that form within a layer (e.g. tetragonal ZrO2, tetragonal HfO2, and orthorhombic HfO2) and at interfaces (e.g. monoclinic (Zr,Ti)O2). These phases are not bulk standard temperature and pressure phases. Their formation is understood in terms of self-assembly into the lowest energy structure in individual critical nuclei.

Reduction and Simultaneous Removal of 99 Tc and Cr by Fe(OH) 2 (s) Mineral Transformation

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

Saslow, Sarah A.; Um, Wooyong; Pearce, Carolyn I.

Technetium (Tc) remains a priority remediation concern due to persistent challenges, including rapid re-oxidation of immobilized Tc, and competing contaminants, e.g. Cr(VI), that inhibit targeted Tc reduction and incorporation into stable mineral phases. Here Fe(OH) 2(s) is investigated as a comprehensive solution for overcoming these challenges, by serving as both the reductant, (Fe(II)), and immobilization agent to form Tc-incorporated magnetite (Fe 3O 4). Trace metal analysis suggests removal of Tc(VII) and Cr(VI) from solution occurs simultaneously; however, complete removal and reduction of Cr(VI) is achieved earlier than the removal/reduction of co-mingled Tc(VII). Bulk oxidation state analysis of the magnetite solidmore » phase by XANES confirms that the majority of Tc is Tc(IV), which is corroborated by XPS. Furthermore, EXAFS results show successful Tc(IV) incorporation into magnetite octahedral sites without additional substitution of Cr or Tc into neighboring Fe octahedral sites. XPS analysis of Cr confirms reduction to Cr(III) and the formation of a Cr-incorporated spinel, Cr2O 3, and Cr(OH)3 phases. Spinel (modeled as Fe 3O 4), goethite, and feroxyhyte are detected in all reacted solid phase samples analyzed by XRD, where Tc(IV) incorporation has little effect on the spinel lattice structure. In the presence of Cr(III) a spinel phase along the magnetite-chromite (Fe 3O 4-FeCr 2O 4) solid-solution line is formed.« less

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.

[Risk factors associated with the diagnosis of chronic Chagasic miocardiopathy in seropositive individuals from Barinas state, Venezuela].

PubMed

González, Beatriz; Silva, Martha; Al-Atrache, Yusra; Delgado, Yelitze; Serrano, José Luis; Doccimo, Angelina; Hernández, Huber; Verde, Juan; Morillo, Daniela; Marín, Jaime; Concepción, Juan Luis; Bonfante-Cabarcas, Rafael; Rodríguez-Bonfante, Claudina

2014-06-01

This study evaluates the risk factors associated with the diagnosis of chronic chagasic miocardiopathy (CChM) in 115 seropositive individuals to anti-Trypanosoma cruzi antibodies, in Barinas state, Venezuela. Serology was performed with ELISA and MABA; while the CChM diagnosis was established by electrocardiography and echocardiography. A complete clinical history including epidemiological, personal/familiar antecedents and psychobiological habits, plus socioeconomic, psychosocial and alimentary habits interviews were performed for each individual. Risk factors were determined through binary logistic regression. Results showed that 81 patients (70,4%; CI 95% = 66.4-74.4) had criteria for CChM, of which 74 (64.4%; IC 95% = 60.2-68.6) were in phase II; while 34 (29.6%; IC 95% = 25.5-33.5) were in phase I of the disease and 7 (6.1%; IC 95% = 4.0-8.2) in phase III. In a one year period, two patients in phase III died of heart failure. The diagnosis of CChM was associated with hunting practice, maternal history of cardiopathies, chewing chimó, medical history of hypertension and apex beat visible; it was negatively associated with canned and preserved foods ingest. In conclusion the CChM diagnosis has high frequency in seropositive individuals in Barinas and heart failure prevention must be based on an early medical attention and educative strategies in order to control risk factors.

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.

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.

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).

Design and evaluation of a computer tutorial on electric fields

NASA Astrophysics Data System (ADS)

Morse, Jeanne Jackson

Research has shown that students do not fully understand electric fields and their interactions with charged particles after completing traditional classroom instruction. The purpose of this project was to develop a computer tutorial to remediate some of these difficulties. Research on the effectiveness of computer-delivered instructional materials showed that students would learn better from media incorporating user-controlled interactive graphics. Two versions of the tutorial were tested. One version used interactive graphics and the other used static graphics. The two versions of the tutorial were otherwise identical. This project was done in four phases. Phases I and II were used to refine the topics covered in the tutorial and to test the usability of the tutorial. The final version of the tutorial was tested in Phases III and IV. The tutorial was tested using a pretest-posttest design with a control group. Both tests were administered in an interview setting. The tutorial using interactive graphics was more effective at remediating students' difficulties than the tutorial using static graphics for students in Phase III (p = 0.001). In Phase IV students who viewed the tutorial with static graphics did better than those viewing interactive graphics. The sample size in Phase IV was too small for this to be a statistically meaningful result. Some student reasoning errors were noted during the interviews. These include difficulty with the vector representation of electric fields, treating electric charge as if it were mass, using faulty algebraic reasoning to answer questions involving ratios and proportions, and using Coulomb's law in situations in which it is not appropriate.

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.

Working With Parents to Prevent Childhood Obesity: Protocol for a Primary Care-Based eHealth Study

PubMed Central

Avis, Jillian LS; Cave, Andrew L; Donaldson, Stephanie; Ellendt, Carol; Holt, Nicholas L; Jelinski, Susan; Martz, Patricia; Maximova, Katerina; Padwal, Raj; Wild, T Cameron

2015-01-01

Background 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. Objective (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. Methods 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). Results 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. Conclusions 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. Trial Registration ClinicalTrials.gov NCT02330588; http://clinicaltrials.gov/ct2/show/NCT02330588 (Archived by WebCite at http://www.webcitation.org/6WyUOeRlr). PMID:25831265

Set-up of an XAFS beamline for measurements between 2.4-8 keV at DORIS III

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

Welter, Edmund

2010-06-23

In this paper results from the commissioning phase and from first user experiments of a new EXAFS beamline at the DORIS III storage ring are presented. The bending magnet EXAFS beamline A1 underwent a complete rebuild and now covers the energy range 2.4-8 keV. A Ni-coated toroidal mirror, placed in a 2:1 focusing position and a plane mirror with one Ni coated stripe and one uncoated (SiO{sub 2}) stripe are used for effective higher harmonics suppression and focusing. The UHV-compatible fixed-exit Double Crystal Monochromator (DCM) is equipped with two Si(111) crystal pairs. The second crystal of one of the twomore » crystal pairs is tilted by 90 deg. around the surface normal to shift the position of glitches. It allows Bragg angles between 5 deg. and 55.5 deg. and continuous scans in quick-EXAFS mode. Test measurements during the commissioning phase proved the excellent performance of the monochromator and a high quality of the XAFS spectra over the entire working range.« less

Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease and Multiorgan Failure after Stem Cell Transplantation: A Multicenter, Randomized, Dose-Finding Trial

PubMed Central

Richardson, Paul G.; Soiffer, Robert J.; Antin, Joseph H.; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L.; Steinbach, Gideon; Murray, Karen F.; Vogelsang, Georgia B.; Chen, Allen R.; Krishnan, Amrita; Kernan, Nancy A.; Avigan, David E.; Spitzer, Thomas R.; Shulman, Howard M.; Di Salvo, Donald N.; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L. J.; Iacobelli, Massimo; McDonald, George B.; Guinan, Eva C.

2010-01-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for ≥ 14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day + 100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day + 100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD. PMID:20167278

Schwertmannite stability in anoxic Fe(II)-rich aqueous solution

NASA Astrophysics Data System (ADS)

Paikaray, Susanta; Schröder, Christian; Peiffer, Stefan

2017-11-01

Schwertmannite (SHM) is a powerful scavenger for As(III) leading to As(III)-enriched precipitates around acid mine drainage environments that may become exposed to aqueous Fe(II). In this study we have investigated the stability of pure SHM and SHM containing 0.92 wt% As(III) under Fe(II)aq-rich (0.4-1.0 mM) anoxic conditions using XRD, SEM, Mössbauer and FTIR spectroscopic techniques. Schwertmannite transformation proceeded through an alkalinity-driven pathway releasing sulfate and a Fe(II)-catalyzed pathway that generated lepidocrocite and goethite at pH 6 and 6.9 in the presence of 1 mM Fe(II)aq. Lepidocrocite was found to be needle shaped if the SHM contained As(III) and platy for pure SHM. Goethite had a poor degree of crystallinity in As(III) containing SHM. Pre-adsorption of As(III) inhibited the extent of SHM transformation. Fe(II) sorption onto SHM was pH dependent and reflected a sorption edge with complete consumption at pH 6.9, while only ∼20% were adsorbed at pH 5. Surface coverage with Fe(II) appears to be the key parameter controlling extent and products of the transformation process. As(III) concentrations in solution are controlled by two mechanisms: (1) exchange of As(III) for sulfate upon alkalinity-driven transformation of schwertmannite and (2) re-adsorption to new phases formed upon Fe(II)-catalyzed transformation. The adsorbed As(III) has inhibited the extent of transformation and was partly released with the maximum release at pH 5 (0.5%) in the absence of Fe(II)aq.

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.

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.

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.

Comparison of reporting phase III randomized controlled trials of antibiotic treatment for common bacterial infections in ClinicalTrials.gov and matched publications.

PubMed

Shepshelovich, D; Yelin, D; Gafter-Gvili, A; Goldman, S; Avni, T; Yahav, D

2018-02-15

Discrepancies between ClinicalTrials.gov entries and matching publications were previously described in general medicine. We aimed to evaluate the consistency of reporting in trials addressing systemic antibiotic therapy. We searched ClinicalTrials.gov for completed phase III trials comparing antibiotic regimens until May 2017. Matched publications were identified in PubMed. Two independent reviewers extracted data and identified inconsistencies. Reporting was assessed among studies started before and after 1 July 2005, when the International Committee of Medical Journal Editors (ICMJE) required mandatory registration as a prerequisite for considering a trial for publication. Matching publications were identified for 75 (70%) of 107 ClinicalTrials.gov entries. Median time from study completion to publication was 26 months (interquartile range 19-42). Primary outcome definition was inconsistent between ClinicalTrials.gov and publications in seven trials (7/72, 10%) and reporting of the primary outcome timeframe was inconsistent in 14 (14/71, 20%). Secondary outcomes definitions were inconsistent in 36 trials (36/66, 55%). Reporting of inclusion criteria and study timeline were inconsistent in 17% (13/65) and 3% (2/65), respectively. Trials started after July 2005 were significantly less likely to have reporting inconsistencies and were published in higher impact factor journals. We found a lower inconsistency rate of outcome reporting compared with other medical disciplines. Reporting completeness and consistency were significantly better after July 2005. The ICMJE requirement for mandatory registration was associated with significant improvement in reporting quality in infectious diseases trials. Prolonged time lag to publication and missing data from unpublished trials should raise a discussion on current reporting and publishing procedures. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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.

Therapeutic cancer vaccines: are we there yet?

PubMed Central

Klebanoff, Christopher A.; Acquavella, Nicholas; Yu, Zhiya; Restifo, Nicholas P.

2011-01-01

Summary Enthusiasm for therapeutic cancer vaccines has been rejuvenated with the recent completion of several large, randomized phase III clinical trials that in some cases have reported an improvement in progression free or overall survival. However, an honest appraisal of their efficacy reveals modest clinical benefit and a frequent requirement for patients with relatively indolent cancers and minimal or no measurable disease. Experience with adoptive cell transfer-based immunotherapies unequivocally establishes that T cells can mediate durable complete responses, even in the setting of advanced metastatic disease. Further, these findings reveal that the successful vaccines of the future must confront (i) a corrupted tumor microenvironment containing regulatory T cells and aberrantly matured myeloid cells, (ii) a tumor-specific T-cell repertoire that is prone to immunologic exhaustion and senescence, and (iii) highly mutable tumor targets capable of antigen loss and immune evasion. Future progress may come from innovations in the development of selective preparative regimens that eliminate or neutralize suppressive cellular populations, more effective immunologic adjuvants, and further refinement of agents capable of antagonizing immune check-point blockade pathways. PMID:21198663

UV light assisted decolorization of dark brown colored coffee effluent by photo-Fenton reaction.

PubMed

Tokumura, Masahiro; Ohta, Ayano; Znad, Hussein T; Kawase, Yoshinori

2006-12-01

The photochemical decolorization of coffee effluent has been examined by photo-Fenton (UV/Fe2+/H2O2) process. Effects of UV light intensity, initial coffee concentration, iron dose and H2O2 dose on the color removal of model coffee effluent have been investigated. The rate of decolorization increased with decreasing initial coffee effluent concentration. It was found that the Fe ion dose and UV light intensity enhanced the decolorization rate. The decolorization process of coffee effluent could be divided into three established phases. At the beginning of the photo-Fenton process, the instantaneous and significant increase in color of the solution was found (Phase-I). In the subsequent phase (Phase-II), the decolorization rate was initially fast and subsequently decreased. In Phase-III, the rate was accelerated and then the complete decolorization of model coffee effluent was achieved. In order to elucidate the mechanisms of coffee effluent color removal process, the concentration changes in Fe3+ and Fe2+ besides H2O2 were measured during the course of the photo-Fenton process. The rate-determining step in Phase-II was the photo-Fenton reaction or photoreduction of Fe3+. On the other hand, the decolorization process in Phase-III was highly affected by Fenton reaction or decomposition of H2O2 with Fe2+. About 93% mineralization of 250 mg L(-1) model coffee effluent was achieved after 250 min. A comparative study for TiO2, ZnO and photo-Fenton oxidation processes has been also carried out and the photo-Fenton process was found to be the most effective for color removal of coffee effluent.

Idraparinux sodium: SANORG 34006, SR 34006.

PubMed

2004-01-01

Idraparinux sodium [SANORG 34006, SR 34006], a synthetic, anti Xa pentasaccharide and analogue of SR 32701 and fondaparinux sodium, was in development with Sanofi (now Sanofi-Synthélabo) and Organon (Akzo Nobel) in Europe and the USA (now Sanofi-Synthélabo alone). It may have potential in the treatment and secondary prevention of thrombosis, especially deep-vein thrombosis (DVT). Because of the long duration of action of idraparinux sodium, it may be suitable for once-weekly administration. In January 2004, Sanofi-Synthélabo announced it was to acquire, before the end of the first quarter 2004, all the rights of Organon relating to idraparinux sodium, subject to approval of the regulatory authorities. Sanofi-Synthélabo is to make payments to Organon based on future sales. Idraparinux sodium has completed phase IIb development with the PERSIST study and it is in phase III clinical trials. In June 2003, Organon announced the initiation of pivotal phase III studies as a once-weekly treatment of DVT and pulmonary embolism (PE), and for the prevention of stroke in patients with atrial fibrillation. The AMADEUS study will focus on patients with atrial fibrillation while the Van Gogh PE, Van Gogh DVT and the Van Gogh extension (EXT) will focus on patients with DVT or PE.

Cr(VI) Sorption by Nanosized FeS-Coated Sand

NASA Astrophysics Data System (ADS)

Park, M.; Jeong, H. Y.; Lee, S.; Kang, N.; Kim, K. H.; Choi, H. J.

2015-12-01

Cr(VI) sorption experiments were conducted as a function of pH (4.7, 7.0 and 9.7) using nanosized FeS-coated sand under anoxic environments. Under the experimental conditions, the sand used, with the FeS content of 0.068 mmol per 1 g sand, completely reduced the initially added Cr(VI) to Cr(III) over the pH range examined. The sorption of the once-reduced Cr(III) varied greatly with the solution pH. By the solution-phase analysis, significant amounts of Cr(III) remained as dissolved species at pH 4.7. On the other hands, dissolved Cr was below the detection limit (0.2 μM) at pH 7.0 and 9.7, indicating the greater sorption of Cr(III) at neutral to basic pH than acidic pH. From Cr-K edge X-ray absorption spectroscopy (XAS) analysis of the solid products, the sorbed Cr was shown to be present predominantly as trivalent state in all samples. Regardless of pH, the second coordination shell around Cr (i.e., the Cr-Cr(Fe) shell) was shown to be located at ~2.6 Å, which was far shorter than those in Cr(III)-bearing model compounds such as Cr(OH)3(s) and [Cr, Fe](OH)3(s). Furthermore, the coordination numbers of the second and third shells in the sorption samples (N = 0.7-1.8) were much lower than those in Cr(OH)3(s) and [Cr, Fe](OH)3(s). Taken together, the sorption of the once-reduced Cr(III) was likely to occur via surface-mediated processes (e.g., surface complexation and/or surface precipitation) rather than the bulk-phase precipitation. Financial support was provided by the "R&D Project on Environmental Management of Geologic CO2 Storage" from the KEITI (Project Number: 2014001810003).

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.

Cinacalcet: AMG 073, Calcimimetics--Amgen/NPS Pharmaceuticals, KRN 1493, NPS 1493.

PubMed

2003-01-01

Cinacalcet [AMG 073, KRN 1493, NPS 1493] is an orally active, second-generation calcimimetic compound licensed by NPS Pharmaceuticals to Amgen in the US for potential treatment of hyperparathyroidism (HPT). Cinacalcet modulates (increases the sensitivity of) calcium receptors on the surface of parathyroid cells thereby inhibiting the oversecretion of parathyroid hormone, which characterises HPT. It also represents a potentially significant advance for chronic kidney disease patients diagnosed with secondary HPT, a common yet serious metabolic disorder where parathyroid hormone levels are elevated. Patients with this disease can suffer from bone disease, bone pain and fractures, soft tissue calcification, vascular calcification and cardiovascular complications. Amgen has rights to develop and sell cinacalcet throughout the world except in Japan, Taiwan and China, where the compound was licensed to Kirin Brewery. Kirin is developing it as KRN 1493 in phase II clinical studies in Japan. In December 2001, commencement of a phase III clinical trial with cinacalcet for the treatment of secondary HPT, triggered a 3 million US dollars milestone payment to NPS Pharmaceuticals. In September 2003, submission of an NDA to the US FDA for cinacalcet for secondary HPT will be followed by a milestone payment of 6 million US dollars to NPS. NPS, Kirin and Amgen were also developing another compound, tecalcet, for HPT, but that project has been discontinued in favour of cinacalcet. In September 2003, Amgen submitted an NDA to the US FDA for secondary HPT in patients with chronic kidney disease. In April 2003, Amgen announced positive results from a phase III clinical trial with cinacalcet in patients with secondary HPT. In a clinical study in patients on dialysis suffering from the effects of chronically elevated levels parathyroid hormone, cinacalcet appeared to be safe and well tolerated and was significantly more effective than placebo. Two more additional efficacy studies with cinacalcet have also been completed. Phase II trials of cinacalcet in dialysis patients with secondary HPT and in patients with primary HPT were successfully completed.

Rethinking anaerobic As(III) oxidation in filters: Effect of indigenous nitrate respirers.

PubMed

Cui, Jinli; Du, Jingjing; Tian, Haixia; Chan, Tingshan; Jing, Chuanyong

2018-04-01

Microorganisms play a key role in the redox transformation of arsenic (As) in aquifers. In this study, the impact of indigenous bacteria, especially the prevailing nitrate respirers, on arsenite (As(III)) oxidation was explored during groundwater filtration using granular TiO 2 and subsequent spent TiO 2 anaerobic landfill. X-ray absorption near edge structure spectroscopy analysis showed As(III) oxidation (46% in 10 days) in the presence of nitrate in the simulated anaerobic landfills. Meanwhile, iron (Fe) species on the spent TiO 2 were dominated by amorphous ferric arsenate, ferrihydrite and goethite. The Fe phase showed no change during the anaerobic landfill incubation. Batch incubation experiments implied that the indigenous bacteria completely oxidized As(III) to arsenate (As(V)) in 10 days using nitrate as the terminal electron acceptor under anaerobic conditions. The bacterial community analysis indicated that various kinds of microbial species exist in groundwater matrix. Phylogenetic tree analysis revealed that Proteobacteria was the dominant phylum, with Hydrogenophaga (34%), Limnohabitans (16%), and Simplicispira (7%) as the major bacterial genera. The nitrate respirers especially from the Hydrogenophaga genus anaerobically oxidized As(III) using nitrate as an electron acceptor instead of oxygen. Our study implied that microbes can facilitate the groundwater As oxidation using nitrate on the adsorptive media. Copyright © 2017 Elsevier Ltd. All rights reserved.

Abagovomab As Maintenance Therapy in Patients With Epithelial Ovarian Cancer: A Phase III Trial of the AGO OVAR, COGI, GINECO, and GEICO—The MIMOSA Study

PubMed Central

Sabbatini, Paul; Harter, Philipp; Scambia, Giovanni; Sehouli, Jalid; Meier, Werner; Wimberger, Pauline; Baumann, Klaus H.; Kurzeder, Christian; Schmalfeldt, Barbara; Cibula, David; Bidzinski, Mariusz; Casado, Antonio; Martoni, Andrea; Colombo, Nicoletta; Holloway, Robert W.; Selvaggi, Luigi; Li, Andrew; del Campo, Jose; Cwiertka, Karel; Pinter, Tamas; Vermorken, Jan B.; Pujade-Lauraine, Eric; Scartoni, Simona; Bertolotti, Monica; Simonelli, Cecilia; Capriati, Angela; Maggi, Carlo Alberto; Berek, Jonathan S.; Pfisterer, Jacobus

2013-01-01

Purpose To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission. Patients and Methods Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response. Results Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti–anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response. Conclusion Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS. PMID:23478059

Experiences of social harm and changes in sexual practices among volunteers who had completed a phase I/II HIV vaccine trial employing HIV-1 DNA priming and HIV-1 MVA boosting in Dar es Salaam, Tanzania.

PubMed

Tarimo, Edith A M; Munseri, Patricia; Aboud, Said; Bakari, Muhammad; Mhalu, Fred; Sandstrom, Eric

2014-01-01

Volunteers in phase I/II HIV vaccine trials are assumed to be at low risk of acquiring HIV infection and are expected to have normal lives in the community. However, during participation in the trials, volunteers may encounter social harm and changes in their sexual behaviours. The current study aimed to study persistence of social harm and changes in sexual practices over time among phase I/II HIV vaccine immunogenicity (HIVIS03) trial volunteers in Dar es Salaam, Tanzania. A descriptive prospective cohort study was conducted among 33 out of 60 volunteers of HIVIS03 trial in Dar es Salaam, Tanzania, who had received three HIV-1 DNA injections boosted with two HIV-1 MVA doses. A structured interview was administered to collect data. Analysis was carried out using SPSS and McNemars' chi-square (χ2) was used to test the association within-subjects. Participants reported experiencing negative comments from their colleagues about the trial; but such comments were less severe during the second follow up visits (χ2 = 8.72; P<0.001). Most of the comments were associated with discrimination (χ2 = 26.72; P<0.001), stigma (χ2 = 6.06; P<0.05), and mistrust towards the HIV vaccine trial (χ2 = 4.9; P<0.05). Having a regular sexual partner other than spouse or cohabitant declined over the two follow-up periods (χ2 = 4.45; P<0.05). Participants in the phase I/II HIV vaccine trial were likely to face negative comments from relatives and colleagues after the end of the trial, but those comments decreased over time. In this study, the inherent sexual practice of having extra sexual partners other than spouse declined over time. Therefore, prolonged counselling and support appears important to minimize risky sexual behaviour among volunteers after participation in HIV Vaccine trials.

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...

Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors.

PubMed

Cai, Shuang; Zhang, Ti; Forrest, W C; Yang, Qiuhong; Groer, Chad; Mohr, Eva; Aires, Daniel J; Axiak-Bechtel, Sandra M; Flesner, Brian K; Henry, Carolyn J; Selting, Kimberly A; Tate, Deborah; Swarz, Jeffrey A; Bryan, Jeffrey N; Forrest, M Laird

2016-09-01

OBJECTIVE To conduct a phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate (HA-Pt) in dogs with naturally occurring malignant tumors. ANIMALS 18 healthy rats, 9 healthy mice, and 16 dogs with cancer. PROCEDURES HA-Pt was prepared and tested by inductively coupled plasma mass spectrometry; DNA-platinum adduct formation and antiproliferation effects of cisplatin and HA-Pt were compared in vitro. Effects of cisplatin (IV) and HA-Pt (SC) in rodents were tested by clinicopathologic assays. In the clinical trial, dogs with cancer received 1 to 4 injections of HA-Pt (10 to 30 mg/m(2), intratumoral or peritumoral, q 3 wk). Blood samples were collected for pharmacokinetic analysis; CBC, serum BUN and creatinine concentration measurement, and urinalysis were conducted before and 1 week after each treatment. Some dogs underwent hepatic enzyme testing. Tumors were measured before the first treatment and 3 weeks after each treatment to assess response. RESULTS No adverse drug effects were detected in pretrial assessments in rodents. Seven of 16 dogs completed the study; 3 had complete tumor responses, 3 had stable disease, and 1 had progressive disease. Three of 7 dogs with oral and nasal squamous cell carcinoma (SCC) that completed the study had complete responses. Myelosuppression and cardiotoxicosis were identified in 6 and 2 dogs, respectively; none had nephrotoxicosis. Four of 5 dogs with hepatic enzymes assessed had increased ALT activities, attributed to diaquated cisplatin products in the HA-Pt. Pharmacokinetic data fit a 3-compartment model. CONCLUSIONS AND CLINICAL RELEVANCE HA-Pt treatment resulted in positive tumor responses in some dogs, primarily those with SCC. The adverse effect rate was high. IMPACT FOR HUMAN MEDICINE Oral SCC in dogs has characteristics similar to human head and neck SCC; these results could be useful in developing human treatments.

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…

Use of defibrotide in the treatment and prevention of veno-occlusive disease.

PubMed

Richardson, Paul; Linden, Erica; Revta, Carolyn; Ho, Vincent

2009-08-01

Hepatic veno-occlusive disease (VOD) is one of the most important complications of high-dose chemotherapy and stem cell transplantation. VOD is a clinical syndrome characterized by jaundice, hepatic enlargement and fluid retention typically seen by day +30 after transplantation. Severe VOD is complicated by multiorgan failure and a high mortality rate approaching 100%. Defibrotide (DF) is a novel agent with both antithrombotic and fibrinolytic properties that has emerged as an effective therapy for severe VOD. In Phase II studies, treatment of severe VOD has resulted in complete responses of 30-60% and survival past day 100 ranging between 32-50%. A Phase III, historically controlled study of DF for treatment of severe VOD has recently been completed and results are awaited with interest. In addition, DF may be effective prophylaxis for VOD in high-risk patients. This review will focus on a summary of the pharmacology of DF and the clinical evidence for its use in VOD.

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.

SAGE III on the International Space Station

NASA Astrophysics Data System (ADS)

McCormick, M. P.; Damadeo, R. P.; Hill, C. A.

2017-12-01

A much-improved Stratospheric Aerosol and Gas Experiment (SAGE III) instrument was launched on February 19, 2017 from NASA's Kennedy Space Center aboard the SpaceX CRS-10 Dragon Spacecraft. It subsequently docked with the International Space Station (ISS), completed commissioning on July 1, 2017, and is now in its Mission Operations phase. SAGE III-ISS will combine the experience and capabilities of its successful predecessor satellite instruments SAM II, SAGE, SAGE II, and SAGE III-Meteor-3M to measure aerosol, cloud, O3, H2O, and NO2 profiles from the upper troposphere through the stratosphere. In addition to solar and lunar occultation with vertical resolutions of about 1.0 km, SAGE III-ISS will make limb scattering measurements on the solar side of each orbit greatly expanding the measurement coverage per spacecraft orbit, and tie the very high resolution and precise solar occultation measurements with the limb scattering measurements. The programmable readout array detector enhances its measurement capability and should allow for experimental data products like BrO, and IO, and along with a single photodiode detector, the measurement of larger aerosols. The wavelengths covered by SAGE III-ISS range from 280 to 1050 nm with 1 to 2 nm spectral resolution using a grating spectrometer. The single photodiode extends measurements to 1550 nm. This talk will describe the measurement capabilities of SAGE III, and include early data and validation examples, its additional modes and increased geographical coverage, its calibration and characterization, and data archival and validation approach.

Unveiling the control of quenched disorder in rare earth nickelates

NASA Astrophysics Data System (ADS)

Das, Sarmistha; Phanindra, V. Eswara; Philip, Sharon S.; Rana, D. S.

2017-10-01

The role of quenched disorder, a key control to obtain novel phases and functionalities, has not yet been determined in the complex phase diagram of RNi O3 (R = rare-earth ion) perovskites. Here we present such a study by investigating (L a0.5E u0.5 ) Ni O3 (LENO) having large R-site cation disorder. We show that in the presence of quenched disorder, (i) the resistivity drops by a few orders of magnitude across the metal-insulator transition (MIT) but the MIT shows only a subtle decrease, (ii) compressive films are completely metallic while largely tensile films are completely insulating sans a MIT, (iii) orthorhombic distortion promotes sharp MIT, and (iv) a Fermi liquid behavior even as high temperature resistivity exceeds the Mott-Ioffe-Regel limit with a bad metallic state. The low-energy terahertz conductivity dynamics obey Drude and Drude-Smith models for compressive and tensile films, respectively. All these features of disordered LENO, which are not typical of prototype ordered NdNi O3 , reveal an extraordinary sensitivity to slight structural perturbations. This study depicts the ease with which a variety of electronic phases can be tuned in disordered nickelates and emphasize the need to incorporate quenched disorder as a key control in the phase diagram of nickelates.

Evaluating the accuracy of technicians and pharmacists in checking unit dose medication cassettes.

PubMed

Ambrose, Peter J; Saya, Frank G; Lovett, Larry T; Tan, Sandy; Adams, Dale W; Shane, Rita

2002-06-15

The accuracy rates of board-registered pharmacy technicians and pharmacists in checking unit dose medication cassettes in the inpatient setting at two separate institutions were examined. Cedars-Sinai Medical Center and Long Beach Memorial Medical Center, both in Los Angeles county, petitioned the California State Board of Pharmacy to approve a waiver of the California Code of Regulations to conduct an experimental program to compare the accuracy of unit dose medication cassettes checked by pharmacists with that of cassettes checked by trained, certified pharmacy technicians. The study consisted of three parts: assessing pharmacist baseline checking accuracy (Phase I), developing a technician-training program and certifying technicians who completed the didactic and practical training (Phase II), and evaluating the accuracy of certified technicians checking unit dose medication cassettes as a daily function (Phase III). Twenty-nine pharmacists and 41 technicians (3 of whom were pharmacy interns) participated in the study. Of the technicians, all 41 successfully completed the didactic and practical training, 39 successfully completed the audits and became certified checkers, and 2 (including 1 of the interns) did not complete the certification audits because they were reassigned to another work area or had resigned. In Phase II, the observed accuracy rate and its lower confidence limit exceeded the predetermined minimum requirement of 99.8% for a certified checker. The mean accuracy rates for technicians were identical at the two institutions (p = 1.0). The difference in mean accuracy rates between pharmacists (99.52%; 95% confidence interval [CI] 99.44-99.58%) and technicians, (99.89%; 95% CI 99.87-99.90%) was significant (p < 0.0001). Inpatient technicians who had been trained and certified in a closely supervised program that incorporated quality assurance mechanisms could safely and accurately check unit dose medication cassettes filled by other technicians.

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.

Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years.

PubMed

Lovell, Daniel J; Ruperto, Nicolino; Mouy, Richard; Paz, Eliana; Rubio-Pérez, Nadina; Silva, Clovis A; Abud-Mendoza, Carlos; Burgos-Vargas, Ruben; Gerloni, Valeria; Melo-Gomes, Jose A; Saad-Magalhaes, Claudia; Chavez-Corrales, J; Huemer, Christian; Kivitz, Alan; Blanco, Francisco J; Foeldvari, Ivan; Hofer, Michael; Huppertz, Hans-Iko; Job Deslandre, Chantal; Minden, Kirsten; Punaro, Marilynn; Block, Alan J; Giannini, Edward H; Martini, Alberto

2015-10-01

The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease-modifying antirheumatic drugs were previously established in a phase III study that included a 4-month open-label lead-in period, a 6-month double-blind withdrawal period, and a long-term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient-reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup. Patients enrolled in the phase III trial could enter the open-label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double-blind period. One hundred fifty-three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient-years) of adverse events decreased during the LTE phase (433.61 events during the short-term phase [combined lead-in and double-blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time. Long-term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality-of-life benefits in patients with JIA. © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Long‐Term Safety, Efficacy, and Quality of Life in Patients With Juvenile Idiopathic Arthritis Treated With Intravenous Abatacept for Up to Seven Years

PubMed Central

Ruperto, Nicolino; Mouy, Richard; Paz, Eliana; Rubio‐Pérez, Nadina; Silva, Clovis A.; Abud‐Mendoza, Carlos; Burgos‐Vargas, Ruben; Gerloni, Valeria; Melo‐Gomes, Jose A.; Saad‐Magalhaes, Claudia; Chavez‐Corrales, J.; Huemer, Christian; Kivitz, Alan; Blanco, Francisco J.; Foeldvari, Ivan; Hofer, Michael; Huppertz, Hans‐Iko; Job Deslandre, Chantal; Minden, Kirsten; Punaro, Marilynn; Block, Alan J.; Giannini, Edward H.; Martini, Alberto

2015-01-01

Objective The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease‐modifying antirheumatic drugs were previously established in a phase III study that included a 4‐month open‐label lead‐in period, a 6‐month double‐blind withdrawal period, and a long‐term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient‐reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup. Methods Patients enrolled in the phase III trial could enter the open‐label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double‐blind period. Results One hundred fifty‐three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient‐years) of adverse events decreased during the LTE phase (433.61 events during the short‐term phase [combined lead‐in and double‐blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time. Conclusion Long‐term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality‐of‐life benefits in patients with JIA. PMID:26097215

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.

Outcomes of Category III DOTS treatment in immunocompetent patients with tuberculosis pleural effusion.

PubMed

Sharma, S K; Solanki, R; Mohan, A; Jain, N K; Chauhan, L S

2012-11-01

To study the efficacy and safety of Category III DOTS treatment (intermittent thrice-weekly rifampicin [RMP], isoniazid [INH] and pyrazinamide for 2 months, followed by RMP and INH for 4 months) under India's Revised National Tuberculosis Control Programme in patients with uncomplicated small unilateral pleural effusion (<1500 ml). This prospective, multicentre, observational study recruited 351 patients between 2006 and 2010. Patients were regularly followed up clinically as well as with ultrasound examination of the chest. Successful outcome (clinical response with complete resolution on ultrasound examination at 6 months) was seen in 274 patients (78.1%). Efficacy was 88.9% (excluding defaulters), and 94% among those completing follow-up as per protocol. None of the patients received corticosteroids. Other outcomes included treatment extension (n = 26, 7.4%), default (n = 43, 12.2%), treatment failure (n = 3, 0.9%) and death (n = 3, 0.9%). Seventy-nine mild/moderate adverse events and one treatment-related serious adverse event were noted; one patient developed recurrent drug-induced hepatotoxicity. Two patients (0.7%) had relapse/re-infection at 24 months follow-up. Intermittent thrice-weekly treatment for 6 months with three drugs in the intensive phase is effective and safe for unilateral small pleural effusion in immunocompetent patients. Although Category III no longer exists in the programme, the results are reassuring for intermittent treatment in extra-pulmonary TB under programme conditions.

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,…

Virtual reality exercise on a home-based phase III cardiac rehabilitation program, effect on executive function, quality of life and depression, anxiety and stress: a randomized controlled trial.

PubMed

Vieira, Ágata; Melo, Cristina; Machado, Jorge; Gabriel, Joaquim

2018-02-01

To analyse the effect of a six-month home-based phase III cardiac rehabilitation (CR) specific exercise program, performed in a virtual reality (Kinect) or conventional (booklet) environment, on executive function, quality of life and depression, anxiety and stress of subjects with coronary artery disease. A randomized controlled trial was conducted with subjects, who had completed phase II, randomly assigned to intervention group 1 (IG1), whose program encompassed the use of Kinect (n = 11); or intervention group 2 (IG2), a paper booklet (n = 11); or a control group (CG), only subjected to the usual care (n = 11). The three groups received education on cardiovascular risk factors. The assessed parameters, at baseline (M0), 3 (M1) and 6 months (M2), were executive function, control and integration in the implementation of an adequate behaviour in relation to a certain objective, specifically the ability to switch information (Trail Making Test), working memory (Verbal Digit Span test), and selective attention and conflict resolution ability (Stroop test), quality of life (MacNew questionnaire) and depression, anxiety and stress (Depression, Anxiety and Stress Scale 21). Descriptive and inferential statistical measures were used, significance level was set at .05. The IG1 revealed significant improvements, in the selective attention and conflict resolution ability, in comparison with the CG in the variable difference M0 - M2 (p = .021) and in comparison with the IG2 in the variable difference M1 - M2 and M0 - M2 (p = .001 and p = .002, respectively). No significant differences were found in the quality of life, and depression, anxiety and stress. The virtual reality format had improved selective attention and conflict resolution ability, revealing the potential of CR, specifically with virtual reality exercise, on executive function. Implications for Rehabilitation In cardiac rehabilitation, especially in phase III, it is important to develop and to present alternative strategies, as virtual reality using the Kinect in a home context. Taking into account the relationship between the improvement of the executive function with physical exercise, it is relevant to access the impact of a cardiac rehabilitation program on the executive function. Enhancing the value of the phase III of cardiac rehabilitation.

A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial.

PubMed

Battersby, Nick J; Dattani, Mit; Rao, Sheela; Cunningham, David; Tait, Diana; Adams, Richard; Moran, Brendan J; Khakoo, Shelize; Tekkis, Paris; Rasheed, Shahnawaz; Mirnezami, Alex; Quirke, Philip; West, Nicholas P; Nagtegaal, Iris; Chong, Irene; Sadanandam, Anguraj; Valeri, Nicola; Thomas, Karen; Frost, Michelle; Brown, Gina

2017-08-29

Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a 'good' mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a 'poor response' identifies an adverse prognostic group which may benefit from additional pre-operative therapy. TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016.

Agomelatine: AGO 178, AGO178, S 20098.

PubMed

2008-01-01

Novartis and Servier are developing agomelatine for the treatment of depression. Agomelatine is a specific melatonin (MT1 and MT2) receptor agonist that also has antagonistic activities at serotonin-(2C) (5-HT(2C)) receptors. Novartis believes agomelatine is comparable to current standard therapies for depression with improved tolerability, including a low propensity to cause sexual dysfunction and weight gain. Clinical development is being conducted in the US for the treatment of depression; approval for this indication was declined in the EU, apparently due to insufficient data. Servier has also conducted a trial of the agent in patients with generalized anxiety disorder in France, South Africa and Finland, and a phase II trial in sleep disorders in France. In March 2006, Servier and Novartis signed a licensing agreement for agomelatine. Novartis obtained the exclusive rights for the development and marketing of agomelatine in the US and several other countries. Servier retained the rights to the product in the rest of the world. The clinical development plan for agomelatine includes phase III trials being conducted under the parAGOn clinical trial programme. One US-based trial that began in March 2007 (NCT00463242) is recruiting 490 patients with depression who will receive placebo or agomelatine 25 or 50 mg for 8 weeks and will then receive open-label agomelatine for 52 weeks. Novartis is also conducting an 8-week phase III trial (NCT00411099) comparing the safety and efficacy of agomelatine 25 and 50 mg in patients with major depressive disorder. A follow-up, 52-week open-label extension study (CAGO178A2301E) will also be conducted. Another phase III study underway is NCT00411242, which has the same design and is also followed by a 52-week open-label extension study (CAGO178A2302E). These studies are all expected to be completed by January 2009. In July 2006, the Committee for Medicinal Products for Human Use recommended the refusal of marketing authorisation for agomelatine for the treatment of depression. Servier had applied for a re-examination of the finding but withdrew the request in November 2006. Servier's MAA was not supported due to insufficient data and no recent development has been reported in this indication in the EU. Agomelatine prevented relapse in patients with depression compared with placebo and was well tolerated in an international phase III trial.

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

Increasing Efficiency of Recruitment in Early Parkinson's Disease Trials: A Case Study Examination of the STEADY-PD III Trial.

PubMed

Berk, Sarah; Greco, Brittany L; Biglan, Kevin; Kopil, Catherine M; Holloway, Robert G; Meunier, Claire; Simuni, Tanya

2017-01-01

Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson's disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule. STEADY PD III aimed to enroll 336 individuals with early stage idiopathic PD within 18 months using 57 sites across the United States and Canada. The study included a 10% NIH minority recruitment goal. Eligible participants agreed to be followed for up to 36 months, complete 12 in-person visits and 4 telephone visits. A Recruitment Committee of key stakeholders was critical in the development of a comprehensive recruitment strategy involving: multi-modal outreach, protocol modifications and comprehensive site selection and activation. Efforts to increase site-specific minority recruitment strategies were encouraged through additional funding. A total of 336 individuals, including 34 minorities, were enrolled within 12 months - 6 months ahead of the projected timeline. Quantitative analysis of recruitment activity questionnaires found that of the sites that completed them (n = 54), (20.4%) met goals, (24.1%) exceeded goals, and (55.6%) fell below projected goals. Referral sources completed at time of screening indicate top four study referral sources as: site personnel (53.8%); neurologists (24%); Fox Trial Finder (10.2%); and communications from The Michael J. Fox Foundation (3.9%). STEADY PD III serves as an important example of methods that can be used to increase clinical trial recruitment. This research highlights a continued need to improve site infrastructure and dedicate more resources to increased participation of minorities in clinical research.

Increasing Efficiency of Recruitment in Early Parkinson’s Disease Trials: A Case Study Examination of the STEADY-PD III Trial

PubMed Central

Berk, Sarah; Greco, Brittany L.; Biglan, Kevin; Kopil, Catherine M.; Holloway, Robert G.; Meunier, Claire; Simuni, Tanya

2017-01-01

Background: Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson’s disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. Objective: This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule. Methods: STEADY PD III aimed to enroll 336 individuals with early stage idiopathic PD within 18 months using 57 sites across the United States and Canada. The study included a 10% NIH minority recruitment goal. Eligible participants agreed to be followed for up to 36 months, complete 12 in-person visits and 4 telephone visits. A Recruitment Committee of key stakeholders was critical in the development of a comprehensive recruitment strategy involving: multi-modal outreach, protocol modifications and comprehensive site selection and activation. Efforts to increase site-specific minority recruitment strategies were encouraged through additional funding. Results: A total of 336 individuals, including 34 minorities, were enrolled within 12 months – 6 months ahead of the projected timeline. Quantitative analysis of recruitment activity questionnaires found that of the sites that completed them (n = 54), (20.4%) met goals, (24.1%) exceeded goals, and (55.6%) fell below projected goals. Referral sources completed at time of screening indicate top four study referral sources as: site personnel (53.8%); neurologists (24%); Fox Trial Finder (10.2%); and communications from The Michael J. Fox Foundation (3.9%). Conclusions: STEADY PD III serves as an important example of methods that can be used to increase clinical trial recruitment. This research highlights a continued need to improve site infrastructure and dedicate more resources to increased participation of minorities in clinical research. PMID:29103052

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.

Antibody for the prevention of neonatal noscocomial staphylococcal infection: a review of the literature.

PubMed

Weisman, L E

2007-09-01

Staphylococci, especially coagulase negative staphylococci (CONS), are responsible for over 75 % of late-onset infections in very low birth weight infants. These infections cause increased length of hospital stay, need for antibiotics, and cost of medical care. Several drug companies have developed and evaluated hyperimmune polyclonal and monoclonal antibodies for the prevention of neonatal staphylococcal infection including 1) Altastaph by North American Biologics Inc., 2) Veronate by Inhibitex Inc., and 3) Pagibaximab by Biosynexus Inc, and Glaxo Smith Kline Inc. We will review the development and status of these potential products. Altastaph is a S. aureus serotype 5 and 8 vaccine induced hyperimmune polyclonal antibody whose development has been placed on hold due to its failure to demonstrate any trend toward efficacy in a recently completed Phase II study. Veronate is a polyclonal antibody obtained by plasmapheresis from donors with high titers of MSCRAMM (microbial surface components recognizing adhesion matrix molecules) activity against CONS whose development has been placed on hold due to its failure to demonstrate effectiveness in a recently completed Phase III study. Pagibaximab is a humanized mouse chimeric monoclonal antibody (previously known as BSYX-A110) directed against lipoteichoic acid (LTA), a major cell wall component of gram-positive bacteria, that has recently completed a Phase II study suggesting efficacy and is being developed further for clinical investigation.

[Long-term physical activity after a myocardial infarction : a permanent challenge].

PubMed

Tessitore, Elena; Sigaud, Philippe; Meyer, Philippe; Mach, François

2017-05-24

Cardiac rehabilitation is a well-defined multidisciplinary program with the objective to reduce mortality and morbidity, while also improving the exercise capacity and quality of life of the patient following a myocardial infarction. Despite the fact that a cardiovascular rehabilitation program is now recommended by international guidelines for all patients who have suffered from an acute coronary syndrome, only half of all patients actually participate to such a program in Switzerland. Even worse, especially when taking into consideration the population in Geneva, less than 5 % of patients follow a long-term cardiac maintenance program (phase III). Since 2015, our project has been to encourage patients who have completed a phase II cardiac rehabilitation program, to resume regular physical activity in the long term.

Addressing the immunopathogenesis of atopic dermatitis: advances in topical and systemic treatment.

PubMed

Eichenfield, Lawrence F; Stein Gold, Linda F

2017-03-01

Several immunologic mediators-phosphodiesterase (PDE), interleukin (IL), small molecules, and Janus kinase-have been implicated in the pathogenesis of atopic dermatitis, and evidence has shown that blocking these mediators can help modify the disease process. Several new topical medications have been developed that target the enzyme PDE; crisaborole was recently approved by the US Food and Drug Administration (FDA) for the treatment of atopic dermatitis, and phase II studies have been completed on OPA-15406. The phase III clinical trial results of the systemic medication dupilumab, an inhibitor of the IL-4 receptor α subunit (which inhibits both IL-4 and IL-13 signaling), are currently being reviewed by the FDA. ©2017 Frontline Medical Communications.

Targeting radioimmunotherapy of hepatocellular carcinoma with iodine ({sup 131}I) metuximab injection: Clinical Phase I/II trials

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

Chen Zhinan; Mi Li; Xu Jing

2006-06-01

Purpose: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine ({sup 131}I) metuximab injection (Licartin), a novel {sup 131}I-labeled HAb18G/CD147-specific monoclonal antibody F(ab'){sub 2} fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. Methods and Materials: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. Results: No life-threatening toxicmore » effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p 0.0019). Conclusion: Iodine ({sup 131}I) metuximab injection is safe and active for HCC patients.« less

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.

Rotigotine transdermal patch in Chinese patients with early Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

PubMed

Zhang, Zhen-Xin; Shang, Hui-Fang; Hu, Xingyue; Chen, Shengdi; Zhao, Zhongxin; Du, Xinlu; Surmann, Erwin; Bauer, Lars; Asgharnejad, Mahnaz

2016-07-01

Two phase3 studies (SP512; SP513) involving mostly Caucasian patients showed that rotigotine (≤8 mg/24 h) was efficacious and welltolerated in early-stage Parkinson's disease (PD). We report results from a phase 3 study (SP0914/NCT01646268) investigating rotigotine in Chinese patients with early-stage PD. Patients were randomized 1:1 to rotigotine or placebo, titrated over 1-4 weeks, maintained at optimal/maximum dose (≤8 mg/24 h) for 24 weeks. Primary efficacy variable: change in Unified Parkinson's Disease Rating Scale (UPDRS) II + III total score from Baseline to End-of-Maintenance. Secondary variables: UPDRS II + III responders (≥20% decrease in UPDRS II + III) and changes in UPDRS II (activities of daily living [ADL]) and III (motor examination) subscores. Of 247 patients randomized, 113/124 (91.1%) rotigotine- and 107/123 (87.0%) placebo-treated patients completed the study. mean (SD) age: 59.4 (10.2) years; time since PD diagnosis: 1.01 (1.22) years, 60.7% male. Rotigotine significantly improved UPDRS II + III total score (change from Baseline LSmean [95%CI] treatment difference, -4.82 [-7.18 to -2.45]; P < 0.0001). UPDRS II + III responder rates were higher with rotigotine (42.3% vs 22.3%; P = 0.0006). UPDRS II and III subscores improved with rotigotine (both subscores: P < 0.0005 vs. placebo). Most frequent adverse events (AEs): nausea (8.9% rotigotine, 3.3% placebo), dizziness (8.1%, 5.7%), pruritus (8.1%, 4.1%), somnolence (8.1%, 3.3%), erythema (6.5%, 1.6%), and vomiting (5.6%, 1.6%). Thirteen (5.3%) patients discontinued due to AEs (6 rotigotine, 7 placebo). Rotigotine was efficacious in Chinese patients with early-stage PD, providing benefits to control of ADL and motor function. Rotigotine was generally welltolerated, with similar AEs to those observed in Caucasian patients. Copyright © 2016 Elsevier Ltd. 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

Environmental, health, and safety issues of fuel cells in transportation. Volume 1: Phosphoric acid fuel-cell buses

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

Ring, S

1994-12-01

The U.S. Department of Energy (DOE) chartered the Phosphoric Acid Fuel-Cell (PAFC) Bus Program to demonstrate the feasibility of fuel cells in heavy-duty transportation systems. As part of this program, PAFC- powered buses are being built to meet transit industry design and performance standards. Test-bed bus-1 (TBB-1) was designed in 1993 and integrated in March 1994. TBB-2 and TBB-3 are under construction and should be integrated in early 1995. In 1987 Phase I of the program began with the development and testing of two conceptual system designs- liquid- and air-cooled systems. The liquid-cooled PAFC system was chosen to continue, throughmore » a competitive award, into Phase H, beginning in 1991. Three hybrid buses, which combine fuel-cell and battery technologies, were designed during Phase III. After completing Phase II, DOE plans a comprehensive performance testing program (Phase HI) to verify that the buses meet stringent transit industry requirements. The Phase III study will evaluate the PAFC bus and compare it to a conventional diesel bus. This NREL study assesses the environmental, health, and safety (EH&S) issues that may affect the commercialization of the PAFC bus. Because safety is a critical factor for consumer acceptance of new transportation-based technologies the study focuses on these issues. The study examines health and safety together because they are integrally related. In addition, this report briefly discusses two environmental issues that are of concern to the Environmental Protection Agency (EPA). The first issue involves a surge battery used by the PAFC bus that contains hazardous constituents. The second issue concerns the regulated air emissions produced during operation of the PAFC bus.« less

Impact of etanercept tapering on work productivity in patients with early rheumatoid arthritis: results from the PRIZE study

PubMed Central

Zhang, Wei; Bansback, Nick; Sun, Huiying; Pedersen, Ronald; Kotak, Sameer; Anis, Aslam H

2016-01-01

Objective To assess changes in work productivity in patients who have achieved response using etanercept (ETN) 50 mg+methotrexate (MTX) (phase I) are randomised to ETN 25 mg+MTX versus MTX versus placebo (phase II) and then withdrawn from treatment (phase III). Methods Patients included in the analysis were in employment entering phase II of the PRIZE trial and had one or more follow-ups. Phase II was a 39-week, randomised and double-blind comparison of the 3 dose-reduction treatments. Phase III was a 26-week observational study where treatment was withdrawn. The Valuation of Lost Productivity was completed approximately every 13 weeks to estimate productivity impacts from a societal perspective. Results A total of 120 participants were included in our analyses. During phase II, ETN25+MTX or MTX improved paid work productivity by over 100 hours compared with placebo, amounting to a gain of €1752 or €1503, respectively. ETN25+MTX compared with placebo gains €1862 in total paid/unpaid productivity. At week 52, the 3-month paid work productivity loss was 21.8, 12.8 and 14.0 hours, respectively. The productivity loss increased at week 64 from week 52, dropped at week 76 for all treatment groups and then continued rising after week 76 for the placebo group (71.9 hours at week 91) but not for the other 2 groups (21.9 hours for ETX25+MTX and 27.6 hours for MTX). Conclusions The work productivity gain in phase I as a result of ETN50+MTX was marginally lost in the dose-reduction treatment groups, ETN25+MTX and MTX, but substantially lost in the placebo group during phase II. Trial registration number NCT00913458; Results. PMID:27486524

Coping with missing data in phase III pivotal registration trials: Tolvaptan in subjects with kidney disease, a case study.

PubMed

Ouyang, John; Carroll, Kevin J; Koch, Gary; Li, Junfang

2017-07-01

Missing data cause challenging issues, particularly in phase III registration trials, as highlighted by the European Medicines Agency (EMA) and the US National Research Council. We explore, as a case study, how the issues from missing data were tackled in a double-blind phase III trial in subjects with autosomal dominant polycystic kidney disease. A total of 1445 subjects were randomized in a 2:1 ratio to receive active treatment (tolvaptan), or placebo. The primary outcome, the rate of change in total kidney volume, favored tolvaptan (P < .0001). The key secondary efficacy endpoints of clinical progression of disease and rate of decline in kidney function also favored tolvaptan. However, as highlighted by Food and Drug Administration and EMA, the interpretation of results was hampered by a high number of unevenly distributed dropouts, particularly early dropouts. In this paper, we outline the analyses undertaken to address the issue of missing data thoroughly. "Tipping point analyses" were performed to explore how extreme and detrimental outcomes among subjects with missing data must be to overturn the positive treatment effect attained in those subjects who had complete data. Nonparametric rank-based analyses were also performed accounting for missing data. In conclusion, straightforward and transparent analyses directly taking into account missing data convincingly support the robustness of the preplanned analyses on the primary and secondary endpoints. Tolvaptan was confirmed to be effective in slowing total kidney volume growth, which is considered an efficacy endpoint by EMA, and in lessening the decline in renal function in patients with autosomal dominant polycystic kidney disease. Copyright © 2017 John Wiley & Sons, Ltd.

Improved electroacoustic dewatering (EAD) belt press for food products. Phase 3, Technical progress report

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

Not Available

1994-02-01

Battelle`s electroacoustic dewatering (EAD) process improves the performance of mechanical dewatering processes for several food products (such as corn fiber) by superimposing electric and ultrasonic fields. EAD has the potential to save 0.027 to 0.035 quad/yr energy by 1995 in the food processing industry, which consumed 0.15 to 0.18 quad in 1986. This report covers Phase III for demonstrating the EAD prototype on corn wet milling products (corn fiber and gluten); only Task 1 (prototype preparation and planning) was completed. EAD performance was examined in the laboratory; availability of a test site was examined. The single-roll, postdewatering EAD belt pressmore » prototype can accept material predewatered by a screw press, centrifuge, or any other mechanical dewatering device. The two-belt system, utilizing a copper-polymer cathode belt, performed as well as the three-belt system used in Phase II.« less

The Dengue Vaccine Pipeline: Implications for the Future of Dengue Control

PubMed Central

Schwartz, Lauren M.; Halloran, M. Elizabeth; Durbin, Anna P.; Longini, Ira M.

2015-01-01

Dengue has become the most rapidly expanding mosquito-borne infectious disease on the planet, surpassing malaria and infecting at least 390 million people per year. There is no effective treatment for dengue illness other than supportive care, especially for severe cases. Symptoms can be mild or life-threatening as in dengue hemorrhagic fever and dengue shock syndrome. Vector control has been only partially successful in decreasing dengue transmission. The potential use of safe and effective tetravalent dengue vaccines is an attractive addition to prevent disease or minimize the possibility of epidemics. There are currently no licensed dengue vaccines. This review summarizes the current status of all dengue vaccine candidates in clinical evaluation. Currently five candidate vaccines are in human clinical trials. One has completed two Phase III trials, two are in Phase II trials, and three are in Phase I testing. PMID:25989449

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.

Breast cancer: complete response with the combination of sunitinib and trastuzumab in a patient with grade III ductal carcinoma.

PubMed

Puente, Javier; Manzano, Aranzazu; Martin, Miguel; López-Tarruella, Sonia; Díaz-Rubio, Eduardo

2010-01-01

In August 2000, a previously healthy postmenopausal 52-year-old woman was diagnosed with grade III invasive ductal carcinoma. The tumor had an ER -, PR -, and HER2 + profile. Adjuvant treatment with FEC was initiated followed by radiotherapy. In October 2004, the patient presented a clinically asymptomatic supraclavicular and mediastinal lymph node recurrence and treatment with paclitaxel and trastuzumab was initiated. A complete response was achieved after 20 weeks of treatment, and in January 2006 treatment was interrupted due to toxicity. After a 34-month free-of-relapse period, a local recurrence was detected in the chest wall. In September 2007, the patient joined a phase II trial with sunitinib (37.5 mg once a day in 28 days cycles) and trastuzumab (6 mg/kg every 3 weeks), after having verified a normal cardiac function. After two courses, a partial cutaneous response and a complete radiological response were obtained. The most relevant toxicities included cutaneous hyperpigmentation, dysgeusia, mucositis, grade II diarrhea and hypertension. The development of grade III diarrhea led to sunitinib dose reduction (25mg/day). In January 2008, the patient developed hypothyroidism and a significant drop in the left ventricular ejection fraction that led to treatment interruption. In March 2008, once cardiac function was recovered, treatment at the same dose was reinitiated. After two months of treatment, a new descent in cardiac function was noted which led to the suspension of sunitinib, and the interruption of the trastuzumab treatment until recovery of normal cardiac function. In July 2008, trastuzumab monotherapy was resumed and since then no cardiac events have been reported, while maintaining a radiological and clinical response.

Concurrent Chemoradiotherapy With Paclitaxel and Nedaplatin Followed by Consolidation Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Uterine Cervix: Preliminary Results of a Phase II Study

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

Zhang Meiqin, E-mail: pianozmq@hotmail.co; Liu Suping; Wang, Xiang-E.

Purpose: To evaluate the efficacy and toxicities of concurrent chemoradiotherapy (CCRT) and consolidation chemotherapy in patients with locally advanced squamous cell cervical carcinoma. Methods and Materials: Patients with LASCC (FIGO Stage IIB-IIIB) were treated with pelvic external beam radiotherapy (45 Gy for Stage IIB and 50 Gy for Stage III) and high-dose-rate intracavitary brachytherapy (50 Gy for Stage IIB and 35 Gy for Stage III). The cumulative dose at point A was 50 Gy for Stage IIB and 65 Gy for Stage III. Concurrent chemotherapy with paclitaxel (35 mg/m{sup 2}) and nedaplatin (20 mg/m{sup 2}) was given every week formore » 6 weeks. Consolidation chemotherapy with paclitaxel (135 mg/m{sup 2}) and nedaplatin (60 mg/m{sup 2}) was administered every 3 weeks for 4 cycles. Results: All patients completed CCRT, and 28 of 34 patients completed consolidation chemotherapy. The complete response rate was 88% (95% CI, 73-96%). The most common Grade 3 or higher toxicities were leukopenia/neutropenia (10.9% of the cycles). During a median follow up of 23 months (range, 14-30 months), 5 patients had locoregional failure and 1 patient had distant metastasis. The estimated 2-year progression-free survival and overall survival were 82% (95% CI, 68-95%) and 93% (95% CI, 83-100%), respectively. Grade 3 late complications occurred in 3 patients (9%). Conclusions: CCRT with paclitaxel and nedaplatin followed by consolidation chemotherapy is well tolerated and effective in patients with locally advanced squamous cell cervical carcinoma. Further randomized trials of comparing this regimen with the standard treatment are worth while.« less

Supplement Analysis for the Watershed Management Program Final EIS (DOE EIS /SA-156) - Upper Salmon River Anadromous Fish Passage Improvement Projects

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

Keller, Carl J.

2004-07-13

BPA proposes to fund IDFG to plan and complete construction of fish passage improvements and water conservation activities that are contained within IDFG’s Statement of Work (SOW) for the period 7/1/04 to 6/30/05. The funding request contained in their SOW is part of an ongoing IDFG effort to fund anadromous fish passage projects that fall outside the scope of the Mitchell Act. The proposed SOW activities fall within the following four categories: Phase I-Planning and Design (gather data, perform investigations, and exchange information; perform surveys and assessments to be compliant; survey project sites and perform engineering designs; perform contract andmore » project management); Phase II-Construction and Implementation (procure materials and supplies, prepare contracts and solicit bids, plant native seedlings, complete capital improvements); Phase III-Operation and Maintenance (maintain office operations); and Phase IV- Monitoring and Evaluation (monitor and evaluate post-project effects, reporting). The SOW culminates with proposed construction of 18 capital improvement projects (Table 1 attached). The types of capital improvements include: screening gravity water diversions; consolidating and/or eliminating ditches; evaluating and screening pump diversions; evaluating and implementing water conservation activities; constructing screens along migration routes and rearing areas for hatchery and wild salmon; improving upstream and downstream passage for anadromous fish; and maximize benefits to aquatic habitat. Because each of the proposed projects in the SOW is still in the planning stages, the specifics of each still need to be completed.« less

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...

Magnetic and low temperature phonon studies of CoCr2O4 powders doped with Fe(III) and Ni(II) ions

NASA Astrophysics Data System (ADS)

Ptak, M.; Mączka, M.; Pikul, A.; Tomaszewski, P. E.; Hanuza, J.

2014-04-01

Extensive temperature-dependent phonon studies and low-temperature magnetic measurements of CoCr2-xFexO4 (for x=0.5, 1 and 2) and Co0.9Ni0.1Cr2O4 polycrystalline powders are presented. The main aim of these studies was to obtain information on phonon and structural properties of these compounds as well as strength of spin-phonon coupling in the magnetically ordered phases. IR and Raman spectra show that doping of CoCr2O4 with Fe(III) ions leads to broadening of bands and appearance of new bands due to the formation of inverted spinel structure. In contrast to this behavior, doping with 10 mol% of Ni(II) ions leads to weak increase of band width only. Magnetization measured as a function of temperature and external magnetic field showed that magnetic properties of Co0.9Ni0.1Cr2O4 sample are similar to those reported for pure CoCr2O4, i.e., partial substitution of Ni(II) for Co(II) leads to slight shift of the ferrimagnetic phase transition at TC and spiral spin order transition at TS towards lower values. The change of crystallization preference induced by incorporation of increasing concentration of Fe(III) ions in the spinel lattice causes significant increase of TC and decrease of TS. The latter transition disappears completely for higher concentrations of Fe(III). The performed temperature-dependent IR studies revealed interesting anomalous behavior of phonons below TC for CoCr1.5Fe0.5O4 and Co0.9Ni0.1Cr2O4, which was attributed to spin-phonon coupling.

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…

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

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

Chen, Chunmei; Kukkadapu, Ravi K.; Lazareva, Olesya

Properties of Fe minerals are poorly understood in natural soils and sediments with variable redox conditions. In this study, we combined 57Fe Mössbauer and Fe K-edge X-ray absorption spectroscopic techniques to assess solid-phase Fe speciation along the vertical redox gradients of floodplain profiles, which exhibited a succession of oxic, anoxic and suboxic-oxic zones with increasing depth along the vertical profiles. The anoxic conditions at the intermediate horizon (55-80 cm) of the eastern floodplain resulted in extensive depletion of Fe(III)-oxides including both ferrihydrite and goethite, concurrent with a corresponding reduction of phyllosilicates(PS)-Fe(III) to PS-Fe(II). In addition, the anoxic conditions increased themore » crystallinity of Fe(III)-oxides in this reduced zone, relative to the oxic zones. In the most reduced intermediate sediments at 80-120cm of the western floodplain, the anoxic conditions drove the complete reductive dissolution of Fe(III) oxides, as well as the greatest reduction (48-55%) in PS-Fe(III). In both oxic near-surface horizon and oxic-suboxic gravel aquifers beneath the soil horizons, Fe(III)-oxides were mainly present as ferrihydrite with a less amount of goethite, which preferentially occurred as nanogoethite or Al/Si-substituted goethite. Ferrihydrite with varying crystallinity or impurities such as organic matter, Al or Si, persisted under suboxic-oxic conditions in the floodplain. This study indicates that vertical redox gradients exert a major control on the quantity and speciation of Fe(III) oxides as well as the oxidation state of structural Fe in PS, which could significantly affect nutrient cycling and carbon (de)stabilization.« less

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.

Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients.

PubMed

Labarrière, Nathalie; Pandolfino, Marie-Christine; Gervois, Nadine; Khammari, Amir; Tessier, Marie-Hélène; Dréno, Brigitte; Jotereau, Francine

2002-11-01

Adoptive therapy for cancer using tumor-infiltrating lymphocytes (TIL) has mainly been investigated in cancer patients with advanced stage disease. The limited clinical success has not been encouraging, although this might be explained by poor TIL specificity and/or high tumor burden. To re-evaluate the effectiveness of adoptive therapy, we analyzed the capacity of tumor-reactive TIL injection in preventing the further development of disease in stage III melanoma patients after complete tumor resection. A phase II/III randomized trial was performed on 88 melanoma patients, who received autologous TIL plus interleukin-2 (IL-2) or IL-2 only. The duration of relapse-free survival was analyzed, taking into account the immunological specificity of injected TIL and the number of metastatic lymph nodes removed before treatment. Kaplan-Meyer analysis revealed that the injection of tumor-reactive TIL was statistically correlated with prolonged relapse-free survival in patients with only one metastatic lymph node. Therefore, improved clinical outcome could be obtained after adoptive therapy by selecting appropriate groups of patients and monitoring the specificity of the injected TIL populations.

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;…

Clinical pharmacology of novel anti-Alzheimer disease modifying medications.

PubMed

Caraci, Filippo; Bosco, Paolo; Leggio, Gian Marco; Malaguarnera, Michele; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

2013-01-01

In recent years, efforts have been directed to develop "disease-modifying" medications to treat Alzheimer's disease (AD), able to halt or slow the pathological process. Because the earlier the treatment starts, the greater is the possibility of efficacy, it is important to set up biomarkers for early diagnosis of functional brain abnormalities, before the clinical manifestation of the overt disease. Up to now, strategies to develop disease-modifying drugs have mainly targeted β amyloid (Aβ, accumulation, aggregation, clearance) and/or tau protein (phosphorylation and aggregation). Active and passive immunotherapy is the main strategy aimed at increasing Aβ clearance. Unfortunately several candidate diseasemodifying drugs have failed in phase III clinical trials conducted in mild to moderate AD. More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. Several methological problems have been recently pointed out to explain the lack of clinical efficacy of novel disease-modifying drug-treatments; moreover, new insights in pathophysiology of AD give the premise to develop novel drug targeting. Clinical trials recently completed and/or still ongoing are discussed in the present review.

Ethinyl estradiol and levonorgestrel in a transdermal contraceptive delivery system.

PubMed

Sriprasert, Intira; Stanczyk, Frank Z; Archer, David F

2015-01-01

The new transdermal contraceptive delivery system (TCDS) developed by Agile Therapeutics containing ethinyl estradiol and levonorgestrel (EE/LNG) is a reversible contraceptive method that maintains stable serum levels of both estrogen and progestin, and has efficacy similar to that of combination oral contraceptives (COC). We provided information of this new TCDS compared with the only TCDS available on the market that contains EE and norelgestromin, and has a higher EE exposure than a COC with 35 µg of EE potentially increasing the risk of venous thromboembolism. The article will summarize finding from clinical studies Phase I, II and III of EE/LNG TCDS. The development of the lower dose EE/LNG TCDS has demonstrated less EE exposure. The serum levels of EE and LNG were stable and comparable between various application sites and daily life conditions. Moreover, the EE/LNG TCDS showed comparable efficacy among obese and non-obese users. However, the Pearl index of this EE/LNG TCDS is questionable and the problem of compliance is a potential confounder of the results. The current Phase III efficacy study will contribute to a further evaluation of compliance and efficacy and will be completed in 2016.

Mipomersen sodium: first global approval.

PubMed

Hair, Philip; Cameron, Fiona; McKeage, Kate

2013-04-01

Mipomersen sodium (Kynamro™) (henceforth mipomersen) is a second-generation antisense oligonucleotide inhibitor of apolipoprotein B-100, which is the main structural component of atherogenic lipid particles. Mipomersen is administered via subcutaneous injection and is indicated as adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH). The drug was developed by Isis Pharmaceuticals, which now collaborates with Genzyme Corporation for on-going development and product marketing. Multinational phase III trials of mipomersen as adjunctive therapy were completed in patients with HoFH, severe FH, heterozygous FH (HeFH) with coronary artery disease (CAD), and in those with hypercholesterolaemia at high risk of CAD. Mipomersen 200 mg once weekly has been approved in the USA as an adjunct to lipid-lowering medications and diet in HoFH patients and is undergoing regulatory review in the EU for the same indication. Genzyme is also conducting a multinational phase III, open-label extension study to evaluate long-term treatment in HoFH and HeFH patients, as well as a multinational trial to evaluate a three-times-per-week mipomersen regimen in patients with severe FH. This article summarises the milestones in the development of once-weekly, subcutaneous mipomersen leading to this first approval.

High-speed counter-current chromatography in separation of betacyanins from flowers of red Gomphrena globosa L. cultivars.

PubMed

Spórna-Kucab, Aneta; Hołda, Ewelina; Wybraniec, Sławomir

2016-10-15

Antioxidant and possible chemopreventive properties of betacyanins, natural plant pigments, contribute to a growing interest in their chemistry and separation. Mixtures of betacyanins from fresh red Gomphrena globosa L. cultivar flowers were separated in three highly polar solvent systems by high-speed counter-current chromatography (HSCCC) for a direct comparison of their separation effectiveness. Three samples of crude extract (600mg) were run on semi-preparative scale in solvent system (NH4)2SO4soln - EtOH (2.0:1.0, v/v) (system I) and the modified systems: EtOH - ACN - 1-PrOH - (NH4)2SO4satd.soln - H2O (0.5:0.5:0.5:1.2:1.0, v/v/v/v/v) (system II) and EtOH - ACN - (NH4)2SO4satd.soln - H2O (1.0:0.5:1.2:1.0, v/v/v/v) (system III). The systems were used in the head-to-tail (system I) or tail-to-head (systems II and III) mode. The flow rate of the mobile phase was 2.0ml/min and the column rotation speed was 860rpm. The retention of the stationary phase was 52.0% (system I), 80.2% (systems II) and 82.0% (system III). The betacyanins in the crude extract as well as HSCCC fractions were analyzed by LC-MS/MS. System I was applied for the first time in HSCCC for the separation of betacyanins and was quite effective in separation of amaranthine and 17-decarboxy-amaranthine (αI=1.19) and very effective for 17-decarboxy-amaranthine and betanin (αI=2.20). Modification of system I with acetonitrile (system III) as well as acetonitrile and propanol (system II) increased their separation effectiveness. Systems II-III enable complete separation of 17-decarboxy-amaranthine (KD(II)=2.94,KD(III)=2.42) and betanin (KD(II)=2.46,KD(III)=1.10) as well as betanin and gomphrenin I (KD(II)=1.62, KD(III)=0.74). In addition, separation of amaranthine and 17-decarboxy-amaranthine is the most effective in system II, therefore, this system proved to be the most suitable for the separation of all polar betacyanins. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Engineering Chimeric Antigen Receptor T cells to Treat Glioblastoma.

PubMed

Choi, Bryan D; O'Rourke, Donald M; Maus, Marcela V

2017-08-01

Immunotherapy has emerged as a promising strategy for glioblastoma (GBM), a disease that remains universally fatal despite currently available standard-of-care. Adoptive T cell therapy has been shown to produce potent antitumor immunity while obviating the need for traditional antigen presentation and primary immune responses. Chimeric antigen receptors (CARs) are specialized molecules that can be expressed on the surface of T cells allowing for redirected cytotoxicity against tumor antigens of interest. To date, the application of CAR T cells for GBM has been relatively limited, in large part due to a dearth of well-described tumor specific antigens that are both homogenously and frequently expressed. A mutated version of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase that is expressed on the surface of GBM and other common neoplasms, but completely absent from all normal tissues. We have recently generated CAR T cells directed against EGFRvIII and reported results from a Phase I clinical trial investigating this platform in patients with EGFRvIII-expressing GBM. Our study showed that despite conventional notions of central nervous system "immune-privilege," EGFRvIII CAR T cells trafficked to intracerebral tumors, leading to successful targeting and eradication of this antigen in the brain. Here, we review our experience with EGFRvIII CAR T cells and highlight important considerations for the clinical translation of this therapy in patients with GBM.

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

Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

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

Kato, Ken, E-mail: kenkato@ncc.go.jp; Muro, Kei; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi

Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m{sup 2}/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m{sup 2}) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-weekmore » break. Responders received two courses of 5-FU (800 mg/m{sup 2}/day) on Days 1-5 and CDDP (80 mg/m{sup 2}) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.« less

A model of irreversible jam formation in dense traffic

NASA Astrophysics Data System (ADS)

Brankov, J. G.; Bunzarova, N. Zh.; Pesheva, N. C.; Priezzhev, V. B.

2018-03-01

We study an one-dimensional stochastic model of vehicular traffic on open segments of a single-lane road of finite size L. The vehicles obey a stochastic discrete-time dynamics which is a limiting case of the generalized Totally Asymmetric Simple Exclusion Process. This dynamics has been previously used by Bunzarova and Pesheva (2017) for an one-dimensional model of irreversible aggregation. The model was shown to have three stationary phases: a many-particle one, MP, a phase with completely filled configuration, CF, and a boundary perturbed MP+CF phase, depending on the values of the particle injection (α), ejection (β) and hopping (p) probabilities. Here we extend the results for the stationary properties of the MP+CF phase, by deriving exact expressions for the local density at the first site of the chain and the probability P(1) of a completely jammed configuration. The unusual phase transition, characterized by jumps in both the bulk density and the current (in the thermodynamic limit), as α crosses the boundary α = p from the MP to the CF phase, is explained by the finite-size behavior of P(1). By using a random walk theory, we find that, when α approaches from below the boundary α = p, three different regimes appear, as the size L → ∞: (i) the lifetime of the gap between the rightmost clusters is of the order O(L) in the MP phase; (ii) small jams, separated by gaps with lifetime O(1) , exist in the MP+CF phase close to the left chain boundary; and (iii) when β = p, the jams are divided by gaps with lifetime of the order O(L 1 / 2) . These results are supported by extensive Monte Carlo calculations.

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

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.

Phase III Advanced Anodes and Cathodes Utilized in Energy Efficient Aluminum Production Cells

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

R.A. Christini; R.K. Dawless; S.P. Ray

2001-11-05

During Phase I of the present program, Alcoa developed a commercial cell concept that has been estimated to save 30% of the energy required for aluminum smelting. Phase ii involved the construction of a pilot facility and operation of two pilots. Phase iii of the Advanced Anodes and Cathodes Program was aimed at bench experiments to permit the resolution of certain questions to be followed by three pilot cells. All of the milestones related to materials, in particular metal purity, were attained with distinct improvements over work in previous phases of the program. NiO additions to the ceramic phase andmore » Ag additions to the Cu metal phase of the cermet improved corrosion resistance sufficiently that the bench scale pencil anodes met the purity milestones. Some excellent metal purity results have been obtained with anodes of the following composition: Further improvements in anode material composition appear to be dependent on a better understanding of oxide solubilities in molten cryolite. For that reason, work was commissioned with an outside consultant to model the MeO - cryolite systems. That work has led to a better understanding of which oxides can be used to substitute into the NiO-Fe2O3 ceramic phase to stabilize the ferrites and reduce their solubility in molten cryolite. An extensive number of vertical plate bench electrolysis cells were run to try to find conditions where high current efficiencies could be attained. TiB2-G plates were very inconsistent and led to poor wetting and drainage. Pure TiB2 did produce good current efficiencies at small overlaps (shadowing) between the anodes and cathodes. This bench work with vertical plate anodes and cathodes reinforced the importance of good cathode wetting to attain high current efficiencies. Because of those conclusions, new wetting work was commissioned and became a major component of the research during the third year of Phase III. While significant progress was made in several areas, much work needs to be done. The anode composition needs further improvements to attain commercial purity targets. At the present corrosion rate, the vertical plate anodes will wear too rapidly leading to a rapidly increasing anode-cathode gap and thermal instabilities in the cell. Cathode wetting as a function of both cathode plate composition and bath composition needs to be better understood to ensure that complete drainage of the molten aluminum off the plates occurs. Metal buildup appears to lead to back reaction and low current efficiencies.« less

Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia.

PubMed

Meaney, Calvin J; Beccari, Mario V; Yang, Yang; Zhao, Jiwei

2017-04-01

To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia. A systematic review and meta-analysis of phase II and III clinical trial data was completed. Eight studies (two phase II and four phase III trials with two subgroup analyses) were included in the qualitative analysis, and six studies (two phase II and four phase III trials) were included in the meta-analysis. Significant heterogeneity was found in the meta-analysis with an I 2 value ranging from 80.6-99.6%. A random-effects meta-analysis was applied for all end points. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, a significant -0.70 mEq/L (95% confidence interval [CI] -0.48 to -0.91 mEq/L) change was noted in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was -0.36 mEq/L (range of standard deviation 0.07-0.30). The primary end point for ZS-9-change in potassium at 48 hours-was -0.67 mEq/L (95% CI -0.45 to -0.89 mEq/L). By 1 hour after ZS-9 administration, change in potassium was -0.17 mEq/L (95% CI -0.05 to -0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with the adverse effects of urinary tract infections (1.1%) and edema (0.9%). Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary end point of this meta-analysis. Given the adverse effect profile and the observed time-dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia. © 2017 Pharmacotherapy Publications, Inc.

Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia

PubMed Central

Meaney, Calvin J.; Beccari, Mario V.; Yang, Yang; Zhao, Jiwei

2017-01-01

Objective To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia. Design A systematic review and meta-analysis of phase II and III clinical trial data was completed. Patients or Participants Eight studies (2 phase II and 4 phase III trials with 2 subgroup analyses) were included in the qualitative analysis whereas six studies (2 phase II and 4 phase III trials) were included in the meta-analysis. Measurements and Results There was significant heterogeneity in the meta-analysis with an I2 value ranging from 80.6–99.6%. A random-effects meta-analysis was applied for all endpoints. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, there was a significant −0.70mEq/L (95% confidence interval [CI] −0.48 to −0.91mEq/L) change in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was −0.36mEq/L (range of standard deviation: 0.07 to 0.30). The primary endpoint for ZS-9-- change in potassium at 48 hours-- was −0.67mEq/L (95% CI −0.45 to −0.89mEq/L). By 1 hour after ZS-9 administration, change in potassium was −0.17mEq/L (95% CI −0.05 to −0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with adverse effects of urinary tract infections (1.1%) and edema (0.9%). Conclusion Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary endpoint of this meta-analysis. Given the adverse effect profile and the observed time dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia. PMID:28122118

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.

Effect of 60 degrees head-down tilt on peripheral gas mixing in the human lung.

PubMed

Olfert, I Mark; Prisk, G Kim

2004-09-01

The phase III slope of sulfur hexafluoride (SF6) in a single-breath washout (SBW) is greater than that of helium (He) under normal gravity (i.e., 1G), thus resulting in a positive SF6-He slope difference. In microgravity (microG), SF6-He slope difference is smaller because of a greater fall in the phase III slope of SF6 than He. We sought to determine whether increasing thoracic fluid volume using 60 degrees head-down tilt (HDT) in 1G would produce a similar effect to microG on phase III slopes of SF6 and He. Single-breath vital capacity (SBW) and multiple-breath washout (MBW) tests were performed before, during, and 60 min after 1 h of HDT. Compared with baseline (SF6 1.050 +/- 0.182%/l, He 0.670 +/- 0.172%/l), the SBW phase III slopes for both SF6 and He tended to decrease during HDT, reaching nadir at 30 min (SF6 0.609 +/- 0.211%/l, He 0.248 +/- 0.138%/l; P = 0.08 and P = 0.06, respectively). In contrast to microG, the magnitude of the phase III slope decrease was similar for both SF6 and He; therefore, no change in SF6-He slope difference was observed. MBW analysis revealed a decrease in normalized phase III slopes at all time points during HDT, for both SF6 (P < 0.01) and He (P < 0.01). This decrease was due to changes in the acinar, and not the conductive, component of the normalized phase III slope. These findings support the notion that changes in thoracic fluid volume alter ventilation distribution in the lung periphery but also demonstrate that the effect during HDT does not wholly mimic that observed in microG.

Hematoporphyrin-mediated photodynamic therapy for treatment of head and neck cancer: clinical update 1996

NASA Astrophysics Data System (ADS)

Schweitzer, Vanessa G.

1996-04-01

From 1983 to 1996 Phase II and III clinical studies at Henry Ford Hospital demonstrated complete or partial responses in 55 of 56 patients treated with hematoporphyrin-derivative or PHOTOFRIN-mediated photodynamic therapy (HPD-PDT) for a variety of benign and malignant upper aerodigestive tract disease: (1) superficial 'condemned mucosa' or 'field cancerization' of the oral cavity and larynx (7 cases); (2) Stage III/IV head and neck cancer (25 cases); (3) mucocutaneous AIDS-associated Kaposi's sarcoma of the upper aerodigestive tract and non AIDS-related Kaposi's sarcoma of the lower extremity (15 cases); (4) recurrent laryngotracheal papillomatosis (3 cases); (5) severe dysplasia/adenocarcinoma or squamous cell carcinoma in situ in Barrett's esophagus (4 cases); (6) partial or completely obstructing terminal esophageal cancer (9 cases). At the time of this report, HPD-PDT produced complete responses in 24 patients (follow up 6 months to 9 years) with 'field cancerization' (CIS, T1N0M0) of the oral cavity and larynx (6 cases), adenocarcinoma in situ in Barrett's esophagus (3 cases), mucocutaneous Kaposi's sarcoma (12 cases), obstructing esophageal carcinoma (1 case), and stage IV squamous cell carcinoma of the nasopharynx (1 case), and radiation therapy or solar-induced basal cell/squamous cell carcinomas (2 cases). PDT treatment protocols, results, complications, and application as adjunct or primary oncologic therapy for head and neck cancer are reviewed in this article.

Fluocinolone acetonide ophthalmic--Bausch & Lomb: fluocinolone acetonide Envision TD implant.

PubMed

2005-01-01

Bausch & Lomb and Control Delivery Systems have developed an intravitreal implant that can deliver the corticosteroid fluocinolone acetonide [fluocinolone acetonide implant, Retisert] to posterior eye tissue for up to 3 years. The implant uses Bausch & Lomb's Envision TD technology. This fluocinolone acetonide implant has been designed for the treatment of non-infectious uveitis affecting the posterior segment of the eye and other eye disorders, which benefit from local anti-inflammatory therapy. In July 2003, Bausch & Lomb assumed all responsibility for day-to-day clinical development and regulatory activities relating to fluocinolone acetonide implant development from Control Delivery Systems. In May 2002, Control Delivery systems and Bausch & Lomb formally amended their budget for their license and development agreement. Bausch & Lomb will increase its funding to support the development of agents for the treatment of diabetic macular oedema, posterior uveitis and wet age-related macular degeneration to USD $206 million through to 2008. In January 2004, Bausch & Lomb decided to focus development of the fluocinolone acetonide implant in only one indication, non-infectious uveitis affecting the posterior segment of the eye. It had been in development for other indications, including macular oedema and age-related macular degeneration. However, these will be targeted with later-generation implant technologies, different drugs, or combinations of both. The implant delivering fluocinolone acetonide 0.59 mg or 2.1mg has completed enrollment in two pivotal 3-year phase IIb/III trials in the US, Canada, Australia and Asia for the treatment of posterior uveitis. Enrollment in these multicenter randomised, double-masked studies was closed in May 2003. Bausch & Lomb was expected to file an NDA with the US FDA for the use of the agent in the treatment of uveitis in mid-2003. However, in February 2003, the company reported that, after a review of various filing strategies, the date of filing for the treatment of non-infectious uveitis affecting the posterior segment of the eye would be held back until mid-2004, with possible commercialisation during 2005. Positive results based on 34-week data from the first phase III trial of fluocinolone acetonide implant, conducted in 26 US centres and one centre in Singapore, were reported in September 2003. Patients in this trial will be followed for an additional 2.5 years. Thirty-four-week results from the second phase III trial, conducted in 239 patients at 19 centres in Canada, the US, Australia, India, the Philippines and Hong Kong, have confirmed results in the initial phase III study, and were presented at the 37th Annual Meeting of the Retina Society. Bausch & Lomb continues to target commercialisation for 2005. In May 2000, the fluocinolone acetonide implant was granted fast-track status from the FDA and in July 2000 it received Orphan Drug designation from the FDA for posterior uveitis. In addition, enrollment was completed in a phase II trial of a fluocinolone acetonide 0.59 mg implant for the treatment of predominantly occult subfoveal choroidal neovascularisation in patients with AMD in July 2002. However, development in this indication has been discontinued.

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.

The current status of neoadjuvant therapy for esophageal cancer.

PubMed

Lin, Daniel; Leichman, Lawrence

2014-01-01

Through the contribution of a very large number of single-arm phase II trials and many less randomized phase III trials, the standard of care for locally advanced esophageal cancer has evolved to either combination chemotherapy plus radiation or combination chemotherapy. In this review, we focus on the key findings of these studies and selected meta-analyses that have led to this evolution. We note differences in outcomes for adenocarcinomas of the esophagus when compared to squamous cell esophageal cancers. Despite progress in developing a consensus for therapy, the outcome for patients with locally advanced remains poor. We complete the review by noting newer areas of investigation seeking to provide targeted and more personalized therapy to patients with esophageal cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

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.

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).

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.

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…

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

EffectS of non-nutritive sWeetened beverages on appetITe during aCtive weigHt loss (SWITCH): Protocol for a randomized, controlled trial assessing the effects of non-nutritive sweetened beverages compared to water during a 12-week weight loss period and a follow up weight maintenance period.

PubMed

Masic, U; Harrold, J A; Christiansen, P; Cuthbertson, D J; Hardman, C A; Robinson, E; Halford, J C G

2017-02-01

Acute and medium-term intervention studies suggest that non-nutritive sweeteners (NNS) are beneficial for weight loss, however there is limited human data on the long-term effects of consuming NNS on weight loss, maintenance, and appetite. Further research is therefore required to elucidate the prolonged impact of NNS consumption on these outcome measures. A randomized parallel groups design will be used to assess whether regular NNS beverage intake is equivalent to a water control in promoting weight loss over 12-weeks (weekly weight loss sessions; Phase I), then supporting weight maintenance over 40-weeks (monthly sessions; Phase II) and subsequently independent weight maintenance over 52-weeks (Phase III) in 432 participants. A subset of these participants (n=116) will complete laboratory-based appetite probe days (15 sessions; 3 sessions each at baseline, at the start of phase I and the end of each phase). A separate subset (n=50) will complete body composition scans (DXA) at baseline and at the end of each phase. All participants will regularly be weighed and will complete questionnaires and cognitive tasks to assess changes in body weight and appetitive behaviours. Measures of physical activity and biochemical markers will also be taken. The trial will assess the efficacy of NNS beverages compared to water during a behavioural weight loss and maintenance programme. We aim to understand whether the impact of NNS on weight, dietary adherence and well-being are beneficial or transient and effects on prolonged successful weight loss and weight maintenance through sustained changes in appetite and eating behaviour. Clinical Trials: NCT02591134; registered: 23.10.2015. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

INTEGRATED POWER GENERATION SYSTEMS FOR COAL MINE WASTE METHANE UTILIZATION

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

Peet M. Soot; Dale R. Jesse; Michael E. Smith

2005-08-01

An integrated system to utilize the waste coal mine methane (CMM) at the Federal No. 2 Coal Mine in West Virginia was designed and built. The system includes power generation, using internal combustion engines, along with gas processing equipment to upgrade sub-quality waste methane to pipeline quality standards. The power generation has a nominal capacity of 1,200 kw and the gas processing system can treat about 1 million cubic feet per day (1 MMCFD) of gas. The gas processing is based on the Northwest Fuel Development, Inc. (NW Fuel) proprietary continuous pressure swing adsorption (CPSA) process that can remove nitrogenmore » from CMM streams. The two major components of the integrated system are synergistic. The byproduct gas stream from the gas processing equipment can be used as fuel for the power generating equipment. In return, the power generating equipment provides the nominal power requirements of the gas processing equipment. This Phase III effort followed Phase I, which was comprised of a feasibility study for the project, and Phase II, where the final design for the commercial-scale demonstration was completed. The fact that NW Fuel is desirous of continuing to operate the equipment on a commercial basis provides the validation for having advanced the project through all of these phases. The limitation experienced by the project during Phase III was that the CMM available to operate the CPSA system on a commercial basis was not of sufficiently high quality. NW Fuel's CPSA process is limited in its applicability, requiring a relatively high quality of gas as the feed to the process. The CPSA process was demonstrated during Phase III for a limited time, during which the processing capabilities met the expected results, but the process was never capable of providing pipeline quality gas from the available low quality CMM. The NW Fuel CPSA process is a low-cost ''polishing unit'' capable of removing a few percent nitrogen. It was never intended to process CMM streams containing high levels of nitrogen, as is now the case at the Federal No.2 Mine. Even lacking the CPSA pipeline delivery demonstration, the project was successful in laying the groundwork for future commercial applications of the integrated system. This operation can still provide a guide for other coal mines which need options for utilization of their methane resources. The designed system can be used as a complete template, or individual components of the system can be segregated and utilized separately at other mines. The use of the CMM not only provides an energy fuel from an otherwise wasted resource, but it also yields an environmental benefit by reducing greenhouse gas emissions. The methane has twenty times the greenhouse effect as compared to carbon dioxide, which the combustion of the methane generates. The net greenhouse gas emission mitigation is substantial.« less

The role of BRAF V600 mutation in melanoma

PubMed Central

2012-01-01

BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors. PMID:22554099

Complete Genome Sequence of Staphylococcus aureus XN108, an ST239-MRSA-SCCmec III Strain with Intermediate Vancomycin Resistance Isolated in Mainland China

PubMed Central

Zhang, Xia; Xu, Xiaomeng; Yuan, Wenchang; Hu, Qiwen; Shang, Weilong; Hu, Xiaomei

2014-01-01

ST239-MRSA-SCCmec III (ST239, sequence type 239; MRSA, methicillin-resistant Staphylococcus aureus; SCCmec III, staphylococcal cassette chromosome mec type III) is the most predominant clone of hospital-acquired methicillin-resistant S. aureus in mainland China. We report here the complete genome sequence of XN108, the first vancomycin-intermediate S. aureus strain isolated from a steam-burned patient with a wound infection. PMID:25059856

Vaccine approaches to malaria control and elimination: Insights from mathematical models.

PubMed

White, Michael T; Verity, Robert; Churcher, Thomas S; Ghani, Azra C

2015-12-22

A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts. Several candidate vaccines targeting different stages of the malaria parasite's lifecycle are currently under development, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection, having recently completed Phase III trials. Predicting the public health impact of a candidate malaria vaccine requires using clinical trial data to estimate the vaccine's efficacy profile--the initial efficacy following vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacy profile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematical models. Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocytic vaccines and transmission-blocking vaccines from clinical trial data. In the case of RTS,S/AS01, model estimates from Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection, with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waning over the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II or Phase III clinical trials so we review ongoing work investigating how a clinical trial might be designed to ensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstrate how parameters estimated from clinical trials can be used to predict the impact of vaccination campaigns on malaria using a mathematical model of malaria transmission. Copyright © 2015 Elsevier Ltd. All rights reserved.

Size of clinical trials and Introductory prices of prophylactic vaccine series

PubMed Central

Weinberg, Steven H.; Butchart, Amy T.; Davis, Matthew M.

2012-01-01

Costs of completing the recommended immunization schedule have increased over the last decade. Access to prophylactic vaccines may become limited due to financing obstacles within current delivery systems. Vaccine prices reflect research and development expenses incurred by vaccine manufacturers, including costs associated with evaluating candidate vaccines in human subjects. If the number of subjects in clinical trials is increasing over time and associated with vaccine price, this may help explain increases in prices of vaccine series. We examined whether: (A) the initial public- and private-sector prices for recommended prophylactic vaccine series licensed and recommended in the US increased from 2000–2011, (B) the number of human subjects per licensed vaccine increased during the time period, and (C) the number of human subjects was associated with the initial public–and private–sector prices of the vaccine series. In regression analyses of 13 vaccines, approval year was not significantly associated with the number of human subjects, initial public-sector prices, or initial private-sector prices. While the number of phase II subjects was not significantly associated with prices, the numbers of phase III and combined late phase (phases II + III) subjects were significantly associated with initial public- and private-sector series prices (p < 0.05). The association between number of subjects and initial prices demonstrated diminishing marginal increases in price with increasing numbers of subjects. These findings may help guide the number of subjects required by the FDA in clinical trials, in order to reduce expenses for manufacturers and thereby help mitigate increases in initial vaccine series prices. PMID:22854668

Size of clinical trials and Introductory prices of prophylactic vaccine series.

PubMed

Weinberg, Steven H; Butchart, Amy T; Davis, Matthew M

2012-08-01

Costs of completing the recommended immunization schedule have increased over the last decade. Access to prophylactic vaccines may become limited due to financing obstacles within current delivery systems. Vaccine prices reflect research and development expenses incurred by vaccine manufacturers, including costs associated with evaluating candidate vaccines in human subjects. If the number of subjects in clinical trials is increasing over time and associated with vaccine price, this may help explain increases in prices of vaccine series. We examined whether: (A) the initial public- and private-sector prices for recommended prophylactic vaccine series licensed and recommended in the US increased from 2000-2011, (B) the number of human subjects per licensed vaccine increased during the time period, and (C) the number of human subjects was associated with the initial public-and private-sector prices of the vaccine series. In regression analyses of 13 vaccines, approval year was not significantly associated with the number of human subjects, initial public-sector prices, or initial private-sector prices. While the number of phase II subjects was not significantly associated with prices, the numbers of phase III and combined late phase (phases II + III) subjects were significantly associated with initial public- and private-sector series prices (p < 0.05). The association between number of subjects and initial prices demonstrated diminishing marginal increases in price with increasing numbers of subjects. These findings may help guide the number of subjects required by the FDA in clinical trials, in order to reduce expenses for manufacturers and thereby help mitigate increases in initial vaccine series prices.

Phase-II trials in osteosarcoma recurrences: A systematic review of past experience.

PubMed

Omer, Natacha; Le Deley, Marie-Cécile; Piperno-Neumann, Sophie; Marec-Berard, Perrine; Italiano, Antoine; Corradini, Nadège; Bellera, Carine; Brugières, Laurence; Gaspar, Nathalie

2017-04-01

The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. To study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Systematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Design specifications for NALDA (Naval Aviation Logistics Data Analysis) CAI (computer aided instruction): Phase 2, Interim report

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

Twitty, A.F.; Handler, B.H.; Duncan, L.D.

Data Systems Engineering Organization (DSEO) personnel are developing a prototype computer aided instruction (CAI) system for the Naval Aviation Logistics Data Analysis (NALDA) system. The objective of this project is to provide a prototype for implementing CAI as an enhancement to existing NALDA training. The CAI prototype project is being performed in phases. The task undertaken in Phase I was to analyze the problem and the alternative solutions and to develop a set of recommendations on how best to proceed. In Phase II a structured design and specification document was completed that will provide the basis for development and implementationmore » of the desired CAI system. Phase III will consist of designing, developing, and testing a user interface which will extend the features of the Phase II prototype. The design of the CAI prototype has followed a rigorous structured analysis based on Yourdon/DeMarco methodology and Information Engineering tools. This document includes data flow diagrams, a data dictionary, process specifications, an entity-relationship diagram, a curriculum description, special function key definitions, and a set of standards developed for the NALDA CAI Prototype.« less

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.

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.

Flight Test of an Intelligent Flight-Control System

NASA Technical Reports Server (NTRS)

Davidson, Ron; Bosworth, John T.; Jacobson, Steven R.; Thomson, Michael Pl; Jorgensen, Charles C.

2003-01-01

The F-15 Advanced Controls Technology for Integrated Vehicles (ACTIVE) airplane (see figure) was the test bed for a flight test of an intelligent flight control system (IFCS). This IFCS utilizes a neural network to determine critical stability and control derivatives for a control law, the real-time gains of which are computed by an algorithm that solves the Riccati equation. These derivatives are also used to identify the parameters of a dynamic model of the airplane. The model is used in a model-following portion of the control law, in order to provide specific vehicle handling characteristics. The flight test of the IFCS marks the initiation of the Intelligent Flight Control System Advanced Concept Program (IFCS ACP), which is a collaboration between NASA and Boeing Phantom Works. The goals of the IFCS ACP are to (1) develop the concept of a flight-control system that uses neural-network technology to identify aircraft characteristics to provide optimal aircraft performance, (2) develop a self-training neural network to update estimates of aircraft properties in flight, and (3) demonstrate the aforementioned concepts on the F-15 ACTIVE airplane in flight. The activities of the initial IFCS ACP were divided into three Phases, each devoted to the attainment of a different objective. The objective of Phase I was to develop a pre-trained neural network to store and recall the wind-tunnel-based stability and control derivatives of the vehicle. The objective of Phase II was to develop a neural network that can learn how to adjust the stability and control derivatives to account for failures or modeling deficiencies. The objective of Phase III was to develop a flight control system that uses the neural network outputs as a basis for controlling the aircraft. The flight test of the IFCS was performed in stages. In the first stage, the Phase I version of the pre-trained neural network was flown in a passive mode. The neural network software was running using flight data inputs with the outputs provided to instrumentation only. The IFCS was not used to control the airplane. In another stage of the flight test, the Phase I pre-trained neural network was integrated into a Phase III version of the flight control system. The Phase I pretrained neural network provided realtime stability and control derivatives to a Phase III controller that was based on a stochastic optimal feedforward and feedback technique (SOFFT). This combined Phase I/III system was operated together with the research flight-control system (RFCS) of the F-15 ACTIVE during the flight test. The RFCS enables the pilot to switch quickly from the experimental- research flight mode back to the safe conventional mode. These initial IFCS ACP flight tests were completed in April 1999. The Phase I/III flight test milestone was to demonstrate, across a range of subsonic and supersonic flight conditions, that the pre-trained neural network could be used to supply real-time aerodynamic stability and control derivatives to the closed-loop optimal SOFFT flight controller. Additional objectives attained in the flight test included (1) flight qualification of a neural-network-based control system; (2) the use of a combined neural-network/closed-loop optimal flight-control system to obtain level-one handling qualities; and (3) demonstration, through variation of control gains, that different handling qualities can be achieved by setting new target parameters. In addition, data for the Phase-II (on-line-learning) neural network were collected, during the use of stacked-frequency- sweep excitation, for post-flight analysis. Initial analysis of these data showed the potential for future flight tests that will incorporate the real-time identification and on-line learning aspects of the IFCS.

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.

PubMed

Cohen, Ezra E W; Davis, Darren W; Karrison, Theodore G; Seiwert, Tanguy Y; Wong, Stuart J; Nattam, Sreenivasa; Kozloff, Mark F; Clark, Joseph I; Yan, Duen-Hwa; Liu, Wen; Pierce, Carolyn; Dancey, Janet E; Stenson, Kerstin; Blair, Elizabeth; Dekker, Allison; Vokes, Everett E

2009-03-01

Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.

Efficacy and safety of Privigen(®) in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase III study (the PRIMA study).

PubMed

Léger, Jean-Marc; De Bleecker, Jan L; Sommer, Claudia; Robberecht, Wim; Saarela, Mika; Kamienowski, Jerzy; Stelmasiak, Zbigniew; Mielke, Orell; Tackenberg, Björn; Shebl, Amgad; Bauhofer, Artur; Zenker, Othmar; Merkies, Ingemar S J

2013-06-01

This prospective, multicenter, single-arm, open-label Phase III study aimed to evaluate the efficacy and safety of Privigen(®) (10% liquid human intravenous immunoglobulin [IVIG], stabilized with L-proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2 g/kg body weight [bw]) and up to seven maintenance doses (1 g/kg bw) at 3-week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of ≥1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being ≥35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG-pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%-76.43%). IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naïve patients (76.9% vs. 46.7%). The median (25%-75% quantile) INCAT score improved from 3.5 (3.0-4.5) points at baseline to 2.5 (1.0-3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5-72.0] points vs. 75.5 [71.5-79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well-tolerated induction and maintenance treatment in patients with CIDP. © 2013 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.

Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma.

PubMed

Taphoorn, Martin J B; Henriksson, Roger; Bottomley, Andrew; Cloughesy, Timothy; Wick, Wolfgang; Mason, Warren P; Saran, Frank; Nishikawa, Ryo; Hilton, Magalie; Theodore-Oklota, Christina; Ravelo, Arliene; Chinot, Olivier L

2015-07-01

As glioblastoma progresses, patients experience a decline in health-related quality of life (HRQoL). Delaying this decline is an important treatment goal. In newly diagnosed glioblastoma, progression-free survival was prolonged when bevacizumab was added to radiotherapy plus temozolomide (RT/TMZ) versus placebo plus RT/TMZ (phase III AVAglio study; hazard ratio, 0.64; 95% CI, 0.55 to 0.74; P < .001). To ensure that addition of bevacizumab to standard-of-care therapy was not associated with HRQoL detriment, HRQoL assessment was a secondary objective. Patients completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BN20 at each tumor assessment (Appendix Table A1, online only). Raw scores were converted to a 100-point scale and mean changes from baseline scores were evaluated (stable: < 10-point change; clinically relevant deterioration/improvement: ≥ 10-point change). Deterioration-free survival was the time to deterioration/progression/death; time to deterioration was the time to deterioration/death. Most evaluable patients who had not progressed (> 74%) completed all HRQoL assessments for at least 1 year of treatment, and almost all completed at least one HRQoL assessment at baseline (98.3% and 97.6%, bevacizumab and placebo arms, respectively). Mean changes from baseline did not reach a clinically relevant difference between arms for most items. HRQoL declined at progression in both arms. The addition of bevacizumab to RT/TMZ resulted in statistically longer (P < .001) deterioration-free survival across all items. Time to deterioration was not statistically longer in the placebo plus RT/TMZ arm (v bevacizumab) for any HRQoL item. The addition of bevacizumab to standard-of-care treatment for newly diagnosed glioblastoma had no impact on HRQoL during the progression-free period. © 2015 by American Society of Clinical Oncology.

The development of coal-based technologies for Department of Defense facilities. Volume 1, Technical report. Semiannual technical progress report, September 28, 1994--March 27, 1995

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

Miller, B.G.; Bartley, D.A.; Hatcher, P.

1996-10-15

This program is being conducted as a cooperative agreement between the Consortium for Coal Water Mixture Technology and the U.S. Department of Energy. Activities this reporting period are summarized by phase. Phase I is nearly completed. During this reporting period, coal beneficiation/preparation studies, engineering designs and economics for retrofitting the Crane, Indiana boiler to fire coal-based fuels, and a 1,000-hour demonstration of dry, micronized coal were completed. In addition, a demonstration-scale micronized-coal water mixture (MCWM) preparation circuit was constructed and a 1,000-hour demonstration firing MCWM began. Work in Phase II focused on emissions reductions, coal beneficiation/preparation studies, and economic analysesmore » of coal use. Emissions reductions investigations involved literature surveys of NO{sub x}, SO{sub 2}, trace metals, volatile organic compounds, and fine particulate matter capture. In addition, vendors and engineering firms were contacted to identify the appropriate emissions technologies for the installation of commercial NO{sub x} and SO{sub 2} removal systems on the demonstration boiler. Information from the literature surveys and engineering firms will be used to identify, design, and install a control system(s). Work continued on the refinement and optimization of coal grinding and MCWM preparation procedures, and on the development of advanced processes for beneficiating high ash, high sulfur coals. Work also continued on determining the basic cost estimation of boiler retrofits, and evaluating environmental, regulatory, and regional economic impacts. In addition, the feasibility of technology adoption, and the public`s perception of the benefits and costs of coal usage was studied. A coal market analysis was completed. Work in Phase III focused on coal preparation studies, emissions reductions and economic analyses of coal use.« less

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...

EXTRA-A Multicenter Phase II Study of Chemoradiation Using a 5 Day per Week Oral Regimen of Capecitabine and Intravenous Mitomycin C in Anal Cancer

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

Glynne-Jones, Rob; Meadows, Helen; UCL Cancer Trials Centre, London

Purpose: 5-Fluorouracil (5-FU) + mitomycin C (MMC)-based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. Methods and Materials: Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m{sup 2}) on Day 1 and capecitabine on each RT treatment day in two divided doses (825more » mg/m{sup 2} b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. Results: Thirty-one patients entered the trial. The median age was 61 years (range 45-86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. Conclusions: Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.« less

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.

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. |

Student Perceptions of Elementary School Climates in the Louisiana School Effectiveness Study: A Comparison of Phase III and Phase IV.

ERIC Educational Resources Information Center

Roberts, Sharon Pol; Heroman, Deborah S.

A 5-year study examined third-graders' perceptions of school climate in 16 Louisiana schools. Part of the Louisiana School Effectiveness Study (LSES), Phase III and IV examined student perceptions in 1984-85 and 1989-90, respectively, and also gathered demographic data and multiple measures of student outcomes through student surveys and classroom…

Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.

PubMed

Robertson, David S; Prevost, A Toby; Bowden, Jack

2016-09-30

Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Participation of a coordinating center pharmacy in a multicenter international study.

PubMed

Jeon, Jihyun Esther; Mighty, Janet; Lane, Karen; McBee, Nichol; Majkowski, Ryan; Mayo, Steven; Hanley, Daniel

2016-11-15

The activities of a coordinating center pharmacy (CCP) supporting a multicenter, international clinical trial are described. Serving in a research support role comparable to that of a commercial clinical trial supply company, a CCP within the Johns Hopkins Hospital Investigational Drug Service (JHH IDS) uses its management expertise and infrastructure to support multicenter trials, such as the recently completed Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage, Phase III (CLEAR III) trial. The role of the CCP staff in supporting the CLEAR III trial was overall investigational product (IP) management through coordination of IP-related operations to ensure high-quality care for study participants at study sites in the United States and abroad. For the CLEAR III trial, the CCP coordinated IP supply activities; provided education to site pharmacists; developed study-specific documents, including pharmacy manuals; communicated with trial stakeholders, including third-party IP distributors; monitored treatment assignments; and performed quality assurance monitoring to ensure compliance with institutional, state, federal, and international regulations regarding IP procurement and storage. Acting as a CCP for a multicenter international study poses a number of operational challenges while providing opportunities for the CCP to contribute to research of global importance and enrich the skill sets of its personnel. The development and implementation of the CCP at JHH IDS for the CLEAR III trial included several responsibilities, such as IP supply management, communication, and database, regulatory, and finance management. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Experimental evaluation of rigor mortis. III. Comparative study of the evolution of rigor mortis in different sized muscle groups in rats.

PubMed

Krompecher, T; Fryc, O

1978-01-01

The use of new methods and an appropriate apparatus has allowed us to make successive measurements of rigor mortis and a study of its evolution in the rat. By a comparative examination on the front and hind limbs, we have determined the following: (1) The muscular mass of the hind limbs is 2.89 times greater than that of the front limbs. (2) In the initial phase rigor mortis is more pronounced in the front limbs. (3) The front and hind limbs reach maximum rigor mortis at the same time and this state is maintained for 2 hours. (4) Resolution of rigor mortis is accelerated in the front limbs during the initial phase, but both front and hind limbs reach complete resolution at the same time.

Development and Demonstration of a Magnesium-Intensive Vehicle Front-End Substructure

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

Logan, Stephen D.; Forsmark, Joy H.; Osborne, Richard

2016-07-01

This project is the final phase (designated Phase III) of an extensive, nine-year effort with the objectives of developing a knowledge base and enabling technologies for the design, fabrication and performance evaluation of magnesium-intensive automotive front-end substructures intended to partially or completely replace all-steel comparators, providing a weight savings approaching 50% of the baseline. Benefits of extensive vehicle weight reduction in terms of fuel economy increase, extended vehicle range, vehicle performance and commensurate reductions in greenhouse gas emissions are well known. An exemplary vehicle substructure considered by the project is illustrated in Figure 1, along with the exterior vehicle appearance.more » This unibody front-end “substructure” is one physical objective of the ultimate design and engineering aspects established at the outset of the larger collective effort.« less

Status of the test phase of K-3 VLBi system developed in RRL

NASA Astrophysics Data System (ADS)

Saburi, Y.; Yoshimura, K.; Kawajiri, N.; Kawano, N.; Takahashi, F.

An account is given of the last phase of a five-year plan to develop the K-3 system - a high precision VLBI system for applications in a wide variety of fields, such as geodesy, astrometry, and radio astronomy. At the end of 1983, the hardware and software of the K-3 system, were almost completed, and tests were undertaken to demonstrate compatibility with the Mark III system. Topics covered include: Characteristics of the 26-m antenna receiving system, the first U.S.-Japan test observations, and experiments to be conducted for the period up through 1989 at least. Precise time comparison experiments between atomic clocks at the Radio Research Laboratories and the U.S. Naval Observatory were to begin in 1985 and produce data at least once a month for several years.

The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation

PubMed Central

Houlihan, Shauna L; Feng, Yuanyi

2014-01-01

Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders. DOI: http://dx.doi.org/10.7554/eLife.03297.001 PMID:25245017

Phase II Trial of β-All-trans-Retinoic Acid for Cervical Intraepithelial Neoplasia Delivered via a Collagen Sponge and Cervical Cap

PubMed Central

Graham, Vivian; Surwit, Earl S.; Weiner, Sheldon; Meyskens, Frank L.

1986-01-01

Retinoids are effective suppressors of the phenotypic development of cancer in many animal systems, whether the process is initiated by chemical, physical or viral carcinogens. Cases of cervical intraepithelial neoplasia are excellent for studying the effectiveness of retinoids as chemopreventive agents because the process can be closely followed by serial colposcopic and pathologic (cytology or biopsy) means and changes in the condition safely monitored. We have previously conducted a phase I study of trans-retinoic acid (Tretinoin) given topically by a collagen sponge and cervical cap. A dose of 0.372% was selected for phase II trial. We have treated 20 patients with topical retinoic acid, and a complete response with total regression of disease was obtained in 50%. Systemic and cervical side effects were mild and vaginal side effects moderate but tolerable. These results provide a clinical basis for a randomized, double-blind phase III study to definitely answer the question of whether retinoic acid is an effective chemopreventive agent for cervical cancer. ImagesFigure. 1. PMID:3765597

Biomedical informatics: development of a comprehensive data warehouse for clinical and genomic breast cancer research.

PubMed

Hu, Hai; Brzeski, Henry; Hutchins, Joe; Ramaraj, Mohan; Qu, Long; Xiong, Richard; Kalathil, Surendran; Kato, Rand; Tenkillaya, Santhosh; Carney, Jerry; Redd, Rosann; Arkalgudvenkata, Sheshkumar; Shahzad, Kashif; Scott, Richard; Cheng, Hui; Meadow, Stephen; McMichael, John; Sheu, Shwu-Lin; Rosendale, David; Kvecher, Leonid; Ahern, Stephen; Yang, Song; Zhang, Yonghong; Jordan, Rick; Somiari, Stella B; Hooke, Jeffrey; Shriver, Craig D; Somiari, Richard I; Liebman, Michael N

2004-10-01

The Windber Research Institute is an integrated high-throughput research center employing clinical, genomic and proteomic platforms to produce terabyte levels of data. We use biomedical informatics technologies to integrate all of these operations. This report includes information on a multi-year, multi-phase hybrid data warehouse project currently under development in the Institute. The purpose of the warehouse is to host the terabyte-level of internal experimentally generated data as well as data from public sources. We have previously reported on the phase I development, which integrated limited internal data sources and selected public databases. Currently, we are completing phase II development, which integrates our internal automated data sources and develops visualization tools to query across these data types. This paper summarizes our clinical and experimental operations, the data warehouse development, and the challenges we have faced. In phase III we plan to federate additional manual internal and public data sources and then to develop and adapt more data analysis and mining tools. We expect that the final implementation of the data warehouse will greatly facilitate biomedical informatics research.

A comparative evaluation of different ionic liquids for arsenic species separation and determination in wine varietals by liquid chromatography - hydride generation atomic fluorescence spectrometry.

PubMed

Castro Grijalba, Alexander; Fiorentini, Emiliano F; Martinez, Luis D; Wuilloud, Rodolfo G

2016-09-02

The application of different ionic liquids (ILs) as modifiers for chromatographic separation and determination of arsenite [As(III)], arsenate [As(V)], dimethylarsonic acid (DMA) and monomethylarsonic acid (MMA) species in wine samples, by reversed-phase high performance liquid chromatography coupled to hydride generation atomic fluorescence spectrometry detection (RP-HPLC-HG-AFS) was studied in this work. Several factors influencing the chromatographic separation of the As species, such as pH of the mobile phase, buffer solution concentration, buffer type, IL concentration and length of alkyl groups in ILs were evaluated. The complete separation of As species was achieved using a C18 column in isocratic mode with a mobile phase composed of 0.5% (v/v) 1-octyl-3-methylimidazolium chloride ([C8mim]Cl) and 5% (v/v) methanol at pH 8.5. A multivariate methodology was used to optimize the variables involved in AFS detection of As species after they were separated by HPLC. The ILs showed remarkable performance for the separation of As species, which was obtained within 18min with a resolution higher than 0.83. The limits of detection for As(III), As(V), MMA and DMA were 0.81, 0.89, 0.62 and 1.00μg As L(-1). The proposed method was applied for As speciation analysis in white and red wine samples originated from different grape varieties. Copyright © 2016 Elsevier B.V. All rights reserved.

Investigations on FCAM-III (Ca2.38Mg2.09Fe3+10.61Fe2+1.59Al9.33O36): A new homologue of the aenigmatite structure-type in the system CaO-MgO-Fe2O3-Al2O3

NASA Astrophysics Data System (ADS)

Zöll, Klaus; Kahlenberg, Volker; Krüger, Hannes; Tropper, Peter

2018-02-01

In the course of a systematic study of a part of the quaternary system Fe2O3-CaO-Al2O3-MgO (FCAM) the previously unknown compound Ca2.38Mg2.09Fe3+10.61Fe2+1.59Al9.33O36 (FCAM-III) has been synthesized. By analogy with the so-called SFCA series [1-5], our investigation in the system of FCAM shows the existence of a stoichiometric homologous series M14+6nO20+8n, where M = Fe, Ca, Al, Mg and n = 1 or 2. In air, we can prove the formation of coexisting FCAM-III and FCAM-I solid solutions at 1400 °C. By increasing the temperature up to 1425 °C FCAM-I disappears completely and FCAM-III co-exists with magnesiumferrite and a variety of calcium iron oxides. At 1450 °C FCAM-III breaks down to a mixture of FCAM-I again as well as magnesioferrite and melt. Small single-crystals of FCAM-III up to 35 μm in size could be retrieved from the 1425 °C experiment and were subsequently characterized using electron microprobe analysis and synchroton X-ray single-crystal diffraction. Finally the Fe2+/Fetot ratio was calculated from the total iron content based on the crystal-chemical formula obtained from EMPA measurements and charge balance considerations. FCAM-III or Ca2.38Mg2.09Fe3+10.61Fe2+1.59Al9.33O36 has a triclinic crystal structure (space group P 1 ̅). The basic crystallographic data are: a = 10.223(22) Å, b = 10.316(21) Å, c = 14.203(15) Å, α = 93.473(50)°, β = 107.418(67)°, γ = 109.646(60)°, V = 1323.85(2) ų, Z = 1. Using Schreinemaker's technique to analyze the phase relations in the system Fe2O3-CaO-Al2O3-MgO it was possible to obtain the semi-quantitative stability relations between the participating phases and construct a topologically correct phase sequence as a function of T and fO2. The analysis shows that Ca2Al0.5Fe1.5O5 (C2A0.25F0.75) and CaAl1.5Fe2.5O7 (CA0.75F1.25) with higher calculated Fe2+ contents are preferably formed at lower oxygen fugacity and react to CaAl0.5Fe1.5O4 (CA0.25F0.75) by increasing fO2. Spinel-type magnesium-aluminium-ferrite (Mg,Fe2+)Fe3+1.25Al0.75O4 or (MA0.375F0.625) is the typical phase which occurs at high temperature (1400 °C).

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.

Translating and testing the ENABLE: CHF-PC concurrent palliative care model for older adults with heart failure and their family caregivers.

PubMed

Dionne-Odom, J Nicholas; Kono, Alan; Frost, Jennifer; Jackson, Lisa; Ellis, Daphne; Ahmed, Ali; Azuero, Andres; Bakitas, Marie

2014-09-01

Heart failure (HF) and palliative care (PC) organizations recommend early PC to improve the quality of life of patients living with HF. We conducted a two-phase formative evaluation study to translate a cancer-focused concurrent PC intervention into one that would be appropriate for rural-dwelling adults with New York Heart Association Class III-IV HF and their primary caregivers. Phase I: We tailored the intervention for an HF population via literature review, expert consultation, and clinician (N=15) small group interviews. Phase II: We enrolled 11 patient/caregiver dyads to assess intervention feasibility and satisfaction. We assessed participants' experiences and satisfaction after session/week three and session/week six via digitally recorded interviews. Clinician and participant interviews were transcribed and content analyzed. Outcome measures were evaluated for completion rates and effect sizes. Phase I: Clinicians described barriers to initiating PC in HF, triggers for initiating PC, and suggestions for intervention improvement. Phase II: Participants were able to complete the majority of study sessions, measures, and interviews. Satisfaction interviews revealed the content to be relevant and comprehensive in addressing HF patient and caregiver primary concerns; however, participants unanimously suggested making the intervention available earlier in the illness trajectory. Efficacy measures demonstrated small to medium effect sizes. We tailored and demonstrated feasibility of providing an early, concurrent palliative care intervention to patients with advanced HF and their caregivers. Based on this experience we are now conducting an efficacy trial in a racially diverse sample.

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

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.

An open-label, single arm, phase III clinical study to evaluate the efficacy and safety of CJ smallpox vaccine in previously vaccinated healthy adults.

PubMed

Kim, Nak-Hyun; Kang, Yu Min; Kim, Gayeon; Choe, Pyoeng Gyun; Song, Jin Su; Lee, Kwang-Hee; Seong, Baik-Lin; Park, Wan Beom; Kim, Nam Joong; Oh, Myoung-don

2013-10-25

The increased possibility of bioterrorism has led to reinitiation of smallpox vaccination. In Korea, more than 30 years have passed since the last smallpox vaccinations, and even people who were previously vaccinated are not regarded as adequately protected against smallpox. We evaluated the efficacy and safety of CJ-50300, a newly developed cell culture-derived smallpox vaccine, in healthy adults previously vaccinated against smallpox. We conducted an open label, single arm, phase III clinical trial to evaluate the efficacy and safety of CJ-50300. Healthy volunteers, previously vaccinated against smallpox, born between 1950 and 1978 were enrolled. CJ-50300 was administered with a bifurcated needle over the deltoid muscle according to the recommended method. The rate of the cutaneous take reaction, humoral immunogenicity, and safety of the vaccine was assessed. Of 145 individuals enrolled for vaccination, 139 completed the study. The overall rates of cutaneous take reactions and humoral immunogenicity were 95.0% (132/139) and 88.5% (123/139), respectively. Although 95.9% (139/145) reported adverse events related to vaccination, no serious adverse reactions were observed. CJ-50300 can be used safely and effectively in healthy adults previously vaccinated against smallpox. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

New Equations for the Sublimation Pressure and Melting Pressure of H2O Ice Ih

NASA Astrophysics Data System (ADS)

Wagner, Wolfgang; Riethmann, Thomas; Feistel, Rainer; Harvey, Allan H.

2011-12-01

New reference equations, adopted by the International Association for the Properties of Water and Steam (IAPWS), are presented for the sublimation pressure and melting pressure of ice Ih as a function of temperature. These equations are based on input values derived from the phase-equilibrium condition between the IAPWS-95 scientific standard for thermodynamic properties of fluid H2O and the equation of state of H2O ice Ih adopted by IAPWS in 2006, making them thermodynamically consistent with the bulk-phase properties. Compared to the previous IAPWS formulations, which were empirical fits to experimental data, the new equations have significantly less uncertainty. The sublimation-pressure equation covers the temperature range from 50 K to the vapor-liquid-solid triple point at 273.16 K. The ice Ih melting-pressure equation describes the entire melting curve from 273.16 K to the ice Ih-ice III-liquid triple point at 251.165 K. For completeness, we also give the IAPWS melting-pressure equation for ice III, which is slightly adjusted to agree with the ice Ih melting-pressure equation at the corresponding triple point, and the unchanged IAPWS melting-pressure equations for ice V, ice VI, and ice VII.

Structural phase transitions in GaAs to 108 GPa

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

Weir, S.T.; Vohra, Y.K.; Vanderborgh, C.A.

1989-01-15

The III-V compound GaAs was studied using energy-dispersive x-ray diffraction with a synchro- tron source up to a pressure of 108 GPa. When the pressure was increased to 16.6 GPa, the GaAs sample transformed from the zinc-blende structure to an orthorhombic structure (GaAs(II)), space group Pmm2, consisting of a primitive orthorhombic lattice with a basis of (0,0,0) and (0,(1/2,..cap alpha..), where ..cap alpha.. = 0.35. Upon a further increase of pressure to 24 +- 1 GPa, GaAs(II) transformed to another orthorhombic structure (GaAs(III)), space group Imm2, consisting of a body-centered orthorhombic lattice with a basis of (0,0,0) and (0, (1/2,..delta..),more » where ..delta.. is 0.425 at 28.1 GPa. With increasing pressure, ..delta.. approached (1/2 and the GaAs(III) structure gradually assumed the symmetry of the simple hexagonal structure. The transition to the simple hexagonal structure (GaAs(IV)) was completed in the vicinity of 60--80 GPa. The structure remains simple hexagonal up to at least 108 GPa, the highest pressure reached in this study.« less

Independence From Parenteral Nutrition and Intravenous Fluid Support During Treatment With Teduglutide Among Patients With Intestinal Failure Associated With Short Bowel Syndrome

PubMed Central

Iyer, Kishore R.; Kunecki, Marek; Boullata, Joseph I.; Fujioka, Ken; Joly, Francisca; Gabe, Simon; Pape, Ulrich-Frank; Schneider, Stéphane M.; Virgili Casas, María Nuria; Ziegler, Thomas R.; Li, Benjamin; Youssef, Nader N.; Jeppesen, Palle B.

2016-01-01

Background: In phase III clinical studies, treatment with teduglutide was associated with clinically meaningful reductions (≥20% from baseline) in parenteral support (PS; parenteral nutrition and/or intravenous fluids) requirements in adult patients with intestinal failure associated with short bowel syndrome (SBS-IF). This analysis reports clinical characteristics of patients who achieved complete independence from PS during teduglutide treatment. Materials and Methods: Post hoc analysis of adult patients who achieved complete PS independence during treatment with teduglutide 0.05 mg/kg/d. Data were pooled from 5 teduglutide clinical trials (2 phase III placebo-controlled trials [NCT00081458 and NCT00798967] and their respective extension studies [NCT00172185, NCT00930644, NCT01560403]). Descriptive statistics were used; no between-group comparisons were performed because of the small sample size and lack of comparator. Results: Of 134 patients, 16 gained oral or enteral autonomy after a median of 5 years of PS dependence and 89 weeks of teduglutide treatment. Demographic and baseline disease characteristics varied among patients (median age, 55 years; 50% men; median baseline PS volume, 5.1 L/wk; median residual small intestine length, 52.5 cm). Most patients who achieved PS independence had colon-in-continuity; however, there was no significant difference in the frequency of PS independence among patients who maintained colon-in-continuity vs those who did not. Conclusion: Findings from this post hoc analysis suggest that oral or enteral autonomy is possible for some patients with SBS-IF who are treated with teduglutide, regardless of baseline characteristics and despite long-term PS dependence. PMID:27875291

Silver Clear Nylon Dressing is Effective in Preventing Radiation-Induced Dermatitis in Patients With Lower Gastrointestinal Cancer: Results From a Phase III Study

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

Niazi, Tamim M.; Vuong, Te, E-mail: tvuong@jgh.mcgill.ca; Azoulay, Laurant

2012-11-01

Purpose: For patients with anal canal and advanced rectal cancer, chemoradiation therapy is a curative modality or an important adjunct to surgery. Nearly all patients treated with chemoradiation experience some degree of radiation-induced dermatitis (RID). Prevention and effective treatment of RID, therefore, is of considerable clinical relevance. The present phase III randomized trial compared the efficacy of silver clear nylon dressing (SCND) with that of standard skin care for these patients. Methods and Materials: A total of 42 rectal or anal canal cancer patients were randomized to either a SCND or standard skin care group. SCND was applied from Daymore » 1 of radiation therapy (RT) until 2 weeks after treatment completion. In the control arm, sulfadiazine cream was applied at the time of skin dermatitis. Printed digital photographs taken 2 weeks prior to, on the last day, and two weeks after the treatment completion were scored by 10 blinded readers, who used the common toxicity scoring system for skin dermatitis. Results: The radiation dose ranged from 50.4 to 59.4 Gy, and there were no differences between the 2 groups. On the last day of RT, when the most severe RID occurs, the mean dermatitis score was 2.53 (standard deviation [SD], 1.17) for the standard and 1.67 (SD, 1.2; P=.01) for the SCND arm. At 2 weeks after RT, the difference was 0.39 points in favor of SCND (P=.39). There was considerable intraclass correlation among the 10 observers. Conclusions: Silver clear nylon dressing is effective in reducing RID in patients with lower gastrointestinal cancer treated with combined chemotherapy and radiation treatment.« less

Phase I/II trial of single-fraction high-dose-rate brachytherapy-boosted hypofractionated intensity-modulated radiation therapy for localized adenocarcinoma of the prostate.

PubMed

Myers, Michael A; Hagan, Michael P; Todor, Dorin; Gilbert, Lynn; Mukhopadhyay, Nitai; Randolf, Jessica; Heimiller, Jeffrey; Anscher, Mitchell S

2012-01-01

A Phase I/II protocol was conducted to examine the toxicity and efficacy of the combination of intensity-modulated radiation therapy (IMRT) with a single-fraction high-dose-rate (HDR) brachytherapy implant. From 2001 through 2006, 26 consecutive patients were treated on the trial. The primary objective was to demonstrate a high rate of completion without experiencing a treatment-limiting toxicity. Eligibility was limited to patients with T stage ≤2b, prostate-specific antigen (PSA) ≤20, and Gleason score ≤7. Treatment began with a single HDR fraction of 6Gy to the entire prostate and 9Gy to the peripheral zone, followed by IMRT optimized to deliver in 28 fractions with a normalized total dose of 70Gy. Patients received 50.4Gy to the pelvic lymph node. The prostate dose (IMRT and HDR) resulted in an average biologic equivalent dose >128Gy (α/β=3). Patients whose pretreatment PSA was ≥10ng/mL, Gleason score 7, or stage ≥T2b received short-term androgen ablation. Median followup was 53 months (9-68 months). There were no biochemical failures by either the American Society of Therapeutic Radiology and Oncology or the Phoenix definitions. The median nadir PSA was 0.32ng/mL. All the 26 patients completed the treatment as prescribed. The rate of Grade 3 late genitourinary toxicity was 3.8% consisting of a urethral stricture. There was no other Grade 3 or 4 genitourinary or gastrointestinal toxicities. Single-fraction HDR-boosted IMRT is a safe effective method of dose escalation for localized prostate cancer. Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Quality of Life Outcomes for Cabozantinib Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma: METEOR Phase III Randomized Trial.

PubMed

Cella, David; Escudier, Bernard; Tannir, Nizar M; Powles, Thomas; Donskov, Frede; Peltola, Katriina; Schmidinger, Manuela; Heng, Daniel Y C; Mainwaring, Paul N; Hammers, Hans J; Lee, Jae Lyun; Roth, Bruce J; Marteau, Florence; Williams, Paul; Baer, John; Mangeshkar, Milan; Scheffold, Christian; Hutson, Thomas E; Pal, Sumanta; Motzer, Robert J; Choueiri, Toni K

2018-03-10

Purpose In the phase III METEOR trial ( ClinicalTrials.gov identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive cabozantinib or everolimus. The cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study. The nine-item FKSI-Disease-Related Symptoms (FKSI-DRS), a subset of FKSI-19, was also investigated. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size ≥ 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or ≥ 4-point decrease from baseline in FKSI-DRS. Results The QoL questionnaire completion rates remained ≥ 75% through week 48 in each arm. There was no difference over time for FKSI-19 Total, FKSI-DRS, or EQ-5D data between the cabozantinib and everolimus arms. Among the individual FKSI-19 items, cabozantinib was associated with worse diarrhea and nausea; everolimus was associated with worse shortness of breath. These differences are consistent with the adverse event profile of each drug. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline. Conclusion In patients with advanced renal cell carcinoma, relative to everolimus, cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.

Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials.

PubMed

Lebwohl, Mark; Dinehart, Scott; Whiting, David; Lee, Peter K; Tawfik, Naji; Jorizzo, Joseph; Lee, James H; Fox, Terry L

2004-05-01

The immune system plays a critical role in the development and pathogenesis of actinic keratosis (AK). Imiquimod has been shown to stimulate the cutaneous immune response and be effective for the treatment of nonmelanoma skin cancers. Two phase III, randomized, double-blind, vehicle-controlled studies evaluated the efficacy of imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp. A total of 436 participants at 24 centers in the United States and Canada were randomized to either imiquimod 5% or vehicle cream. Study cream was applied one time per day, 2 days per week for 16 weeks. Clearance of AK lesions was clinically assessed at an 8-week posttreatment visit. The complete clearance rate was 45.1% for the imiquimod group and 3.2% for the vehicle group. The difference in complete clearance rates (imiquimod minus vehicle) was 41.9% with a 95% confidence interval of 34.9% to 49%. The partial (> or =75%) clearance rate was 59.1% for the imiquimod group and 11.8% for the vehicle group. The difference in partial clearance rates (imiquimod minus vehicle) was 47.3% with a 95% confidence interval of 39.5% to 55.1%. The median percent reduction in AK lesions was 83.3% for the imiquimod group and 0% for the vehicle group. Local skin reactions were common. Severe erythema was reported by 17.7% of participants who received imiquimod and 2.3% of participants who received vehicle. Overall, imiquimod was very well tolerated. Imiquimod 5% cream used 2 times per week for 16 weeks is an effective and well-tolerated treatment for AK.

Corrigendum to "Long-term results of a phase II study of gemcitabine and cisplatin chemotherapy combined with intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma" [Oral Oncol. 73 (2017) 118-123].

PubMed

Wu, Mingyao; Ou, Dan; He, Xiayun; Hu, Chaosu

2017-11-01

To evaluate long-term results of a phase II study of induction and adjuvant gemcitabine and cisplatin (GP) chemotherapy with intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). One hundred and twelve patients (Stage III: 65, IVA-B: 47) with locoregionally advanced NPC were enrolled in this study. All patients received induction chemotherapy consisting of 1000 mg/m 2 gemcitabine on day 1 and 8, and cisplatin 25 mg/m 2 on day 1-3, every 3 weeks for 2 cycles. Adjuvant chemotherapy for 2 cycles of the same regime was given 28 days after the end of IMRT. The IMRT technique was utilized for all patients. In total, 97.3% patients completed 2 cycles of induction chemotherapy. The overall response rate (RR) of cervical lymph nodes was 89.0%. Acute toxicities were mainly grade 1-2 myleosuppression and vomiting. And 83.9% patients completed 2 cycles of adjuvant chemotherapy. All patients finished IMRT with RR at the end of IMRT for nasopharynx, lymph nodes of neck and retropharyngeal area being 99.1%, 97.9% and 97.7%, respectively. The 5-year local control, regional control, distant metastasis-free and overall survival rates were 93.2%, 92.3%, 89.0% and 82.1%, respectively. The 5-year overall survival of stage III and IVA-B were 87.0%, and 75.5%, respectively. The incidence of grade 3-4 acute radiotherapy-related mucositis was 28.6%. Severe late toxicities were uncommon. IMRT combined with GP for locoregionally advanced NPC is well tolerated, effective, and convenient, and warrants further studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.

PubMed

Schadendorf, Dirk; Amonkar, Mayur M; Stroyakovskiy, Daniil; Levchenko, Evgeny; Gogas, Helen; de Braud, Filippo; Grob, Jean-Jacques; Bondarenko, Igor; Garbe, Claus; Lebbe, Celeste; Larkin, James; Chiarion-Sileni, Vanna; Millward, Michael; Arance, Ana; Mandalà, Mario; Flaherty, Keith T; Nathan, Paul; Ribas, Antoni; Robert, Caroline; Casey, Michelle; DeMarini, Douglas J; Irani, Jhangir G; Aktan, Gursel; Long, Georgina V

2015-05-01

To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination. HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms. Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6-13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy. This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648). Copyright © 2015 Elsevier Ltd. All rights reserved.

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...

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...

Influence of oxygen on the carbide formation on tungsten

NASA Astrophysics Data System (ADS)

Luthin, J.; Linsmeier, Ch.

2001-03-01

As a first wall material in nuclear fusion devices, tungsten will interact with carbon and oxygen from the plasma. In this study, we report on the process of thermally induced carbide formation of thin carbon films on polycrystalline tungsten and the influence of oxygen on this process. All investigations are performed using X-ray photoelectron spectroscopy (XPS). Carbon films are supplied through electron beam evaporation of graphite. The carbidization process, monitored during increased substrate temperature, can be divided into four phases. In phase I disordered carbon converts into graphite-like carbon. In phase II significant diffusion and the reaction to W 2C is observed, followed by phase III which is dominated by the presence of W 2C and the beginning reaction to WC. Finally in phase IV only WC is present, but the total carbon amount has strongly decreased. Different mechanisms of oxygen influence on the carbide formation are proposed and measurements of the reaction of carbon on tungsten with intermediate oxide layers are presented in detail. A WO 2+ x intermediate layer completely inhibits the carbide formation, while a WO 2 layer leads to WC formation at temperatures above 1270 K.

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.

Peripheral apelin-13 administration inhibits gastrointestinal motor functions in rats: The role of cholecystokinin through CCK1 receptor-mediated pathway.

PubMed

Bülbül, Mehmet; Sinen, Osman; Birsen, İlknur; Nimet İzgüt-Uysal, V

2017-06-01

Apelin is the endogenous ligand of the G protein-coupled receptor APJ. The APJ receptor is widely expressed in gastrointestinal (GI) tissues including stomach and small intestine. Apelin administration was shown to induce the release of cholecystokinin (CCK) which is a well-known alimentary hormone with its inhibitory actions on GI motor functions through CCK 1 receptors on vagal afferent fibers. We investigated whether; (i) peripherally injected apelin-13 alters GI motor functions, (ii) apelin-induced changes are mediated by APJ receptor or CCK 1 receptor and (iii) vagal afferents are involved in inhibitory effects of apelin. Solid gastric emptying (GE) and colon transit (CT) were measured, whereas duodenal phase III-like contractions were recorded in rats administered with apelin-13 (300μg/kg, ip). CCK 1 receptor antagonist lorglumide (10mg/kg, ip) or APJ receptor antagonist F13A (300μg/kg, ip) was administered 30min prior to the apelin-13 injections. Vagal afferent denervation was achieved by systemic administration of vanilloid receptor agonist capsaicin (125mg/kg, sc). Apelin-13 administration significantly (p<0.01) increased the CCK level in portal venous plasma samples. Compared with vehicle-treated rats, apelin-13 significantly delayed both GE (p<0.001) and CT (p<0.01). Pretreatment of lorglumide or F13A completely abolished the apelin-13-induced inhibitory effects on GE and CT, moreover, apelin-13 was found ineffective in rats underwent afferent denervation. F13A administration alone significantly accelerated the basal CT. Apelin-13 noticeably disturbed the duodenal fasting motor pattern by impairing phase III-like contractions while increasing the amplitudes of phase II contractions which were prevented by pretreatment of lorglumide and capsaicin. Compared with vehicle-treated rats, lorglumide and capsaicin significantly (p<0.05) reduced the apelin-13-induced increases in phase II motility index. Peripherally administered apelin-13 inhibits GI motor functions through CCK-dependent pathway which appears to be mediated by CCK 1 receptors on vagal afferents. Peripheral apelin might contribute to the motility changes occurred in postprandial period. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

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.

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

Assessing the Eligibility Criteria in Phase III Randomized Controlled Trials of Drug Therapy in Heart Failure With Preserved Ejection Fraction: The Critical Play-Off Between a "Pure" Patient Phenotype and the Generalizability of Trial Findings.

PubMed

Patel, Hitesh C; Hayward, Carl; Dungu, Jason N; Papadopoulou, Sofia; Saidmeerasah, Abdel; Ray, Robin; Di Mario, Carlo; Shanmugam, Nesan; Cowie, Martin R; Anderson, Lisa J

2017-07-01

To investigate the effect of the different eligibility criteria used by phase III clinical studies in heart failure with preserved ejection fraction (HFpEF) on patient selection, phenotype, and survival. We applied the key eligibility criteria of 7 phase III HFpEF studies (Digitalis Investigation Group Ancillary, Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction, Perindopril in Elderly People With Chronic Heart Failure, Irbesartan in Heart Failure With Preserved Systolic Function, Japanese Diastolic Heart Failure, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist, and Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF; ongoing]) to a typical and well-characterized HFpEF population (n = 557) seen in modern European cardiological practice. Follow-up was available for a minimum of 24 months in each patient. Increasing the number of study eligibility criteria identifies a progressively smaller group of patients from real-life practice suitable for recruitment into clinical trials; using the J-DHF criteria, 81% of our clinic patients would have been eligible, whereas the PARAGON-HF criteria significantly reduced this proportion to 32%. The patients identified from our clinical population had similar mortality rates using the different criteria, which were consistently higher than those reported in the actual clinic trials. Trial eligibility criteria have become stricter with time, which reduces the number of eligible patients, affecting both generalizability of any findings and feasibility of completing an adequately powered trial. We could not find evidence that the additional criteria used in more recent randomized trials in HFpEF have identified patients at higher risk of all-cause mortality. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

The 12-week progressive quadriceps resistance training improves muscle strength, exercise capacity and quality of life in patients with stable chronic heart failure.

PubMed

Jankowska, Ewa A; Wegrzynowska, Kinga; Superlak, Malgorzata; Nowakowska, Katarzyna; Lazorczyk, Malgorzata; Biel, Bartosz; Kustrzycka-Kratochwil, Dorota; Piotrowska, Katarzyna; Banasiak, Waldemar; Wozniewski, Marek; Ponikowski, Piotr

2008-10-30

Abnormalities in the skeletal musculature underlie exercise intolerance in chronic heart failure (CHF). We investigated, whether in CHF selective resistance training without accompanying aerobic regime favourably affects muscle strength, muscle mass and improves exercise capacity. Ten patients with stable ischaemic CHF in NYHA class III (9 men, age: 70+/-6 years [mean+/-SD], left ventricular ejection fraction: 30+/-5%, peak oxygen consumption [peak VO(2)]: 12.4+/-3.0 mL/min/kg) underwent the rehabilitation programme which consisted of a 12-week training phase (progressive resistance exercises restricted to the quadriceps muscles) followed by a 12-week detraining phase. All subjects completed a training phase of the programme with no adverse events. Resistance training markedly increased quadriceps strength (right leg: 260+/-34 vs. 352+/-28 N, left leg: 264+/-38 vs. 342+/-30 N, both p<0.01 - all comparisons: baseline vs. after training), but did not affect lean tissue mass of lower extremities (both p>0.2). It was accompanied by an improvement in clinical status (all NYHA III vs. all NYHA II, p<0.01), quality of life (Minnesota questionnaire: 44+/-15 vs. 33+/-18 points, p<0.05), exercise capacity assessed using a distance during 6-minute walk test (6MWT: 362+/-83 vs. 455+/-71 m, p<0.01), but not peak VO(2) (p>0.2). Plasma NT-proBNP remained unchanged during the training. At the end of detraining phase, only a partial improvement in quadriceps strength (p<0.05), a 6MWT distance (p<0.05) and NYHA class (p=0.07 vs. baseline) persisted. Applied resistance quadriceps training is safe in patients with CHF. It increases muscle strength, improves clinical status, exercise capacity, and quality of life.

Review of nemonoxacin with special focus on clinical development

PubMed Central

Qin, Xiaohua; Huang, Haihui

2014-01-01

Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone with remarkably enhanced in vitro activity against a wide variety of clinically relevant pathogens, especially gram-positive bacteria, including multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. It has a low propensity for selecting resistant pathogens than fluoroquinolones, since bacteria become resistant to nemonoxacin only when three different mutations occur in their quinolone resistance-determining regions. Nemonoxacin shows greater efficacy than most of the widely used fluoroquinolones in the murine model of systemic, pulmonary, or ascending urinary tract infection. Nemonoxacin has a sound PK profile in healthy volunteers. It rapidly reaches maximum concentration Cmax 1–2 hours after oral administration in the fasting state and has a relatively long elimination half-life of more than 10 hours, which is similar to fluoroquinolones. Approximately 60%–75% of the administered dose is excreted in unchanged form via kidneys over 24–72 hours. Phase II and III studies of oral nemonoxacin and Phase II studies of intravenous nemonoxacin have been completed in patients with community-acquired pneumonia (CAP), before which the Phase I studies of oral and intravenous nemonoxacin indicated sound tolerance and safety with healthy volunteers. The published results demonstrate that an oral dose of either 500 mg or 750 mg nemonoxacin once daily for 7 days is as effective and safe as levofloxacin 500 mg once daily for 7 days. Nemonoxacin is well-tolerated in patients with CAP. The most common adverse events of oral administration are observed in the gastrointestinal and nervous system, the incidence of which is similar to levofloxacin treatment. The Phase III studies of intravenous nemonoxacin for treating CAP and oral nemonoxacin for diabetic foot infection has been registered with promising outcomes to be expected. PMID:25045247

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.

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.

Microbial production of isotopically light iron(II) in a modern chemically precipitated sediment and implications for isotopic variations in ancient rocks

USGS Publications Warehouse

Tangalos, G.E.; Beard, B.L.; Johnson, C.M.; Alpers, Charles N.; Shelobolina, E.S.; Xu, H.; Konishi, H.; Roden, E.E.

2012-01-01

The inventories and Fe isotope composition of aqueous Fe(II) and solid-phase Fe compounds were quantified in neutral-pH, chemically precipitated sediments downstream of the Iron Mountain acid mine drainage site in northern California, USA. The sediments contain high concentrations of amorphous Fe(III) oxyhydroxides [Fe(III)am] that allow dissimilatory iron reduction (DIR) to predominate over Fe–S interactions in Fe redox transformation, as indicated by the very low abundance of Cr(II)-extractable reduced inorganic sulfur compared with dilute HCl-extractable Fe. δ56Fe values for bulk HCl- and HF-extractable Fe were ≈ 0. These near-zero bulk δ56Fe values, together with the very low abundance of dissolved Fe in the overlying water column, suggest that the pyrite Fe source had near-zero δ56Fe values, and that complete oxidation of Fe(II) took place prior to deposition of the Fe(III) oxide-rich sediment. Sediment core analyses and incubation experiments demonstrated the production of millimolar quantities of isotopically light (δ56Fe ≈ -1.5 to -0.5‰) aqueous Fe(II) coupled to partial reduction of Fe(III)am by DIR. Trends in the Fe isotope composition of solid-associated Fe(II) and residual Fe(III)am are consistent with experiments with synthetic Fe(III) oxides, and collectively suggest an equilibrium Fe isotope fractionation between aqueous Fe(II) and Fe(III)am of approximately -2‰. These Fe(III) oxide-rich sediments provide a model for early diagenetic processes that are likely to have taken place in Archean and Paleoproterozoic marine sediments that served as precursors for banded iron formations. Our results suggest pathways whereby DIR could have led to the formation of large quantities of low-δ56Fe minerals during BIF genesis.

Oxidative dissolution potential of biogenic and abiogenic TcO 2 in subsurface sediments

NASA Astrophysics Data System (ADS)

Fredrickson, James K.; Zachara, John M.; Plymale, Andrew E.; Heald, Steve M.; McKinley, James P.; Kennedy, David W.; Liu, Chongxuan; Nachimuthu, Ponnusamy

2009-04-01

Technetium-99 (Tc) is an important fission product contaminant associated with sites of nuclear fuels reprocessing and geologic nuclear waste disposal. Tc is highly mobile in its most oxidized state [Tc(VII)O4-] and less mobile in the reduced form [Tc(IV)O 2· nH 2O]. Here we investigate the potential for oxidation of Tc(IV) that was heterogeneously reduced by reaction with biogenic Fe(II) in two sediments differing in mineralogy and aggregation state; unconsolidated Pliocene-age fluvial sediment from the upper Ringold (RG) Formation at the Hanford Site and a clay-rich saprolite from the Field Research Center (FRC) background site on the Oak Ridge Site. Both sediments contained Fe(III) and Mn(III/IV) as redox active phases, but FRC also contained mass-dominant Fe-phyllosilicates of different types. Shewanella putrefaciens CN32 reduced Mn(III/IV) oxides and generated Fe(II) that was reactive with Tc(VII) in heat-killed, bioreduced sediment. After bioreduction and heat-killing, biogenic Fe(II) in the FRC exceeded that in RG by a factor of two. More rapid reduction rates were observed in the RG that had lower biogenic Fe(II), and less particle aggregation. EXAFS measurements indicated that the primary reduction product was a TcO 2-like phase in both sediments. The biogenic redox product Tc(IV) oxidized rapidly and completely in RG when contacted with air. Oxidation, in contrast, was slow and incomplete in the FRC, in spite of similar molecular scale speciation of Tc compared to RG. X-ray microprobe, electron microprobe, X-ray absorption spectroscopy, and micro X-ray diffraction were applied to the whole sediment and isolated Tc-containing particles. These analyses revealed that non-oxidizable Tc(IV) in the FRC existed as complexes with octahedral Fe(III) within intra-grain domains of 50-100 μm-sized, Fe-containing micas presumptively identified as celadonite. The markedly slower oxidation rates in FRC as compared to RG were attributed to mass-transfer-limited migration of O 2 into intra-aggregate and intraparticle domains where Tc(IV) existed; and the formation of unique, oxidation-resistant, intragrain Tc(IV)-Fe(III) molecular species.

Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies.

PubMed

Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

2016-01-01

Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. PubMed, Cochrane's Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55-1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors.

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

Swanner, E. D.; Bayer, T.; Wu, W.

In this study, we couple iron isotope analysis to microscopic and mineralogical investigation of iron speciation during circumneutral Fe(II) oxidation and Fe(III) precipitation with photosynthetically produced oxygen. In the presence of the cyanobacterium Synechococcus PCC 7002, aqueous Fe(II) (Fe(II) aq) is oxidized and precipitated as amorphous Fe(III) oxyhydroxide minerals (iron precipitates, Fe ppt), with distinct isotopic fractionation (ε 56Fe) values determined from fitting the δ 56Fe(II) aq (1.79‰ and 2.15‰) and the δ 56Fe ppt (2.44‰ and 2.98‰) data trends from two replicate experiments. Additional Fe(II) and Fe(III) phases were detected using microscopy and chemical extractions and likely represent Fe(II)more » and Fe(III) sorbed to minerals and cells. The iron desorbed with sodium acetate (FeNaAc) yielded heavier δ 56Fe compositions than Fe(II) aq. Modeling of the fractionation during Fe(III) sorption to cells and Fe(II) sorption to Feppt, combined with equilibration of sorbed iron and with Fe(II) aq using published fractionation factors, is consistent with our resulting δ 56FeNaAc. The δ 56Fe ppt data trend is inconsistent with complete equilibrium exchange with Fe(II)aq. Because of this and our detection of microbially excreted organics (e.g., exopolysaccharides) coating Feppt in our microscopic analysis, we suggest that electron and atom exchange is partially suppressed in this system by biologically produced organics. These results indicate that cyanobacteria influence the fate and composition of iron in sunlit environments via their role in Fe(II) oxidation through O 2 production, the capacity of their cell surfaces to sorb iron, and the interaction of secreted organics with Fe(III) minerals.« less

Development and validation of a simple and robust method for arsenic speciation in human urine using HPLC/ICP-MS.

PubMed

Sen, Indranil; Zou, Wei; Alvaran, Josephine; Nguyen, Linda; Gajek, Ryszard; She, Jianwen

2015-01-01

In order to better distinguish the different toxic inorganic and organic forms of arsenic (As) exposure in individuals, we have developed and validated a simple and robust analytical method for determining the following six As species in human urine: arsenous (III) acid (As-III), As (V) acid, monomethylarsonic acid, dimethylarsinic acid, arsenobetaine (AsB), and arsenocholine. In this method, human urine is diluted using a pH 5.8 buffer, separation is performed using an anion exchange column with isocratic HPLC, and detection is achieved using inductively coupled plasma-MS. The method uses a single mobile phase consisting of low concentrations of both phosphate buffer (5 mM) and ammonium nitrate salt (5 mM) at pH 9.0; this minimizes the column equilibration time and overcomes challenges with separation between AsB and As-III. In addition, As-III oxidation is prevented by degassing the sample preparation buffer at pH 5.8, degassing the mobile phase online at pH 9.0, and by the use of low temperature (-70 °C) and flip-cap airtight tubes for long term storage of samples. The method was validated using externally provided reference samples. Results were in agreement with target values at varying concentrations and successfully passed external performance test criteria. Internal QC samples were prepared and repeatedly analyzed to assess the method's long-term precision, and further analyses were completed on anonymous donor urine to assess the quality of the method's baseline separation. Results from analyses of external reference samples agreed with target values at varying concentrations, and results from precision studies yielded absolute CV values of 3-14% and recovery from 82 to 115% for the six As species. Analysis of anonymous donor urine confirmed the well-resolved baseline separation capabilities of the method for real participant samples.

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.

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).

Agouron and immune response to commercialize remune immune-based treatment.

PubMed

James, J S

1998-06-19

Agouron Pharmaceuticals agreed in June to collaborate with The Immune Response Corporation on the final development and marketing of an immune-based treatment for HIV. Remune, the vaccine developed by Dr. Jonas Salk, is currently in Phase III randomized trials with 2,500 patients, and the trials are expected to be completed in April 1999. Immune-based treatments have been difficult to test, as there is no surrogate marker, like viral load, to determine if the drug is working. Agouron agreed to participate in the joint venture after reviewing encouraging results from preliminary trials in which remune was taken in combination with highly active antiretroviral drugs.

Informed consent as an ethical requirement in clinical trials: an old, but still unresolved issue. An observational study to evaluate patient's informed consent comprehension.

PubMed

Sanchini, Virginia; Reni, Michele; Calori, Giliola; Riva, Elisabetta; Reichlin, Massimo

2014-04-01

We explored the comprehension of the informed consent in 77 cancer patients previously enrolled in randomised phase II or phase III clinical trials, between March and July 2011, at the San Raffaele Scientific Institute in Milano. We asked participants to complete an ad hoc questionnaire and analysed their answers. Sixty-two per cent of the patients understood the purpose and nature of the trial they were participating in; 44% understood the study procedures and 40% correctly listed at least one of the major risks or complications related to their participation in the trial. We identified three factors associated with comprehension of the informed consent: age, education and type of tumour/investigator team. We suggest several possible improvements of how to obtain informed consent that will increase patient awareness, as well as the validity and effectiveness of the clinical trials.

Re-defining one's occupational self 2 years after breast cancer: a case study.

PubMed

Newman, Robin M

2013-01-01

Margaret*, a 56 year-old Caucasian Stage III breast cancer survivor, participated in a 5 week occupational therapy pilot program, called Take Action. This program was designed for breast cancer survivors who self-reported changes in cognitive function following completion of chemotherapy. The goals of the program were to improve participants' knowledge and use of strategies to enhance occupational performance and to improve satisfaction and performance of meaningful daily activities or occupations. Through a client-centered and evidence-based approach, this case study highlights the importance of incorporating the survivors' sense of self into an occupation-based intervention. Occupational therapists play an important role in facilitating exploration of sense of self in the survivorship phase of care to support occupational performance in self care, productivity, work, leisure and social participation. This case study highlights the important work of redefining oneself in the survivorship phase of care. (*denotes name change).

A rapid monitoring method for inorganic arsenic in rice flour using reversed phase-high performance liquid chromatography-inductively coupled plasma mass spectrometry.

PubMed

Narukawa, Tomohiro; Chiba, Koichi; Sinaviwat, Savarin; Feldmann, Jörg

2017-01-06

A new rapid monitoring method by means of high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) following the heat-assisted extraction was developed for measurement of total inorganic arsenic species in rice flour. As(III) and As(V) eluted at the same retention time and completely separated from organoarsenic species by an isocratic elution program on a reversed phase column. Therefore, neither ambiguous oxidation of arsenite to arsenate nor the integration of two peaks were necessary to determine directly the target analyte inorganic arsenic. Rapid injection allowed measuring 3 replicates within 6min and this combined with a quantitative extraction of all arsenic species from rice flour by a 15min HNO 3 -H 2 O 2 extraction makes this the fastest laboratory based method for inorganic arsenic in rice flour. Copyright © 2016 Elsevier B.V. All rights reserved.

Rapid determination of ions by combined solid-phase extraction--diffuse reflectance spectroscopy

NASA Technical Reports Server (NTRS)

Fritz, James S.; Arena, Matteo P.; Steiner, Steven A.; Porter, Marc D.

2003-01-01

We introduce colorimetric solid-phase extraction (C-SPE) for the rapid determination of selected ions. This new technique links the exhaustive concentration of an analyte by SPE onto a membrane disk surface for quantitative measurement with a hand-held diffuse reflectance spectrometer. The concentration/measurement procedure is complete in approximately 1 min and can be performed almost anywhere. This method has been used to monitor iodine and iodide in spacecraft water in the 0.1-5.0 ppm range and silver(I) in the range of 5.0-1000 microg/l. Applications to the trace analysis of copper(II), nickel(II), iron(III) and chromium(VI) are described. Studies on the mechanism of extraction showed that impregnation of the disk with a surfactant as well as a complexing reagent results in uptake of additional water, which markedly improves the extraction efficiency.

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

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.

Innovative microchannel plate with reformulation of composition and modification of microstructure

NASA Astrophysics Data System (ADS)

Pan, Jingsheng; Lv, Jingwen; Kesaev, S. A.; Liu, Shulin; Liu, Zhanying; Li, Junguo; Chong, Xiaoqin; Shu, Detan

2009-07-01

The signal-to-noise ratio (SNR) and mean time to failure (MTTF) are two important attributes to describe the performance and operation life of an image intensifier. The presents of the ion barrier film (IBF) in Gen. III image intensifier, which used to suppress MCP's ion feedback, while dramatically improve the MTTF but significantly reduce the SNR, so more completely diminishing the ion poisoning source within the channels of MCP are crucial for improved Gen. III; image intensifier to thinned thickness IBF and achieving this two conflicting attributes promotion simultaneously. This research was originally initiated to develop a MCP with glass composition redesigned specially for GaAs photocathode image intensifier, proved which can be imposed an exceedingly intensive electron bombard degassing but without suffering a fatal gain degrade, and had achieved significantly improved SNR of Gen. III image intensifier but with a short distance to meet the lifetime success, so that our research work step forward to intent upon the restriction of ion poisoning source formation within the MCP substrate, we reformulated the MCP glass composition, and modified the microstructure of this MCP glass substrate though a glass-crystal phase transition during the MCP fabricate heating process, we present an innovative MCP based on a glass-ceramic substrate, with reformulated composition and close-linked network microstructure mix with many of nanometer size crystal grains, provide this MCP with sustainable high gain, lower ion feedback and less outgasing performance, this glass-ceramic MCPs are assembled to Gen. III image intensifiers which results showing promoting both the MTTF and SNR of Gen. III image intensifier.

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.

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.

EARLY ENTRANCE COPRODUCTION PLANT

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

David Storm; Govanon Nongbri; Steve Decanio

2004-01-12

The overall objective of this project is the three phase development of an Early Entrance Coproduction Plant (EECP) which uses petroleum coke to produce at least one product from at least two of the following three categories: (1) electric power (or heat), (2) fuels, and (3) chemicals using ChevronTexaco's proprietary gasification technology. The objective of Phase I is to determine the feasibility and define the concept for the EECP located at a specific site; develop a Research, Development, and Testing (RD&T) Plan to mitigate technical risks and barriers; and prepare a Preliminary Project Financing Plan. The objective of Phase IImore » is to implement the work as outlined in the Phase I RD&T Plan to enhance the development and commercial acceptance of coproduction technology. The objective of Phase III is to develop an engineering design package and a financing and testing plan for an EECP located at a specific site. The project's intended result is to provide the necessary technical, economic, and environmental information needed by industry to move the EECP forward to detailed design, construction, and operation. The partners in this project are Texaco Energy Systems LLC or TES (a subsidiary of ChevronTexaco), General Electric (GE), Praxair, and Kellogg Brown & Root (KBR) in addition to the U.S. Department of Energy (DOE). TES is providing gasification technology and Fischer-Tropsch (F-T) technology developed by Rentech, Inc., GE is providing combustion turbine technology, Praxair is providing air separation technology, and KBR is providing engineering. During Phase I, a design basis for the Fischer-Tropsch Synthesis section was developed based on limited experience with the specified feed gas and operating conditions. The objective of this Task in Phase II RD&T work was to confirm the performance of the F-T reactor at the set design conditions. Although much of the research, development, and testing work were done by TES outside of this project, several important issues were addressed in this phase of the project. They included Rejuvenation/Regeneration of the Fischer-Tropsch Catalyst, online Catalyst Withdrawal and Addition from the synthesis reactor, and the Fischer-Tropsch Design Basis Confirmation. In Phase III the results from these RD&T work will be incorporated in developing the engineering design package. This Topical Report documents the Phase II RD&T work that was completed for this task.« less

Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood.

PubMed

Björkstén, Bengt; Clayton, Tadd; Ellwood, Philippa; Stewart, Alistair; Strachan, David

2008-03-01

In Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC) time trends in the prevalence of rhinoconjunctivitis symptoms were analysed. Cross-sectional questionnaire surveys with identical protocols and questionnaires were completed a mean of 7 yr apart in two age groups comprising 498,083 children. In the 13- to 14-yr age group 106 centres in 56 countries participated, and in the 6- to 7-yr age group 66 centres in 37 countries participated. A slight worldwide increase in rhinoconjunctivitis prevalence was observed, but the variations were large among the centres and there was no consistent regional pattern. Prevalence increases in the older children exceeding 1% per year were recorded in 13 centres, including 3 of 9 centres in Africa, 2 of 15 in Asia-Pacific, 1 of 8 in India, 3 of 15 in Latin America, 3 of 9 in Eastern Europe and 1 of 34 in Western and Northern Europe. Decreasing rhinoconjunctivititis prevalence of similar magnitude was only seen in four centres. The changes were less pronounced in the 6- to 7-yr-old children and only in one centre did any change exceed 1% per year. The decrease in highest prevalence rates in ISAAC Phase I suggests that the prevalence has peaked in those regions. An increase was recorded in several centres, mostly in low and mid-income countries. The increases were more pronounced in the older age group, suggesting that environmental influences on the development of allergy may not be limited to early childhood.

Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity.

PubMed

Mahlangu, J N; Weldingh, K N; Lentz, S R; Kaicker, S; Karim, F A; Matsushita, T; Recht, M; Tomczak, W; Windyga, J; Ehrenforth, S; Knobe, K

2015-11-01

Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity. © 2015 International Society on Thrombosis and Haemostasis.

Vernakalant: RSD 1235, RSD-1235, RSD1235.

PubMed

2007-01-01

Vernakalant is an atrial-selective antiarrhythmic drug discovered by Cardiome Pharma (formerly Nortran Pharmaceuticals). Vernakalant may have potential in the treatment of atrial arrhythmias, including acute atrial fibrillation and atrial flutter. Vernakalant is a mixed sodium/potassium channel blocker and selectively blocks ion channels in the heart that are known to be active during episodes of atrial fibrillation. An IV formulation of vernakalant is awaiting registration in the US for the acute conversion of atrial fibrillation. Also, an oral formulation of the compound is in phase II clinical development as a chronic-use product for the maintenance of normal heart rhythm following termination of atrial fibrillation. Cardiome is seeking co-development partners for intravenous vernakalant in the treatment of atrial arrhythmia, atrial fibrillation and atrial flutter in Europe and Japan. In October 2003, Cardiome Pharma and Fujisawa Healthcare, the US subsidiary of Fujisawa Pharmaceutical Co., Ltd (now Astellas Pharma), executed a $US68 million strategic partnership agreement for the co-development of vernakalant. On 1 April 2005, Fujisawa merged with Yamanouchi to form Astellas Pharma. The partnership grants Astellas Pharma exclusive commercialisation rights for vernakalant. Under the terms of the agreement, Cardiome and Astellas Pharma will co-develop vernakalant as an intravenous formulation for the treatment of atrial fibrillation and atrial flutter for North American markets. Astellas Pharma will be financially responsible for 75% of all future clinical development costs, with Cardiome responsible for the remaining 25% of costs. Astellas Pharma will be responsible for the development plan, NDA application (and NDA re-submission costs) and registration, along with the commercial manufacturing, marketing and sale of vernakalant. Cardiome will manage the phase III trials ACT 1 and ACT 2 and will also be responsible for the continued manufacturing of clinical supplies of vernakalant. Cardiome will receive royalties on end-user sales of vernakalant reflective of Cardiome's 25% share of development costs and other financial considerations. Product rights to the IV formulation of vernakalant for markets outside of North America and world rights to the oral formulation of vernakalant for chronic atrial fibrillation are not included within the scope of this partnership. Cardiome intends to form future additional alliances for these product opportunities or maintain such opportunities for commercialisation on its own. Cardiome and Astellas amended their agreement for vernakalant in relation to the re-submission of the NDA with the US FDA. Under the terms of the new agreement, Astellas agreed to fund 100% of the costs associated with re-submission, including engagement and external consultants. Astellas also agreed to modify the timing of the $US10 million NDA milestone to the date of resubmission. In February 2005, Cardiome Pharma received a $US6 million milestone payment from its co-development partner, Fujisawa Healthcare Inc. This milestone payment was triggered by the successful completion of ACT 1.A pivotal phase II trial demonstrated in September 2002 that vernakalant rapidly and effectively terminated recent onset atrial fibrillation and the study met both primary and secondary study endpoints. Following discussions with the FDA, Cardiome initiated three separate phase III clinical trials in order to enable Cardiome to apply for marketing approval for vernakalant. In August 2003, Cardiome Pharma commenced patient dosing in its first phase III efficacy study of vernakalant for the acute treatment of atrial fibrillation. This initial study, called ACT 1 (Atrial fibrillation Conversion Trial 1), measured the safety and efficacy of vernakalant in 416 patients with atrial arrhythmias. The placebo-controlled study was carried out in 45 centers in the US, Canada and Scandinavia. The ACT 1 study included two substudies of 60 patients with atrial flutter and 119 patients with longer term atrial fibrillation. The primary efficacy endpoint was acute conversion of atrial arrhythmia to normal heart rhythm. Cardiome commenced its second phase III efficacy study in March 2004, known as ACT 2. The ACT 2 study in post-cardiac surgery (coronary artery bypass graft) patients with atrial fibrillation, evaluated the safety and efficacy of vernakalant (IV) in the termination of atrial arrhythmias in patients after cardiac surgery. Around 210 patients from 25 centres in the US, Canada and Europe were enrolled in this study. The primary efficacy endpoint was acute conversion of atrial arrhythmias to normal heart rhythm. The ACT 2 study is ongoing. The third phase III study, known as ACT 3 (Atrial arrhythmia Conversion Trial 3), was initiated by Cardiome Pharma in July 2004. In September 2005, Cardiome and Astellas reported that ACT 3 had been completed, achieving its primary endpoint, with over half of the 170 patients with recent-onset atrial fibrillation (AF) who received vernakalant intravenously converting to normal heart rhythm, compared with only 4% in the placebo group. The study was being conducted by co-development partner Astellas Pharma and measured the safety and efficacy of intravenous vernakalant in recent onset atrial arrhythmia patients. The placebo-controlled study was being carried out in 276 patients in more than 50 centres throughout the world.ACT 4, a phase III safety study evaluating safety of IV vernakalant in approximately 120 AF patients from 30 centres in the US, Canada and Europe, was initiated in October 2005. Results from this trial are expected to supplement trial results from the pivotal ACT 1 and 3 trials. This study is ongoing. Cardiome Pharma successfully completed phase I studies for its controlled-release oral formulation of vernakalant in 2005. The oral, controlled-release formulation of vernakalant is expected to help prevent or slow the recurrence of atrial fibrillation, and will be used as a follow-on therapy to intravenous vernakalant.

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.

Non-enzymatic U(VI) interactions with biogenic mackinawite

NASA Astrophysics Data System (ADS)

Veeramani, H.; Qafoku, N. P.; Kukkadapu, R. K.; Murayama, M.; Hochella, M. F.

2011-12-01

Reductive immobilization of hexavalent uranium [U(VI)] by stimulation of dissimilatory metal and/or sulfate reducing bacteria (DMRB or DSRB) has been extensively researched as a remediation strategy for subsurface U(VI) contamination. These bacteria derive energy by reducing oxidized metals as terminal electron acceptors, often utilizing organic substrates as electron donors. Thus, when evaluating the potential for in-situ uranium remediation in heterogeneous subsurface media, it is important to understand how the presence of alternative electron acceptors such as Fe(III) and sulfate affect U(VI) remediation and the long term behavior and reactivity of reduced uranium. Iron, an abundant subsurface element, represents a substantial sink for electrons from DMRB, and the reduction of Fe(III) leads to the formation of dissolved Fe(II) or to reactive biogenic Fe(II)- and mixed Fe(II)/Fe(III)- mineral phases. Consequently, abiotic U(VI) reduction by reactive forms of biogenic Fe(II) minerals could be a potentially important process for uranium immobilization. In our study, the DMRB Shewanella putrefaciens CN32 was used to synthesize a biogenic Fe(II)-bearing sulfide mineral: mackinawite, that has been characterized by XRD, SEM, HRTEM and Mössbauer spectroscopy. Batch experiments involving treated biogenic mackinawite and uranium (50:1 molar ratio) were carried out at room temperature under strict anoxic conditions. Following complete removal of uranium from solution, the biogenic mackinawite was analyzed by a suite of analytical techniques including XAS, HRTEM and Mössbauer spectroscopy to determine the speciation of uranium and investigate concomitant Fe(II)-phase transformation. Determining the speciation of uranium is critical to success of a remediation strategy. The present work elucidates non-enzymatic/abiotic molecular scale redox interactions between biogenic mackinawite and uranium.

First-line treatment with capecitabine combined with irinotecan in patients with advanced colorectal carcinoma: a phase II study.

PubMed

Assy, Nimer; Basher, Walid; Chetver, Lika; Shnaider, Julia; Zidan, Jamal

2012-04-01

To evaluate the efficacy and toxicity of capecitabine with irinotecan as first-line treatment in metastatic colorectal cancer. The addition of irinotecan to infusional 5 fluorouracil and leucovorin significantly improves the response rate and survival compared with 5 fluorouracil/leucovorin alone in metastatic colorectal cancer. Capecitabine with irinoteacan was reported to yield comparable results in phase II studies. Patients older than 75 years, Eastern Cooperative Oncology Group ≤0 to 3, with measurable disease, no previous treatment for advanced disease, previous adjuvant chemotherapy >6 months, and adequate hepatic, renal, and hematological function were included. The treatment protocol included capecitabine 1000 mg/m twice daily given for 14 days (days 1 to 14) and irinotecan (100 mg/m) given on days 1 and 8. Treatment was repeated on day 21. Thirty patients were included. All were assessable for response and toxicity. Average age was 64 years, male/female ratio 20/10. Fifteen had liver metastases; 9 had abdominal metastases; 5 had liver and lymph nodes metastases; and 1 had lung metastases. The median number of cycles was 8. Grades III and IV diarrheas were observed in 20%, mild vomiting in 20%, grades III and IV leukopenia in 23%, and hand and foot syndrome grade III in 1 patient (3%). A complete response was achieved in 3 (10%) patients, a partial response in 16 (53%), disease stabilization in 6 (20%), and tumor progression in 5 (17%). Progression-free survival was 8.4 months. Overall survival was 19.3 months. This regimen was provided on an outpatient basis with significant antitumor activity and without the need for indwelling catheters and seems to be feasible for patients of all ages, with acceptable toxicity.

Ultrafast electron and energy transfer in dye-sensitized iron oxide and oxyhydroxide nanoparticles.

PubMed

Gilbert, Benjamin; Katz, Jordan E; Huse, Nils; Zhang, Xiaoyi; Frandsen, Cathrine; Falcone, Roger W; Waychunas, Glenn A

2013-10-28

An emerging area in chemical science is the study of solid-phase redox reactions using ultrafast time-resolved spectroscopy. We have used molecules of the photoactive dye 2',7'-dichlorofluorescein (DCF) anchored to the surface of iron(III) oxide nanoparticles to create iron(II) surface atoms via photo-initiated interfacial electron transfer. This approach enables time-resolved study of the fate and mobility of electrons within the solid phase. However, complete analysis of the ultrafast processes following dye photoexcitation of the sensitized iron(III) oxide nanoparticles has not been reported. We addressed this topic by performing femtosecond transient absorption (TA) measurements of aqueous suspensions of uncoated and DCF-sensitized iron oxide and oxyhydroxide nanoparticles, and an aqueous iron(III)-dye complex. Following light absorption, excited state relaxation times of the dye of 115-310 fs were found for all samples. Comparison between TA dynamics on uncoated and dye-sensitized hematite nanoparticles revealed the dye de-excitation pathway to consist of a competition between electron and energy transfer to the nanoparticles. We analyzed the TA data for hematite nanoparticles using a four-state model of the dye-sensitized system, finding electron and energy transfer to occur on the same ultrafast timescale. The interfacial electron transfer rates for iron oxides are very close to those previously reported for DCF-sensitized titanium dioxide (for which dye-oxide energy transfer is energetically forbidden) even though the acceptor states are different. Comparison of the alignment of the excited states of the dye and the unoccupied states of these oxides showed that the dye injects into acceptor states of different symmetry (Ti t2gvs. Fe eg).

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.

Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies

PubMed Central

Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

2016-01-01

Background Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. Methods PubMed, Cochrane’s Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Results Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55–1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Conclusion Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors. PMID:27524907

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.

Orexin OX2 Receptor Antagonists as Sleep Aids.

PubMed

Jacobson, Laura H; Chen, Sui; Mir, Sanjida; Hoyer, Daniel

The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX 1 and OX 2 receptors (OX 2 Rs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OX 2 R antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OX 2 R antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OX 2 R is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OX 2 R antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OX 2 R antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.

A model of jam formation in congested traffic

NASA Astrophysics Data System (ADS)

Bunzarova, N. Zh; Pesheva, N. C.; Priezzhev, V. B.; Brankov, J. G.

2017-12-01

We study a model of irreversible jam formation in congested vehicular traffic on an open segment of a single-lane road. The vehicles obey a stochastic discrete-time dynamics which is a limiting case of the generalized Totally Asymmetric Simple Exclusion Process. Its characteristic features are: (a) the existing clusters of jammed cars cannot break into parts; (b) when the leading vehicle of a cluster hops to the right, the whole cluster follows it deterministically, and (c) any two clusters of vehicles, occupying consecutive positions on the chain, may become nearest-neighbors and merge irreversibly into a single cluster. The above dynamics was used in a one-dimensional model of irreversible aggregation by Bunzarova and Pesheva [Phys. Rev. E 95, 052105 (2017)]. The model has three stationary non-equilibrium phases, depending on the probabilities of injection (α), ejection (β), and hopping (p) of particles: a many-particle one, MP, a completely jammed phase CF, and a mixed MP+CF phase. An exact expression for the stationary probability P(1) of a completely jammed configuration in the mixed MP+CF phase is obtained. The gap distribution between neighboring clusters of jammed cars at large lengths L of the road is studied. Three regimes of evolution of the width of a single gap are found: (i) growing gaps with length of the order O(L) when β > p; (ii) shrinking gaps with length of the order O(1) when β < p; and (iii) critical gaps at β = p, of the order O(L 1/2). These results are supported by extensive Monte Carlo calculations.

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 ...

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.

Radical-lanthanide ferromagnetic interaction in a T bIII bis-phthalocyaninato complex

NASA Astrophysics Data System (ADS)

Komijani, Dorsa; Ghirri, Alberto; Bonizzoni, Claudio; Klyatskaya, Svetlana; Moreno-Pineda, Eufemio; Ruben, Mario; Soncini, Alessandro; Affronte, Marco; Hill, Stephen

2018-02-01

Recent studies have highlighted the importance of organic ligands in the field of molecular spintronics, via which delocalized electron-spin density can mediate magnetic coupling to otherwise localized 4 f moments of lanthanide ions, which show tremendous potential for single-molecule device applications. To this end, high-field/high-frequency electron paramagnetic resonance (EPR) spectroscopy is employed to study a neutral terbium bis-phthalocyaninato metalorganic complex, [TbPc2 ] 0, with the aim of understanding the magnetic interaction between the Ising-like moment of the lanthanide ion and the unpaired spin density on the coordinating organic radical ligand. The measurements were performed on a previously unknown [TbPc2 ] 0 structural phase crystallizing in the Pnma space group. EPR measurements on powder samples of [TbPc2 ] 0 reveal an anisotropic spectrum, which is attributed to the spin-1/2 radical coupled weakly to the EPR-silent T bIII ion. Extensive double-axis rotation studies on a single crystal reveal two independent spin-1/2 signals with differently oriented (albeit identical) uniaxial g -tensors, in complete agreement with x-ray structural studies that indicate two molecular orientations within the unit cell. The easy-axis nature of the radical EPR spectra thus reflects the coupling to the Ising-like T bIII moment. This is corroborated by studies of the isostructural [YPc2 ] 0 analog (where Y is nonmagnetic yttrium), which gives a completely isotropic radical EPR signal. The experimental results for the terbium complex are well explained on the basis of an effective model that introduces a weak ferromagnetic Heisenberg coupling between an isotropic spin-1/2 and an anisotropic spin-orbital moment, J =6 , that mimics the known, strong easy-axis Tb ⋯P c2 crystal-field interaction.

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.

Early investigational tubulin inhibitors as novel cancer therapeutics.

PubMed

Nepali, Kunal; Ojha, Ritu; Lee, Hsueh-Yun; Liou, Jing-Ping

2016-08-01

Microtubules represent one of the most logical and strategic molecular targets amongst the current targets for chemotherapy, alongside DNA. In the past decade, tubulin inhibitors as cancer therapeutics have been an area of focus due to the improved understanding and biological relevance of microtubules in cellular functions. Fueled by the objective of developing novel chemotherapeutics and with the aim of establishing the benefits of tubulin inhibition, several clinical trials have been conducted with others ongoing. At present, the antitubulin development pipeline contains an armful of agents under clinical investigation. This review focuses on novel tubulin inhibitors as cancer therapeutics. The article covers the agents which have completed the phase II studies along with the agents demonstrating promising results in phase I studies. Countless clinical trials evaluating the efficacy, safety and pharmacokinetics of novel tubulin inhibitors highlights the scientific efforts being paid to establish their candidature as cancer therapeutics. Colchicine binding site inhibitors as vascular disrupting agents (VDAs) and new taxanes appear to be the most likely agents for future clinical interest. Numerous agents have demonstrated clinical benefits in terms of efficacy and survival in phase I and II studies. However conclusive benefits can only be ascertained on the basis of phase III studies.

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…

Effects of PECS Phase III Application Training on Independent Mands in Young Children with Autism

ERIC Educational Resources Information Center

Love, Jessica June

2013-01-01

The purpose of this study was to examine the effects of PECS phase III application training on independent mands in young children with autism. Participants were five children with autism ranging from ages 2 to 4 years old. A multiple baseline across participants was used to evaluate acquisition of independent correct mands across baseline and…

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

Syn-Fuel reciprocating charge pump improvement program. Quarterly technical project report, April-June 1984

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

Not Available

1984-01-01

Major accomplishments during the second quarter of 1984 were completion of the Diaphragm Separation Seal clear liquid testing, and initiation of Phase III Field Testing. Diaphragm operational testing was conducted on a clear water test loop. The test goals were to ensure; mechanical reliability of the Diaphragm Seal, safe operation with simulated component failure, and proper operation of the Diaphragm Buffer Volume Control System. This latter system is essential in controlling the phasing of the diaphragm with its driving plunger. These tests were completed successfully. All operational problems were solved. However, it must be emphasized that the Diaphragm Seal wouldmore » be damaged by allowing the pump to operate in a cavitating condition for an extended period of time. A change in the Field Test phase of the program was made regarding choice of field test site. There is no operating Syn-Fuel pilot plant capable of inexpensively producing the slurry stream required for the reciprocating pump testing. The Field Tests will now be conducted by first testing the prototype pump and separation seals in an ambient temperature sand water slurry. This will determine resistence to abrasive wear and determine any operation problems at pressure over a lengthy period of time. After successful conclusion of these tests the pump and seals will be operated with a high temperature oil, but without solids, to identify any problems associated with thermal gradients, thermal shock and differential growth. After successful completion of the high temperature clean oil tests the pump will be deemed ready for in-line installation at a designated Syn-Fuel pilot plant. The above approach avoids the expense and complications of a separate hot slurry test loop. It also reduces risk of operational problems while in-line at the pilot plant. 5 figs.« less

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.

Reduction of aqueous chromate by Fe(II)/Fe(III) carbonate green rust: kinetic and mechanistic studies.

PubMed

Legrand, Ludovic; El Figuigui, Alaaeddine; Mercier, Florence; Chausse, Annie

2004-09-01

This work describes the heterogeneous reaction between FeII in carbonate green rust and aqueous chromate, in NaHCO3 solutions at 25 degrees C, and at pH values of 9.3-9.6. Evidence for reduction of CrVI to CrIII and concomitant solid-state oxidation of lattice FeII to FeIII was found from FeII titration and from structural analysis of the solids using FTIR, XRD, SEM, and XPS methods. Results indicate the formation of ferric oxyhydroxycarbonate and the concomitant precipitation of CrIII monolayers at the surface of the iron compound that induce passivation effects and progressive rate limitations. The number of CrIII monolayers formed at the completion of the reaction depends on [FeII]t=0, the molar concentration of FeII(solid) at t=0; on [n(o)]t=0, the molar concentration of reaction sites present at the surface of the solid phase at t=0; and on [CrVI]t=0, the molar concentration of CrVI at t=0. Kinetic data were modeled using a model based on the formation of successive CrIII monolayers, -(d[CrVI]/dt) = sigma(1)j k(i)[S] [CrVI]([n(i - 1)] - [n(i)]) with k(i)[S] (in s(-1) L mol(-1)), the rate coefficient of formation of CrIII monolayer i, and [n(i)] and [n(i - 1)], the molar concentration of CrIII precipitated in monolayer i and monolayer i - 1, respectively. Good matching curves were obtained with kinetic coefficients: k(1)[S] = 5-8 x 10(-4), k(2)[S] = 0.5-3 x 10(-5), and k(3)[S] about 1.7 x 10(-6) s(-1) m(-2) L. The CrVI removal efficiency progressively decreases along with the accumulation of CrIII monolayers at the surface of carbonate green rust particles. In the case of thick green rust particles resulting from the corrosion of iron in permeable reactive barriers, the quantity of FeII readily accessible for efficient CrVI removal should be rather low.

Opioid Patient Controlled Analgesia (PCA) use during the Initial Experience with the IMPROVE PCA Trial: A Phase III Analgesic Trial for Hospitalized Sickle Cell Patients with Painful Episodes

PubMed Central

Dampier, Carlton D.; Smith, Wally R.; Kim, Hae-Young; Wager, Carrie Greene; Bell, Margaret C.; Minniti, Caterina P.; Keefer, Jeffrey; Hsu, Lewis; Krishnamurti, Lakshmanan; Mack, A. Kyle; McClish, Donna; McKinlay, Sonja M.; Miller, Scott T.; Osunkwo, Ifeyinwa; Seaman, Phillip; Telen, Marilyn J.; Weiner, Debra L.

2015-01-01

Opioid analgesics administered by patient-controlled analgesia (PCA) are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations, a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI-higher demand dose with low constant infusion or LDHI- lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents, mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI and in the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI 0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage. PMID:21953763

Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial.

PubMed

Posner, M R; Lorch, J H; Goloubeva, O; Tan, M; Schumaker, L M; Sarlis, N J; Haddad, R I; Cullen, K J

2011-05-01

The association between human papillomavirus (HPV) and overall survival (OS) in oropharynx cancer (OPC) was retrospectively examined in TAX 324, a phase III trial of sequential therapy for locally advanced head and neck cancer. Accrual for TAX 324 was completed in 2003 and data updated through 2008. Pretherapy tumor biopsies were studied by PCR for human papillomavirus type 16 and linked to OS, progression-free survival (PFS) and demographics. Of 264 patients with OPC, 111 (42%) had evaluable biopsies; 56 (50%) were HPV+ and 55 (50%) were HPV-. HPV+ patients were significantly younger (54 versus 58 years, P = 0.02), had T1/T2 primary cancers (49% versus 20%, P = 0.001), and had a performance status of zero (77% versus 49%, P = 0.003). OS and PFS were better for HPV+ patients (OS, hazard ratio = 0.20, P < 0.0001). Local-regional failure was less in HPV+ patients (13% versus 42%, P = 0.0006); at 5 years, 82% of HPV+ patients were alive compared with 35% of HPV- patients (P < 0.0001). HPV+ OPC has a different biology compared with HPV- OPC; 5-year OS, PFS, and local-regional control are unprecedented. These results support the possibility of selectively reducing therapy and long-term morbidity in HPV+ OPC while preserving survival and approaching HPV- disease with more aggressive treatment.

Ionic liquid-assisted multiwalled carbon nanotube-dispersive micro-solid phase extraction for sensitive determination of inorganic As species in garlic samples by electrothermal atomic absorption spectrometry

NASA Astrophysics Data System (ADS)

Grijalba, Alexander Castro; Escudero, Leticia B.; Wuilloud, Rodolfo G.

2015-08-01

A highly sensitive dispersive micro-solid phase extraction (D-μ-SPE) method combining an ionic liquid (IL) and multi-walled carbon nanotubes (MWCNTs) for inorganic As species (As(III) and As(V)) species separation and determination in garlic samples by electrothermal atomic absorption spectrometry (ETAAS) was developed. Trihexyl(tetradecil)phosphonium chloride IL was used to form an ion pair with the arsenomolybdate complex obtained by reaction of As(V) with molybdate ion. Afterwards, 1.0 mg of MWCNTs was dispersed for As(V) extraction and the supernatant was separated by centrifugation. MWCNTs were re-dispersed with tetradecyltrimethylammonium bromide surfactant and ultrasound followed by direct injection into the graphite furnace of ETAAS for As determination. Pyrolysis and atomization conditions were carefully studied for complete decomposition of MWCNTs and IL matrices. Under optimum conditions, an extraction efficiency of 100% and a preconcentration factor of 70 were obtained with 5 mL of garlic extract. The detection limit was 7.1 ng L- 1 and the relative standard deviations (RSDs) for six replicate measurements at 5 μg L- 1 of As were 5.4% and 4.8% for As(III) and As(V), respectively. The proposed D-μ-SPE method allowed the efficient separation and determination of inorganic As species in a complex matrix such as garlic extract.

Emerging biological therapies to treat acute lymphoblastic leukemia.

PubMed

Huguet, Françoise; Tavitian, Suzanne

2017-03-01

Various settings of acute lymphoblastic leukemia (ALL) represent unmet medical needs: first remission at high risk of relapse, such as persistent minimal residual disease (MRD); relapse/refractoriness (R/R); elderly patients. Biological therapies targeting widely-shared antigens of blast cells have entered the clinic in B-cell precursor (BCP)-ALL. Area covered: Results of phase II/III trials of monoclonal antibodies (MoAbs) and phase I/II trials of adoptive cell therapy by chimeric antigen receptor-engineered T cells (CAR-T cells) are presented. Rituximab, a naked anti-CD20 MoAb, improves the results of chemotherapy in Philadelphia chromosome-negative BCP-ALL. Inotuzumab ozogamicin, an anti-CD22 immunotoxin, yields complete remission (CR) rates of 80% in R/R patients and in elderly newly diagnosed patients. Blinatumomab, a bispecific anti-CD19 and anti-CD3 agent redirects effector T cells towards B leukemic cells, is approved in R/R patients (40% CR, duration 6 months) and under investigation in MRD+ CR patients (80% negativation). Autologous anti-CD19 CAR-T cells undergo proliferation and persistence in the recipient. In limited series, they salvage more than 80% of advanced patients. Cytokine-release syndrome, encephalopathy and B-cell aplasia are shared, to varying extents, by blinatumomab and CAR-T cells. Expert opinion: Despite technological, ethical and clinical issues, biological therapies are currently changing the paradigm of treatment in BCP-ALL, and seem promised to dramatic developments.

A Microfabricated Segmented-Involute-Foil Regenerator for Enhancing Reliability and Performance of Stirling Engines. Phase III Final Report for the Radioisotope Power Conversion Technology NRA

NASA Technical Reports Server (NTRS)

Ibrahim, Mounir B.; Gedeon, David; Wood, Gary; McLean, Jeffrey

2009-01-01

Under Phase III of NASA Research Announcement contract NAS3-03124, a prototype nickel segmented-involute-foil regenerator was microfabricated and tested in a Sunpower Frequency-Test-Bed (FTB) Stirling convertor. The team for this effort consisted of Cleveland State University, Gedeon Associates, Sunpower Inc. and International Mezzo Technologies. Testing in the FTB convertor produced about the same efficiency as testing with the original random-fiber regenerator. But the high thermal conductivity of the prototype nickel regenerator was responsible for a significant performance degradation. An efficiency improvement (by a 1.04 factor, according to computer predictions) could have been achieved if the regenerator was made from a low-conductivity material. Also, the FTB convertor was not reoptimized to take full advantage of the microfabricated regenerator s low flow resistance; thus, the efficiency would likely have been even higher had the FTB been completely reoptimized. This report discusses the regenerator microfabrication process, testing of the regenerator in the Stirling FTB convertor, and the supporting analysis. Results of the pre-test computational fluid dynamics (CFD) modeling of the effects of the regenerator-test-configuration diffusers (located at each end of the regenerator) are included. The report also includes recommendations for further development of involute-foil regenerators from a higher-temperature material than nickel.

Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: a phase III analgesic trial for hospitalized sickle cell patients with painful episodes.

PubMed

Dampier, Carlton D; Smith, Wally R; Kim, Hae-Young; Wager, Carrie Greene; Bell, Margaret C; Minniti, Caterina P; Keefer, Jeffrey; Hsu, Lewis; Krishnamurti, Lakshmanan; Mack, A Kyle; McClish, Donna; McKinlay, Sonja M; Miller, Scott T; Osunkwo, Ifeyinwa; Seaman, Phillip; Telen, Marilyn J; Weiner, Debra L

2011-12-01

Opioid analgesics administered by patient-controlled analgesia (PCA)are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations,a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI—higher demand dose with low constant infusion or LDHI—lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents,mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI andin the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage.

Treatment of elderly ovarian cancer patients in the context of controlled clinical trials: a joint analysis of the AGO Germany experience.

PubMed

Hilpert, Felix; Wimberger, Pauline; du Bois, Andreas; Pfisterer, Jacobus; Harter, Philipp

2012-01-01

Age remains a negative prognostic factor in ovarian cancer (OC). 3 separate analyses by the AGO (Arbeitsgemeinschaft Gynaekologische Onkologie) give insight into the treatment of elderly patients (EPs) in the context of controlled clinical trials (CCTs). 1 retrospective study evaluated the reasons for non-enrolment into CCTs of patients with advanced OC in AGO centers. 2 other exploratory age-specific analyses of a phase III trial in advanced OC treated with platinum/ paclitaxel evaluated (1) feasibility, toxicity and quality of life (QoL) and (2) the clinical outcome. Non-study patients were significantly older (66.7 vs. 57.2 years). Reasons for non-enrolment were predominantly predefined exclusion criteria, numeric age, and the patient's decision. The phase III trial confirmed an under-representation of EPs. Cycle delivery was significantly lower and discontinuation more frequent in EPs than in younger patients (YPs), although QoL, toxicity, cycle delays, and dose reductions were comparable. Delivery of cycles was prognostically significant in EPs but not YPs. The survival advantage of YPs remained significant even in completely debulked patients. There is some kind of investigator reservation for the treatment of EPs, which not only applies for the enrolment into clinical trials but also for the treatment, even under CCT conditions, with impact on outcome. Copyright © 2012 S. Karger AG, Basel.

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.

Phase I/II combined chemoimmunotherapy with carcinoembryonic antigen-derived HLA-A2-restricted CAP-1 peptide and irinotecan, 5-fluorouracil, and leucovorin in patients with primary metastatic colorectal cancer.

PubMed

Weihrauch, Martin R; Ansén, Sascha; Jurkiewicz, Elke; Geisen, Caroline; Xia, Zhinan; Anderson, Karen S; Gracien, Edith; Schmidt, Manuel; Wittig, Burghardt; Diehl, Volker; Wolf, Juergen; Bohlen, Heribert; Nadler, Lee M

2005-08-15

We conducted a phase I/II randomized trial to evaluate the clinical and immunologic effect of chemotherapy combined with vaccination in primary metastatic colorectal cancer patients with a carcinoembryonic antigen-derived peptide in the setting of adjuvants granulocyte macrophage colony-stimulating factor, CpG-containing DNA molecules (dSLIM), and dendritic cells. HLA-A2-positive patients with confirmed newly diagnosed metastatic colorectal cancer and elevated serum carcinoembryonic antigen (CEA) were randomized to receive three cycles of standard chemotherapy (irinotecan/high-dose 5-fluorouracil/leucovorin) and vaccinations with CEA-derived CAP-1 peptide admixed with different adjuvants [CAP-1/granulocyte macrophage colony-stimulating factor/interleukin-2 (IL-2), CAP-1/dSLIM/IL-2, and CAP-1/IL-2]. After completion of chemotherapy, patients received weekly vaccinations until progression of disease. Immune assessment was done at baseline and after three cycles of combined chemoimmunotherapy. HLA-A2 tetramers complexed with the peptides CAP-1, human T-cell lymphotrophic virus type I TAX, cytomegalovirus (CMV) pp65, and EBV BMLF-1 were used for phenotypic immune assessment. IFN-gamma intracellular cytokine assays were done to evaluate CTL reactivity. Seventeen metastatic patients were recruited, of whom 12 completed three cycles. Therapy resulted in five complete response, one partial response, five stable disease, and six progressive disease. Six grade 1 local skin reactions and one mild systemic reaction to vaccination treatment were observed. Overall survival after a median observation time of 29 months was 17 months with a survival rate of 35% (6 of 17) at that time. Eight patients (47%) showed elevation of CAP-1-specific CTLs. Neither of the adjuvants provided superiority in eliciting CAP-1-specific immune responses. During three cycles of chemotherapy, EBV/CMV recall antigen-specific CD8+ cells decreased by an average 14%. The presented chemoimmunotherapy is a feasible and safe combination therapy with clinical and immunologic efficacy. Despite concurrent chemotherapy, increases in CAP-1-specific T cells were observed in 47% of patients after vaccination.

A Hybrid Method for Endocardial Contour Extraction of Right Ventricle in 4-Slices from 3D Echocardiography Dataset.

PubMed

Dawood, Faten A; Rahmat, Rahmita W; Kadiman, Suhaini B; Abdullah, Lili N; Zamrin, Mohd D

2014-01-01

This paper presents a hybrid method to extract endocardial contour of the right ventricular (RV) in 4-slices from 3D echocardiography dataset. The overall framework comprises four processing phases. In Phase I, the region of interest (ROI) is identified by estimating the cavity boundary. Speckle noise reduction and contrast enhancement were implemented in Phase II as preprocessing tasks. In Phase III, the RV cavity region was segmented by generating intensity threshold which was used for once for all frames. Finally, Phase IV is proposed to extract the RV endocardial contour in a complete cardiac cycle using a combination of shape-based contour detection and improved radial search algorithm. The proposed method was applied to 16 datasets of 3D echocardiography encompassing the RV in long-axis view. The accuracy of experimental results obtained by the proposed method was evaluated qualitatively and quantitatively. It has been done by comparing the segmentation results of RV cavity based on endocardial contour extraction with the ground truth. The comparative analysis results show that the proposed method performs efficiently in all datasets with overall performance of 95% and the root mean square distances (RMSD) measure in terms of mean ± SD was found to be 2.21 ± 0.35 mm for RV endocardial contours.

The clinical trials supporting benzyl alcohol lotion 5% (Ulesfia): a safe and effective topical treatment for head lice (pediculosis humanus capitis).

PubMed

Meinking, Terri L; Villar, Maria E; Vicaria, Maureen; Eyerdam, Debbie H; Paquet, Diane; Mertz-Rivera, Kamara; Rivera, Hector F; Hiriart, Javier; Reyna, Susan

2010-01-01

Benzyl alcohol lotion 5% (BAL 5%) is a non-neurotoxic topical head lice treatment that is safe and effective in children as young as 6 months of age. The safety and efficacy of this pediculicide has been studied in 695 (confirm number) subjects in all phases of clinical development. Scanning electron micrographs (SEM) demonstrated that the active agent appears to stun the breathing spiracles open, enabling the vehicle to penetrate the respiratory mechanism (spiracles), therefore asphyxiating the lice. Initial phase II trials compared this novel product to RID using identical volumes of treatment (4 oz/application) and yielding, almost, identical efficacy. This outcome pointed to the significant importance of completely saturating the hair with the product in order to achieve maximum treatment success. A second phase II trial, which allowed the use of sufficient product to saturate the hair, resulted in 100% efficacy after both 10 and 30 minute treatments. A third phase II trial verified an effective dose. Phase III trials compared BAL 5% to vehicle placebo for two 10-minute applications. It proved to be safe and effective (p < 0.001) for treatment of head lice and is the first FDA-approved non-neurotoxic lice treatment, now available in the United States as Ulesfia lotion.

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.

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).

A Phase I Study of Hypofractionated Carbon-ion Radiotherapy for Stage III Non-small Cell Lung Cancer.

PubMed

Saitoh, Jun-Ichi; Shirai, Katsuyuki; Abe, Takanori; Kubo, Nobuteru; Ebara, Takeshi; Ohno, Tatsuya; Minato, Koichi; Saito, Ryusei; Yamada, Masanobu; Nakano, Takashi

2018-02-01

The aim of this study was to assess the feasibility and safety of hypofractionated carbon-ion radiotherapy (C-ion RT) in patients with stage III non-small cell lung cancer (NSCLC). Patients with untreated, histologically proven, unresectable stage III NSCLC and not candidates for chemotherapy were included in this study. C-ion RT was planned and administered with 4 Gy (relative biological effectiveness (RBE)) in daily fractions for a total dose of 64 Gy (RBE) without combined chemotherapy. Dose-limiting toxicity (DLT) was defined as suspension of C-ion RT treatment for 2 weeks due to ≥ grade 2 pneumonitis, or any other ≥ grade 3 adverse event, or as any ≥ grade 4 adverse event within 3 months from the start of treatment. Six patients were treated between June 2013 and December 2014. The planned full dose of C-ion RT (64 Gy (RBE)) was completed in all patients. No patient developed DLT, and no patient experienced toxicities of ≥grade 3 severity. The overall response rate was 100%, and local tumor control was achieved in all patients during the survival period. Hypofractionated C-ion RT of patients with stage III NSCLC was feasible and well tolerated. Although the number of patients in this study was small, the results support further investigations to confirm the long-term therapeutic efficacy of this treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Phase 3 Trial of Postoperative Chemotherapy Alone Versus Chemoradiation Therapy in Stage III-IV Gastric Cancer Treated With R0 Gastrectomy and D2 Lymph Node Dissection

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

Kim, Tae Hyun; Park, Sook Ryun; Ryu, Keun Won

2012-12-01

Purpose: To compare chemotherapy alone with chemoradiation therapy in stage III-IV(M0) gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. Methods and Materials: The chemotherapy arm received 5 cycles of fluorouracil and leucovorin (FL), and the chemoradiation therapy arm received 1 cycle of FL, then radiation therapy of 45 Gy concurrently with 2 cycles of FL, followed by 2 cycles of FL. Intent-to-treat analysis and per-protocol analyses were performed. Results: Between May 6, 2002 and June 29, 2006, a total of 90 patients were enrolled. Forty-four were randomly assigned to the chemotherapy arm and 46 to the chemoradiationmore » therapy arm. Treatment was completed as planned by 93.2% of patients in the chemotherapy arm and 87.0% in the chemoradiation therapy arm. Overall intent-to-treat analysis showed that addition of radiation therapy to chemotherapy significantly improved locoregional recurrence-free survival (LRRFS) but not disease-free survival. In subgroup analysis for stage III, chemoradiation therapy significantly prolonged the 5-year LRRFS and disease-free survival rates compared with chemotherapy (93.2% vs 66.8%, P=.014; 73.5% vs 54.6%, P=.056, respectively). Conclusions: Addition of radiation therapy to chemotherapy could improve the LRRFS in stage III gastric cancer treated with R0 gastrectomy and D2 lymph node dissection.« less

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

Protocol for the ProCare Trial: a phase II randomised controlled trial of shared care for follow-up of men with prostate cancer

PubMed Central

Emery, Jon; Doorey, Juanita; Jefford, Michael; King, Madeleine; Pirotta, Marie; Hayne, Dickon; Martin, Andrew; Trevena, Lyndal; Lim, Tee; Constable, Roger; Hawks, Cynthia; Hyatt, Amelia; Hamid, Akhlil; Violet, John; Gill, Suki; Frydenberg, Mark; Schofield, Penelope

2014-01-01

Introduction Men with prostate cancer require long-term follow-up to monitor disease progression and manage common adverse physical and psychosocial consequences of treatment. There is growing recognition of the potential role of primary care in cancer follow-up. This paper describes the protocol for a phase II multisite randomised controlled trial of a novel model of shared care for the follow-up of men after completing treatment for low-moderate risk prostate cancer. Methods and analysis The intervention is a shared care model of follow-up visits in the first 12 months after completing treatment for prostate cancer with the following specific components: a survivorship care plan, general practitioner (GP) management guidelines, register and recall systems, screening for distress and unmet needs and patient information resources. Eligible men will have completed surgery and/or radiotherapy for low-moderate risk prostate cancer within the previous 8 weeks and have a GP who consents to participate. Ninety men will be randomised to the intervention or current hospital follow-up care. Study outcome measures will be collected at baseline, 3, 6 and 12 months and include anxiety, depression, unmet needs, prostate cancer-specific quality of life and satisfaction with care. Clinical processes and healthcare resource usage will also be measured. The principal emphasis of the analysis will be on obtaining estimates of the treatment effect size and assessing feasibility in order to inform the design of a subsequent phase III trial. Ethics and dissemination Ethics approval has been granted by the University of Western Australia and from all hospital recruitment sites in Western Australia and Victoria. Results of this phase II trial will be reported in peer-reviewed publications and in conference presentations. Trial Registration Australian New Zealand Clinical Trial Registry ACTRN12610000938000 PMID:24604487

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.

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

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

Growth of Iron(III)-Reducing Bacteria on Clay Minerals as the Sole Electron Acceptor and Comparison of Growth Yields on a Variety of Oxidized Iron Forms†

PubMed Central

Kostka, Joel E.; Dalton, Dava D.; Skelton, Hayley; Dollhopf, Sherry; Stucki, Joseph W.

2002-01-01

Smectite clay minerals are abundant in soils and sediments worldwide and are typically rich in Fe. While recent investigations have shown that the structural Fe(III) bound in clay minerals is reduced by microorganisms, previous studies have not tested growth with clay minerals as the sole electron acceptor. Here we have demonstrated that a pure culture of Shewanella oneidensis strain MR-1 as well as enrichment cultures of Fe(III)-reducing bacteria from rice paddy soil and subsurface sediments are capable of conserving energy for growth with the structural Fe(III) bound in smectite clay as the sole electron acceptor. Pure cultures of S. oneidensis were used for more detailed growth rate and yield experiments on various solid- and soluble-phase electron acceptors [smectite, Fe(III) oxyhydroxide FeOOH, Fe(III) citrate, and oxygen] in the same minimal medium. Growth was assessed as direct cell counts or as an increase in cell carbon (measured as particulate organic carbon). Cell counts showed that similar growth of S. oneidensis (108 cells ml−1) occurred with smectitic Fe(III) and on other Fe forms [amorphous Fe(III) oxyhydroxide, and Fe citrate] or oxygen as the electron acceptor. In contrast, cell yields of S. oneidensis measured as the increase in cell carbon were similar on all Fe forms tested while yields on oxygen were five times higher, in agreement with thermodynamic predictions. Over a range of particle loadings (0.5 to 4 g liter−1), the increase in cell number was highly correlated to the amount of structural Fe in smectite reduced. From phylogenetic analysis of the complete 16S rRNA gene sequences, a predominance of clones retrieved from the clay mineral-reducing enrichment cultures were most closely related to the low-G+C gram-positive members of the Bacteria (Clostridium and Desulfitobacterium) and the δ-Proteobacteria (members of the Geobacteraceae). Results indicate that growth with smectitic Fe(III) is similar in magnitude to that with Fe(III) oxide minerals and is dependent upon the mineral surface area available. Iron(III) bound in clay minerals should be considered an important electron acceptor supporting the growth of bacteria in soils or sedimentary environments. PMID:12450850

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.

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

PubMed

Rugo, Hope S; Olopade, Olufunmilayo I; DeMichele, Angela; Yau, Christina; van 't Veer, Laura J; Buxton, Meredith B; Hogarth, Michael; Hylton, Nola M; Paoloni, Melissa; Perlmutter, Jane; Symmans, W Fraser; Yee, Douglas; Chien, A Jo; Wallace, Anne M; Kaplan, Henry G; Boughey, Judy C; Haddad, Tufia C; Albain, Kathy S; Liu, Minetta C; Isaacs, Claudine; Khan, Qamar J; Lang, Julie E; Viscusi, Rebecca K; Pusztai, Lajos; Moulder, Stacy L; Chui, Stephen Y; Kemmer, Kathleen A; Elias, Anthony D; Edmiston, Kirsten K; Euhus, David M; Haley, Barbara B; Nanda, Rita; Northfelt, Donald W; Tripathy, Debasish; Wood, William C; Ewing, Cheryl; Schwab, Richard; Lyandres, Julia; Davis, Sarah E; Hirst, Gillian L; Sanil, Ashish; Berry, Donald A; Esserman, Laura J

2016-07-07

The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

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.

Effect of Persian Medicine Remedy on Chemotherapy Induced Nausea and Vomiting in Breast Cancer: A Double Blind, Randomized, Crossover Clinical Trial

PubMed Central

Nazari, Mohammad; Taghizadeh, Ali; Bazzaz, Mojtaba Mousavi; Rakhshandeh, Hassan; Shokri, Sadegh

2017-01-01

Background Chemotherapy induced nausea and vomiting (CINV) is a side effect, and has negative effect on quality of life and continuation of chemotherapy. Despite new regimen and drugs, the problems still remain and standard guidelines, effective treatment and supportive care for refractory CINV are still not yet established. Persian medicine, the old Iranian medical school, offer Persumac (prepared from Rhus Coriaria and Bunium Persicum Boiss). Objective The specific objectives were to assess the effect of Persumac on the number and severity of nausea and vomiting in refractory CINV in acute and delayed phase. Methods This randomized, double blind, crossover clinical trial study was carried out on 93 patients with breast cancer and refractory CINV, who received outpatient high emetogenic chemotherapy in Imam Reza hospital, Mashhad, Iran from October 2015 to May 2016. The study has three stages: in stage I patients received a questionaire and completed it after chemotherapy. In stage II they were randomly divided into intervention group with Persumac and control group with placebo (lactose were used). In stage III, wash out and crossover was conducted. Both groups in all stages received standard antiemetic therapy for CINV. The following were set as the inclusion criteria of the study: female, Age ≥18 years, clinical diagnosis of breast cancer, history of refractory CINV, normal blood tests and at least three courses of chemotherapy remaining. Exclusion criteria of this study were: Total or upper abdominal radiation therapy along with chemotherapy, drugs/therapy for nausea and vomiting not prescribed in this study, hypersensitivity to Sumac or Bunium Persicum, use of sumac and Bunium Persicum in seven days prior to the intervention, clinical diagnosis of digestion disorders, non-chemotherapy induced nausea and vomiting, milk allergy, loss of two consecutive or three intermittent doses of Persumac or placebo. Outcomes were gathered by Persian questionnaire. Number and severity of nausea and vomiting was measured with a self-reporting tool; visual analog scale. Results Demographic data and other characters in both groups have no significant diffrence. Eighty of 93 eligible patients in stage I completed the study and in stage II, eleven declined participation for stage III (crossover). P value of carry over, period and treatment effects demonstrated that they had not affected the results before and after crossover. The mean severity of nausea in acute phase was in stage I: 4.83 ± 1.40, stage II: 4.54 ± 2.0 and stage III: 4.15 ± 0.92 in sequence AB (first Persumac and then placebo in crossover), and in sequence BA (first placebo and then Persumac in crossover) was respectively 4.83 ± 1.40, 4.54 ± 2.0, 4.15 ± 0.92 with p value of carry over effect: 0.03 and period effect: 0.22. Except for severity of nausea in acute phase, the mean number and severity of nausea and vomiting scores significantly decreased in acute and delayed phase of CINV. Conclusion Persumac may control the refractory CINV. The implicable and clinical importance of this research is that another option exists for refractory CINV. Higher doses, different cancers, patients with more various features, and more complete methodology and tools can provide appropriate designs for new research on this topic. Trial registration This trial was registered at the Clinical Trials.gov ID: NCT02787707. Funding This study is part of a Ph.D. thesis and under grant; No: 930735 of Research Chancellery of MUMS. PMID:28243404

Open-label Bendamustine Monotherapy for Pediatric Patients With Relapsed or Refractory Acute Leukemia: Efficacy and Tolerability

PubMed Central

Brown, Patrick; Megason, Gail; Ahn, Hyo Seop; Cho, Bin; Kirov, Ivan; Frankel, Lawrence; Aplenc, Richard; Bensen-Kennedy, Debra; Munteanu, Mihaela; Weaver, Jennifer; Harker-Murray, Paul

2014-01-01

This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m2. In phase II, 32 patients received bendamustine 120 mg/m2. Two patients with ALL (bendamustine 90 mg/m2) experienced complete response (CR). Among patients who received bendamustine 120 mg/m2, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials. PMID:24072240

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].

Toward Phase IV, Populating the WOVOdat Database

NASA Astrophysics Data System (ADS)

Ratdomopurbo, A.; Newhall, C. G.; Schwandner, F. M.; Selva, J.; Ueda, H.

2009-12-01

One of challenges for volcanologists is the fact that more and more people are likely to live on volcanic slopes. Information about volcanic activity during unrest should be accurate and rapidly distributed. As unrest may lead to eruption, evacuation may be necessary to minimize damage and casualties. The decision to evacuate people is usually based on the interpretation of monitoring data. Over the past several decades, monitoring volcanoes has used more and more sophisticated instruments. A huge volume of data is collected in order to understand the state of activity and behaviour of a volcano. WOVOdat, The World Organization of Volcano Observatories (WOVO) Database of Volcanic Unrest, will provide context within which scientists can interpret the state of their own volcano, during and between crises. After a decision during the 2000 IAVCEI General Assembly to create WOVOdat, development has passed through several phases, from Concept Development (Phase-I in 2000-2002), Database Design (Phase-II, 2003-2006) and Pilot Testing (Phase-III in 2007-2008). For WOVOdat to be operational, there are still two (2) steps to complete, which are: Database Population (Phase-IV) and Enhancement and Maintenance (Phase-V). Since January 2009, the WOVOdat project is hosted by Earth Observatory of Singapore for at least a 5-year period. According to the original planning in 2002, this 5-year period will be used for completing the Phase-IV. As the WOVOdat design is not yet tested for all types of data, 2009 is still reserved for building the back-end relational database management system (RDBMS) of WOVOdat and testing it with more complex data. Fine-tuning of the WOVOdat’s RDBMS design is being done with each new upload of observatory data. The next and main phase of WOVOdat development will be data population, managing data transfer from multiple observatory formats to WOVOdat format. Data population will depend on two important things, the availability of SQL database in volcano observatories and their data sharing policy. Hence, a strong collaboration with every WOVO observatory is important. For some volcanoes where the data are not in an SQL system, the WOVOdat project will help scientists working on the volcano to start building an SQL database.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

PubMed

Moreno, Lucas; Casanova, Michela; Chisholm, Julia C; Berlanga, Pablo; Chastagner, Pascal B; Baruchel, Sylvain; Amoroso, Loredana; Melcón, Soledad Gallego; Gerber, Nicolas U; Bisogno, Gianni; Fagioli, Franca; Geoerger, Birgit; Glade Bender, Julia L; Aerts, Isabelle; Bergeron, Christophe; Hingorani, Pooja; Elias, Ileana; Simcock, Mathew; Ferrara, Stefano; Le Bruchec, Yvan; Slepetis, Ruta; Chen, Nianhang; Vassal, Gilles

2018-06-21

nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m 2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m 2 and grade 4 neutropenia >7 days at 270 mg/m 2 . The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m 2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m 2 . Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. nab-Paclitaxel 240 mg/m 2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. 2013-000144-26. Copyright © 2018 Elsevier Ltd. All rights reserved.

Deep Controlled Source Electro-Magnetic Sensing: A Cost Effective, Long-Term Tool for Sequestration Monitoring

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

LaBrecque, Douglas; Brigham, Russell D.; Schmidt-Hattenburger, Conny

2017-05-01

The proposed system was designed to operate as a permanent, autonomous monitoring and data collection system that can provide much higher temporal data density than can be achieved economically with 3-Dimensional (3D) seismic surveys. It can operate over broad areas for long periods of time providing full 3D data sets on a monthly basis at a very low cost. By borrowing techniques commonly used in marine CSEM, structural information from background seismic surveys can be incorporated into the CSEM modeling to provide high resolution models of CO 2 progression within reservoirs. The system uses borehole-based vertical-electric-dipole sources placed at reservoirmore » depths in the formation. The electric and magnetic fields induced by this source are received on the surface using an array of stations. The project was conducted in three phases. Phase I demonstrated the feasibility of the system to collect static/reference data at the Ketzin CO 2 storage pilot site in Germany. In Phase I, numerical modeling was used to determine the optimal configurations and requirements for sensor sensitivity and data accuracy. Based on the model results, existing hardware and software were modified. The CSEM system was then field tested at the Ketzin site. The data were imaged and the results were compared with independent studies of the reservoir and overburden geo-electrical characteristics. Phase II demonstrated the ability to provide sensitive, cost-effective measurement of changes in reservoir properties and changes in the overlying formations using a second round of measurements at the Ketzin site. A prototype autonomous recording system was developed and tested as a subset of the measurement points. Phase III of the project quantified the advantages (and disadvantages) of the fully autonomous data collection subsystems by comparing them with repeated measurements made with mobile stations. The Phase III also provided an additional time point in measuring post-closure changes in and above the Ketzin CO 2 injection site. Validation of the CSEM field survey results were completed using a method such as other alternative and available field site data.« less

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.

Sphingosine 1-phosphate receptor modulators in multiple sclerosis.

PubMed

Subei, Adnan M; Cohen, Jeffrey A

2015-07-01

Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience, as well as a third phase III trial (FREEDOMS II), also showed favorable results. More selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in relatively early stages of development, but phase I and II trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase III clinical trials.

Current and Emerging Therapy for Celiac Disease

PubMed Central

Makharia, Govind K.

2014-01-01

At present, strict and lifelong gluten-free diet is the only effective treatment for celiac disease. Even small amounts of gluten (50 mg/day) can be immunogenic; therefore all food and food items and drugs that contain gluten and its derivatives must be eliminated completely from the diet. While prescribing gluten-free diet is easy; the key to the success is the dietary counseling by a nutrition specialist and maintenance of adherence to GFD by the patient. In recent times, a number of targets to halt the process of immunological injury have been explored to find out alternative treatment for celiac disease. These targets include exploration of ancient wheat if they are less immunogenic, intra-luminal digestion of gluten using prolylendopeptidases, pretreatment of whole gluten with bacterial-derived peptidase before ingestion; prevention of passage of immunogenic peptides through the tight junctions such as zonulin antagonists, Blocking of HLA-DQ2 to prevent binding of immunogenic peptides, inhibition of transglutaminase 2, immune-modulation, and induction of tolerance to gluten using gluten tolerizing vaccines, use of gluten-sequestering polymers, use of anti-inflammatory drugs (glucocorticoids, budesonides) and anti-cytokines such as anti TNF-α, and anti-interleukin-15. While many of these targets are still in the pre-clinical phase, some of them including zonulin antagonist and endopeptidases have already reached phase II and phase III clinical trials. Furthermore, while these targets appear very exciting; they at best are likely to be used as adjunctive therapy rather than a complete replacement for gluten-free diet. PMID:25705619

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

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

PubMed Central

Wilfong, Angus A.; Mays, Maxwell; Talley, Christina M.; Agricola, Karen; Tudor, Cindy; Capal, Jamie; Holland-Bouley, Katherine; Franz, David Neal

2016-01-01

Objective: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC). Methods: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life. Results: Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported ≥50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months. Conclusions: Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC. Classification of evidence: This study provides Class IV evidence that for patients with TSC with medically refractory epilepsy everolimus improves seizure control. PMID:27815402

Pharmacotherapeutics of Intranasal Scopolamine: FDA Regulations and Procedures for Clinical Applications

NASA Technical Reports Server (NTRS)

Das, H.; Daniels, V. R.; Vaksman, Z.; Boyd, J. L.; Buckey, J. C.; Locke, J. P.; Putcha, L.

2007-01-01

Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during the early flight days of a space mission. Bioavailability of oral (PO) SMS medications is often low and highly variable; additionally, physiological changes in a microgravity environment exacerbate variability and decrease bioavailability. These factors prompted NASA to develop an intranasal dosage form of scopolamine (INSCOP) suitable for the treatment of SMS. However, to assure safety and efficacy of treatment in space, NASA physicians prescribe commercially available pharmaceutical products only. Development of a pharmaceutical preparation for clinical use must follow distinct clinical phases of testing, phase I through IV to be exact, before it can be approved by the FDA for approval for clinical use. After a physician sponsored Investigative New Drug (IND) application was approved by the FDA, a phase I clinical trial of INSCOP formulation was completed in normal human subjects and results published. The current project includes three phase II clinical protocols for the assessment of pharmacokinetics and pharmacodynamics (PK/PD), efficacy, and safety of INSCOP. Three clinical protocols that were submitted to FDA to accomplish the project objectives: 1) 002-A, a FDA Phase II dose ranging study with four dose levels between 0.1 and 0.4 mg in 12 subjects to assess PK/PD, 2) 002-B, a phase II clinical efficacy study in eighteen healthy subjects to compare efficacy of 0.2 (low dose) and 0.4 mg (high dose) INSCOP for prophylactic treatment of motion-induces (off-axis vertical rotation) symptoms, and (3) 002-C, a phase II clinical study with twelve subjects to determine bioavailability and pharmacodynamics of two doses (0.2 and 0.4 mg) of INSCOP in simulated microgravity, antiorthostatic bedrest. All regulatory procedures were competed that include certification for Good laboratory Procedures by Theradex , clinical documentation, personnel training, selection of clinical research operations contractor, data capturing and management, and annual reporting of results to FDA were successfully completed. Protocol 002-A was completed and sample and data analysis is currently in progress. Protocol 002-B is currently in progress at Dartmouth Hitchcock Medical Center and Protocol 002-C has been submitted to the FDA and will be implemented at the same contractor site as 002-A. An annual report was filed as required by FDA on the results of Protocol 002-A. Once all the three Phase II protocols are completed, a New Drug Administration application will be filed with FDA for Phase III clinical assessment and approval for marketing of the formulation. A commercial vendor will be identified for this phase. This is critical for making this available for treatment of SMS in astronauts and military personnel on duty. Once approved by FDA, INSCOP can be also used by civilian population for motion sickness associated with recreational travel and other ailments that require treatment with anticholinergic drugs.

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.

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

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.

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.

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.

Combined carboplatin plus ifosfamide and cisplatin in patients with advanced ovarian carcinoma. A phase I-II study. GOCS (Gynecological Oncology Cooperative Study).

PubMed

Lorusso, V; Leone, B; Di Vagno, G; Manzione, L; Palmeri, S; Vallejo, C; Machiavelli, M; Nacci, G; Bilancia, D; Leonardi, V; Catino, A; Gargano, G; Loverro, G; Selvaggi, L; De Lena, M

1998-02-01

Because of the relative lack of overlapping toxicity, carboplatin (PPL) and cisplatin (CDDP) can be easily combined for treatment of ovarian cancer to increase total platinum dose intensity. Ifosfamide (IFO), one of the most effective single agents in ovarian cancer, has a low hematological toxicity when administered in continuous infusion. From January 1991 to December 1993, 34 patients with advanced ovarian cancer, previously untreated with chemo- or radiotherapy, were enrolled in a phase I-II study with the aim of determining the maximum tolerated dose (MTD) of CDDP (on day 8 of a 28-day cycle) in combination with PPL (300 mg/m2 on day 1) and IFO (4,000 mg/m2/24 h by continuous infusion on day 1). The initial dose level of CDDP was 40 mg/m2, which was continuously increased by 10 mg/m2 up to the MTD defined as one dose level below that inducing dose-limiting toxicity (DLT) in at least two-thirds of treated patients; no dose escalation was allowed in the same patient. Grade 3-4 leukopenia and thrombocytopenia were observed in 54 and 49% of patients, respectively. The DLT was reached at 70 mg/m2 and therefore the dose recommended for the phase II study was 60 mg/m2. Complete (CR) plus partial response was observed in 88% of patients with a 21% pathological CR. With a minimum follow-up of 32 months (median 40 months), median progression-free survival and overall survival were 21 and 39 months, respectively. In conclusion, the combination of CDDP, PPL, and IFO provides an effective regimen for ovarian cancer with an acceptable toxicity profile.

Long-Term Results of Concomitant Boost Radiation Plus Concurrent Cisplatin for Advanced Head and Neck Carcinomas: A Phase II Trial of the Radiation Therapy Oncology Group (RTOG 99-14)

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

Garden, Adam S.; Harris, Jonathan M.S.; Trotti, Andy

2008-08-01

Purpose: The feasibility of combining concomitant boost-accelerated radiation regimen (AFX-C) with cisplatin was previously demonstrated in this Phase II trial. This article reports the long-term toxicity, relapse patterns, and survival in patients with advanced head and neck carcinoma. Methods and Materials: Between April and November 2000, 84 patients with Stage III-IV HNC were enrolled, and 76 patients were analyzable. Radiation consisted of 72 Gy over 6 weeks. Cisplatin dose was 100 mg/m{sup 2} on Days 1 and 22. Tumor and clinical status were assessed, and acute-late toxicities were graded. Results: The median follow-up for surviving patients is 4.3 years. Themore » 2- and 4-year locoregional failure rates were 33% and 36%, respectively, and the 2- and 4-year survival rates were 70% and 54%, respectively. The worst overall late Grade 3 or 4 toxicity rate was 42%. The prevalence rates of a gastrostomy at any time during follow-up, at 12 months, and at 48 months were 83%, 41%, and 17%, respectively. Five of 36 patients (14%) alive and without disease at last follow-up were gastrostomy-tube dependent. Conclusion: These data of long-term follow-up of patients treated with AFX-C with cisplatin show encouraging results with regard to locoregional disease control and survival, with few recurrences after 2 years. The late toxicity rates are relatively high. However, although prolonged dysphagia was noted in our preliminary report, its prevalence does decreased over time. A Phase III trial comparing AFX-C plus cisplatin against standard radiation plus cisplatin has completed accrual.« less

Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial.

PubMed

Strosberg, Jonathan; Wolin, Edward; Chasen, Beth; Kulke, Matthew; Bushnell, David; Caplin, Martyn; Baum, Richard P; Kunz, Pamela; Hobday, Timothy; Hendifar, Andrew; Oberg, Kjell; Sierra, Maribel Lopera; Thevenet, Thomas; Margalet, Ines; Ruszniewski, Philippe; Krenning, Eric

2018-06-07

Purpose Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of 177 Lu-Dotatate treatment on time to deterioration in health-related QoL. Methods The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with 177 Lu-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration ≥ 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date. Results TTD was significantly longer in the 177 Lu-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning. Conclusion This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, 177 Lu-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.

From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine.

PubMed

Guy, Bruno; Barrere, Beatrice; Malinowski, Claire; Saville, Melanie; Teyssou, Remy; Lang, Jean

2011-09-23

Dengue vaccine development has reached a major milestone with the initiation, in 2010, of the first phase III clinical trial to investigate the Sanofi Pasteur CYD tetravalent dengue vaccine (TDV). The CYD TDV candidate is composed of four recombinant, live, attenuated vaccines (CYD-1-4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane and envelope genes of one of the four dengue virus serotypes. The vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D, and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies showed that CYD TDV induces controlled stimulation of human dendritic cells, and significant immune responses in monkeys. Scale up and industrialization are being conducted in parallel with preclinical and clinical development to fulfill the needs of phase II/III trials, and to anticipate and facilitate supply and access to vaccine in the countries where the dengue disease burden makes it an urgent public health priority. The vaccine has now been administered to more than 6000 children and adults from dengue endemic and non-endemic areas and no safety concerns have arisen in any of the completed or ongoing trials. A three-dose vaccination regimen induces an immune response against all four serotypes in the large majority of vaccinees. Preexisting flavivirus immunity favors quicker and higher immune responses to CYD TDV, without adversely effecting clinical safety or increasing vaccine viremia. The observed level and nature of the cellular immune responses in humans are consistent with the good safety and immunogenicity profile of the vaccine. Preliminary results of an ongoing, proof-of-concept efficacy and large scale safety study in Thai children are expected by the end of 2012. Here we discuss the different steps and challenges of developing CYD TDV, from research to industrialization, and summarize some of the challenges to the successful introduction of a dengue vaccine into immunization programs. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

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

Influence of Reactive Transport on the Reduction of U(VI) in the Presence of Fe(III) and Nitrate: Implications for U(VI) Immobilization by Bioremediation / Biobarriers- Final Report

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

B.D. Wood

2007-01-01

Subsurface contamination by metals and radionuclides represent some of the most challenging remediation problems confronting the Department of Energy (DOE) complex. In situ remediation of these contaminants by dissimilatory metal reducing bacteria (DMRB) has been proposed as a potential cost effective remediation strategy. The primary focus of this research is to determine the mechanisms by which the fluxes of electron acceptors, electron donors, and other species can be controlled to maximize the transfer of reductive equivalents to the aqueous and solid phases. The proposed research is unique in the NABIR portfolio in that it focuses on (i) the role ofmore » flow and transport in the initiation of biostimulation and the successful sequestration of metals and radionuclides [specifically U(VI)], (ii) the subsequent reductive capacity and stability of the reduced sediments produced by the biostimulation process, and (iii) the potential for altering the growth of biomass in the subsurface by the addition of specific metabolic uncoupling compounds. A scientifically-based understanding of these phenomena are critical to the ability to design successful bioremediation schemes. The laboratory research will employ Shewanella putrefaciens (CN32), a facultative DMRB that can use Fe(III) oxides as a terminal electron acceptor. Sediment-packed columns will be inoculated with this organism, and the reduction of U(VI) by the DMRB will be stimulated by the addition of a carbon and energy source in the presence of Fe(III). Separate column experiments will be conducted to independently examine: (1) the importance of the abiotic reduction of U(VI) by biogenic Fe(II); (2) the influence of the transport process on Fe(III) reduction and U(VI) immobilization, with emphasis on methods for controlling the fluxes of aqueous species to maximize uranium reduction; (3) the reductive capacity of biologically-reduced sediments (with respect to re-oxidation by convective fluxes of O2 and NO3-) and the long-term stability of immobilized uranium mineral phases after bioremediation processes are complete, and (4) the ability for metabolic uncoupling compounds to maintain microbial growth while limiting biomass production. The results of the laboratory experiments will be used to develop mathematical descriptive models for the coupled transport and reduction processes.« less

Adsorption and desorption of arsenic to aquifer sediment on the Red River floodplain at Nam Du, Vietnam

PubMed Central

Thi Hoa Mai, Nguyen; Postma, Dieke; Thi Kim Trang, Pham; Jessen, Søren; Hung Viet, Pham; Larsen, Flemming

2016-01-01

The adsorption of arsenic onto aquifer sediment from the Red River floodplain, Vietnam, was determined in a series of batch experiments. Due to water supply pumping, river water infiltrates into the aquifer at the field site and has leached the uppermost aquifer sediments. The leached sediments, remain anoxic but contain little reactive arsenic and iron, and are used in our experiments. The adsorption and desorption experiments were carried out by addition or removal of arsenic from the aqueous phase in sediment suspensions under strictly anoxic conditions. Also the effects of HCO3, Fe(II), PO4 and Si on arsenic adsorption were explored. The results show much stronger adsorption of As(V) as compared to As(III), full reversibility for As(III) adsorption and less so for As(V). The presence or absence of HCO3 did not influence arsenic adsorption. Fe(II) enhanced As(V) sorption but did not influence the adsorption of As(III) in any way. During simultaneous adsorption of As(III) and Fe(II), As(III) was found to be fully desorbable while Fe(II) was completely irreversibly adsorbed and clearly the two sorption processes are uncoupled. Phosphate was the only solute that significantly could displace As(III) from the sediment surface. Compiling literature data on arsenic adsorption to aquifer sediment in Vietnam and Bangladesh revealed As(III) isotherms to be almost identical regardless of the nature of the sediment or the site of sampling. In contrast, there was a large variation in As(V) adsorption isotherms between studies. A tentative conclusion is that As(III) and As(V) are not adsorbing onto the same sediment surface sites. The adsorption behavior of arsenic onto aquifer sediments and synthetic Fe-oxides is compared. Particularly, the much stronger adsorption of As(V) than of As(III) onto Red River as well as on most Bangladesh aquifer sediments, indicates that the perception that arsenic, phosphate and other species compete for the same surface sites of iron oxides in sediments with properties similar to those of, for example a synthetic goethite, probably is not correct. A simple two-component Langmuir adsorption model was constructed to quantitatively describe the reactive transport of As(III) and PO4 in the aquifer. PMID:27867209

76 FR 50663 - Effective Date of Requirement for Premarket Approval for Three Class III Preamendments Devices

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-16

... completion of a PDP is not filed by the latter of the two dates, and no IDE is in effect, the device is... availability of a preamendments class III devices strategy document. The strategy document set forth FDA's... approved PMA or a declared completed PDP is required to be in effect for any such devices on or before 180...

A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project.

PubMed

Merle, Corinne S C; Sismanidis, Charalambos; Sow, Oumou Bah; Gninafon, Martin; Horton, John; Lapujade, Olivier; Lo, Mame Bocar; Mitchinson, Denis A; Perronne, Christian; Portaels, Francoise; Odhiambo, Joseph; Olliaro, Piero; Rustomjee, Roxana; Lienhardt, Christian; Fielding, Katherine

2012-05-18

There have been no major advances in tuberculosis (TB) drug development since the first East African/British Medical Research Council short course chemotherapy trial 35 years ago. Since then, the landscape for conducting TB clinical trials has profoundly changed with the emergence of HIV infection, the spread of resistant TB bacilli strains, recent advances in mycobacteriological capacity, and drug discovery. As a consequence questions have arisen on the most appropriate approach to design and conduct current TB trials. To highlight key issues discussed: Is a superiority, equivalence, or non-inferiority design most appropriate? What should be the primary efficacy outcome? How to consider re-infections in the definition of the outcome? What is the optimal length of patient follow-up? Is blinding appropriate when treatment duration in test arm is shorter? What are the appropriate assumptions for sample size calculation? Various drugs are currently in the development pipeline. We are presenting in this paper the design of the most recently completed phase III TB trial, the OFLOTUB project, which is the pivotal trial of a registration portfolio for a gatifloxacin-containing TB regimen. It is a randomized, open-label, multicenter, controlled trial aiming to evaluate the efficacy and safety of a gatifloxacin-containing 4-month regimen (trial registration: ClinicalTrial.gov database: NCT00216385). In the light of the recent scientific and regulatory discussions, we discuss some of the design issues in TB clinical trials and more specifically the reasons that guided our choices, in order to best answer the trial objectives, while at the same time satisfying regulatory authority requirements. When shortening TB treatment, we are advocating for a non-inferiority, non-blinded design, with a composite unfavorable endpoint assessed 12 months post treatment completion, and added trial procedures specifically aiming to: (1) minimize endpoint unavailability; and (2) distinguish between relapse and re-infection.

Safety and immunogenicity of MAGE-A3 cancer immunotherapeutic with dacarbazine in patients with MAGE-A3-positive metastatic cutaneous melanoma: an open phase I/II study with a first assessment of a predictive gene signature.

PubMed

Grob, Jean-Jacques; Mortier, Laurent; D'Hondt, Lionel; Grange, Florent; Baurain, Jean Francois; Dréno, Brigitte; Lebbe, Céleste; Robert, Caroline; Dompmartin, Anne; Neyns, Bart; Gillet, Marc; Louahed, Jamila; Jarnjak, Silvija; Lehmann, Frédéric F

2017-01-01

We assessed safety, immunogenicity and clinical activity of recombinant MAGE-A3 antigen combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) in association with dacarbazine in patients with metastatic melanoma. In this open-label, phase I/II, uncontrolled multicentre trial conducted in Belgium and France, patients with MAGE-A3-positive melanoma received up to 24 doses of MAGE-A3 immunotherapeutic (four cycles) coadministered with eight doses of dacarbazine. Adverse events (AE) were recorded until 31 days postvaccination, and serious AEs (SAE), until 30 days following the last dose. MAGE-A3-specific antibodies were measured by ELISA. Clinical activity of MAGE-A3 immunotherapeutic was assessed in patients positive/negative for previously identified gene signature (GS) associated with clinical outcome. Forty-eight patients were enrolled and treated (32 GS+, 15 GS-, 1 unknown GS status); two patients completed the study. All patients reported AEs, the most common were 'general disorders and administration site conditions' (94%). Treatment-related AEs were reported by 85% of patients; the most common was pain at injection site (38%). Sixteen SAEs were reported by 21% of patients; two were considered as treatment related (neutropenia and thrombocytopenia; grade 4). Postdose 4, all patients were seropositive for MAGE-A3-specific antibodies, with a geometric mean titre of 2778.7 ELISA units (EU)/mL (95% CI 1638.3 to 4712.8). One complete and three partial responses were reported (only in GS+ patients). Median overall survival was 11.4 months for GS+ and 5.3 months for GS- patients. Although this trial shows poor results compared with the new results with checkpoint inhibitors, it gives an interesting insight in rapidly developing fields like combinations of immunotherapy and chemotherapy, new generation vaccines and the use of gene profile as a predictive marker. NCT00849875.

Efficacy and safety of topical SR-T100 gel in treating actinic keratosis in Taiwan: A Phase III randomized double-blind vehicle-controlled parallel trial.

PubMed

Yang, Chao-Chun; Wong, Tak-Wah; Lee, Chih-Hung; Hong, Chien-Hui; Chang, Chung-Hsing; Lai, Feng-Jie; Lin, Shang-Hung; Chi, Ching-Chi; Lin, Tzu-Kai; Yen, Hsi; Wu, Chin-Han; Sheu, Hamm-Ming; Lan, Cheng-Che E

2018-06-01

Currently available topical treatments for actinic keratosis (AK) are associated with substantial side-effects. To evaluate the efficacy and safety of topical SR-T100 gel in treating AK. A multicenter, randomized, double-blinded phase III trial was conducted. Patients with at least two clinically visible AK were enrolled and a punch biopsy was performed on one of the AK to confirm the diagnosis. This study consisted of up to 16-week treatment and 8-week post-treatment periods. Medication was applied daily with occlusive dressing. 123 subjects were recruited and 113 were randomized. 76 subjects were in the SR-T100 and 37 in the vehicle arms. In SR-T100 and vehicle groups, 32.39% and 17.14% of subjects achieved complete clearance, respectively. For 75% partial clearance of lesions, 71.83% and 37.1% of subjects achieved this goal in SR-T100 and vehicle group, respectively. When comparing SR-T100 to vehicle, the odds ratio of complete clearance was 2.14 (p = 0.111), and odds ratio of partial clearance was 4.36 (p < 0.001). Severe local reactions were reported by only one subject using SR-T100. The imitation of the study was that not all the treated AK lesions were confirmed by histopathology. The diagnostic uncertainty may contribute to the high partial clearance rate in the vehicle group since the clinical-diagnosed AK showed higher clearance rate compared to histopathology-confirmed AK. The use of occlusive dressing was another possible explanation for high placebo effects. The results suggested that topical SR-T100 gel may be an effective and safe treatment for field therapy of AK. Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project

PubMed Central

2012-01-01

Background There have been no major advances in tuberculosis (TB) drug development since the first East African/British Medical Research Council short course chemotherapy trial 35 years ago. Since then, the landscape for conducting TB clinical trials has profoundly changed with the emergence of HIV infection, the spread of resistant TB bacilli strains, recent advances in mycobacteriological capacity, and drug discovery. As a consequence questions have arisen on the most appropriate approach to design and conduct current TB trials. To highlight key issues discussed: Is a superiority, equivalence, or non-inferiority design most appropriate? What should be the primary efficacy outcome? How to consider re-infections in the definition of the outcome? What is the optimal length of patient follow-up? Is blinding appropriate when treatment duration in test arm is shorter? What are the appropriate assumptions for sample size calculation? Methods Various drugs are currently in the development pipeline. We are presenting in this paper the design of the most recently completed phase III TB trial, the OFLOTUB project, which is the pivotal trial of a registration portfolio for a gatifloxacin-containing TB regimen. It is a randomized, open-label, multicenter, controlled trial aiming to evaluate the efficacy and safety of a gatifloxacin-containing 4-month regimen (trial registration: ClinicalTrial.gov database: NCT00216385). Results In the light of the recent scientific and regulatory discussions, we discuss some of the design issues in TB clinical trials and more specifically the reasons that guided our choices, in order to best answer the trial objectives, while at the same time satisfying regulatory authority requirements. Conclusion When shortening TB treatment, we are advocating for a non-inferiority, non-blinded design, with a composite unfavorable endpoint assessed 12 months post treatment completion, and added trial procedures specifically aiming to: (1) minimize endpoint unavailability; and (2) distinguish between relapse and re-infection. PMID:22607233

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

PubMed

Ma, Hong-Bing; Di, Zheng-Li; Wen, Jiao; Ke, Yue; Sun, Xiaodong; Ren, Juan

2015-02-01

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients.

PubMed

Yokota, Shumpei; Imagawa, Tomoyuki; Nishikomori, Ryuta; Takada, Hidetoshi; Abrams, Ken; Lheritier, Karine; Heike, Toshio; Hara, Toshiro

2017-01-01

To assess the long-term safety and efficacy of canakinumab in Japanese patients with cryopyrin-associated periodic syndrome (CAPS). In this open-label phase 3 study, Japanese patients aged ≥2 years with CAPS received canakinumab 2-8 mg/kg subcutaneously every 8 weeks. The duration of the core treatment phase was 24 weeks followed by 22 months extension phase. The primary objective was the proportion of patients free of clinical and serologic relapse at week 24. The study enrolled 19 Japanese patients (median age, 14 years; range, 2-48 years) with CAPS [MWS, 7 (36.8%); NOMID, 12 (63.2%)] for a median of 109 weeks. Fifteen patients (79%) achieved a complete response by day 15, 18 (94.7%) by week 24 and all by week 48. At the end of the study, 18 (95%) were free from relapse and 11 (57.9%) were assessed as having no disease activity by the PGA. Thirteen (68%) patients (MWS, 4; NOMID, 9) had their canakinumab dose increased during the trial. All patients experienced at least one adverse event (AE), the most common being infections (100%) and 5 (26.3%) reported serious AEs. No deaths were reported and the only patient who discontinued the study early withdrew consent. Regular canakinumab treatment every 8 weeks at dose levels from 2-8 mg/kg, based on the clinical need, represents a successful strategy to induce rapid and complete response while maintain long-term disease control in Japanese patients with CAPS. The safety profile of canakinumab was consistent with that observed from previous studies.

Chronic shin splints. Classification and management of medial tibial stress syndrome.

PubMed

Detmer, D E

1986-01-01

A clinical classification and treatment programme has been developed for chronic medial tibial stress syndrome. Medial tibial stress syndrome has been reported to be either tibial stress fracture or microfracture, tibial periostitis, or distal deep posterior chronic compartment syndrome. Three chronic types exist and may coexist: Type I (tibial microfracture, bone stress reaction or cortical fracture); type II (periostalgia from chronic avulsion of the periosteum at the periosteal-fascial junction); and type III (chronic compartment syndrome syndrome). Type I disease is treated nonoperatively. Operations for resistant types II and III medial tibial stress syndrome were performed in 41 patients. Bilaterality was common (type II, 50% type III, 88%). Seven had coexistent type II/III; one had type I/II. Preoperative symptoms averaged 24 months in type II, 6 months in type III, and 33 months in types II/III. Mean age was 22 years (15 to 51). Resting compartment pressures were normal in type II (mean 12 mm Hg) and elevated in type III and type II/III (mean 23 mm Hg). Type II and type II/III patients received fasciotomy plus periosteal cauterisation. Type III patients had fasciotomy only. All procedures were performed on an outpatient basis using local anaesthesia. Follow up was complete and averaged 6 months (2 to 14 months). Improved performance was as follows: type II, 93%, type III, 100%; type II/III, 86%. Complete cures were as follows: type II, 78%; type III, 75%; and type II/III, 57%. This experience suggests that with precise diagnosis and treatment involving minimal risk and cost the athlete has a reasonable chance of return to full activity.

ALX 111: ALX1-11, parathyroid hormone (1-84) - NPS Allelix, PREOS, PTH, recombinant human parathyroid hormone, rhPTH (1-84).

PubMed

2003-01-01

ALX 111 [parathyroid hormone (1-84) - NPS Allelix, recombinant human parathyroid hormone, rhPTH (1-84), PREOS] is a full-length, recombinant human parathyroid hormone. It has potential as an anti-osteoporotic agent, due to its properties as a bone formation stimulant. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It has been recommended that ALX 111 should be given for 1 to 2 years and may be given in combination with an antiresorptive agent, such as estrogen or a bisphosphonate. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. NPS harmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. Until 1994, Allelix Biopharmaceuticals and Glaxo in Canada were involved in a joint venture to investigate the efficacy of ALX 111 in osteoporosis. Allelix was subsequently, until September 1998, collaborating with Astra of Sweden in developing ALX 111. Astra had acquired exclusive worldwide rights to ALX 111 and was responsible for development of the agent. However, Astra returned all rights to ALX 111 to Allelix as a result of its merger with Zeneca to form AstraZeneca. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. The phase III trial of ALX 111 for the treatment of osteoporosis has completed patient enrolment, and phase II trials have been completed in Canada and the Netherlands. The 18-month, phase III, multicentre, placebo-controlled trial (Treatment of Osteoporosis with Parathyroid Hormone; TOP) has been designed to assess the bone-building and fracture-reducing potential of the drug, and over 2600 postmenopausal women with osteoporosis who have not received previous drug therapy for osteoporosis have been enrolled. Treatment will be completed in September 2003, but more than 75% of patients enrolled in the TOP study have chosen to enrol in an Open Label Extension Study (OLES), which allows for a total treatment period of up to 24 months. NPS Pharmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. In September 2002, NPS Pharmaceuticals announced that it has met its patient enrolment target (n > 150) for its POWER (PTH for Osteoporotic Women on Estrogen Replacement) study; a 24-month phase III trial initiated in Europe in November 2001. In this trial, women with osteoporosis receive SC injections of ALX 111 or placebo, in combination with their existing hormone replacement therapies, to test the bone building potential of the drug. In addition to the POWER study, a clinical trial sponsored by the National Institutes of Health (NIH) is being conducted to evaluate the potential of ALX 111 to build bone in combination with another osteoporosis medication. The 'PaTH' study (PTH/alendronate) is designed to assess the effect of various combinations and sequential uses of ALX 111 and Merck's Fosamax, a drug for slowing the loss of bone due to osteoporosis. The PaTH study, initiated in May 2000 and scheduled to conclude in September 2003, involved 238 patients with postmenopausal osteoporosis. It is thought that alendronic acid and ALX 111, when administered in combination, may act in an additive manner to treat osteoporosis because they act in different ways; alendronic acid acts to inhibit resorption and ALX 111 speeds up bone formation and resorption, with a net increase in formation. Results of this study are still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures underare still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures under conditions of microgravity was tested in orbit on the Space Shuttle Columbia, which was launched on 16 January 2003 but did not survive re-entry. This study was one in a series of studies known as 'OSTEO' and had been prepared by researchers from NPS Pharmaceuticals using Millenium Biologix' OSTEO Mini-Lab System. Under space flight conditions, astronauts experience a loss in bone density at a rate up to ten times faster than that of earth-bound patients with osteoporosis, and it was hoped that this study would indicate the mechanism of action of ALX 111 at cellular and genetic levels. The results of these studies were represented by the samples of human bone cells, which were lost during the re-entry tragedy.

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.

An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma.

PubMed

von Tresckow, Bastian; Morschhauser, Franck; Ribrag, Vincent; Topp, Max S; Chien, Caly; Seetharam, Shobha; Aquino, Regina; Kotoulek, Sonja; de Boer, Carla J; Engert, Andreas

2015-04-15

This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL). Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics. Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5-8 months). Median number of cycles: 4 (range, 1-16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing). JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL. ©2015 American Association for Cancer Research.

Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

PubMed Central

Sikov, William M.; Berry, Donald A.; Perou, Charles M.; Singh, Baljit; Cirrincione, Constance T.; Tolaney, Sara M.; Kuzma, Charles S.; Pluard, Timothy J.; Somlo, George; Port, Elisa R.; Golshan, Mehra; Bellon, Jennifer R.; Collyar, Deborah; Hahn, Olwen M.; Carey, Lisa A.; Hudis, Clifford A.; Winer, Eric P.

2015-01-01

Purpose One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. Patients and Methods Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m2 once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. Results Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. Conclusion In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent. PMID:25092775

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.

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.

Re-evaluating the kinetics of ATP hydrolysis during initiation of DNA sliding by Type III restriction enzymes

PubMed Central

Tóth, Júlia; Bollins, Jack; Szczelkun, Mark D.

2015-01-01

DNA cleavage by the Type III restriction enzymes requires long-range protein communication between recognition sites facilitated by thermally-driven 1D diffusion. This ‘DNA sliding’ is initiated by hydrolysis of multiple ATPs catalysed by a helicase-like domain. Two distinct ATPase phases were observed using short oligoduplex substrates; the rapid consumption of ∼10 ATPs coupled to a protein conformation switch followed by a slower phase, the duration of which was dictated by the rate of dissociation from the recognition site. Here, we show that the second ATPase phase is both variable and only observable when DNA ends are proximal to the recognition site. On DNA with sites more distant from the ends, a single ATPase phase coupled to the conformation switch was observed and subsequent site dissociation required little or no further ATP hydrolysis. The overall DNA dissociation kinetics (encompassing site release, DNA sliding and escape via a DNA end) were not influenced by the second phase. Although the data simplifies the ATP hydrolysis scheme for Type III restriction enzymes, questions remain as to why multiple ATPs are hydrolysed to prepare for DNA sliding. PMID:26538601

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.

Monte Carlo study of magnetization reversal in the model of a hard/soft magnetic bilayer

NASA Astrophysics Data System (ADS)

Taaev, T. A.; Khizriev, K. Sh.; Murtazaev, A. K.

2017-06-01

Magnetization reversal in the model of a hard/soft magnetic bilayer under the action of an external magnetic field has been investigated by the Monte Carlo method. Calculations have been performed for three systems: (i) the model without a soft-magnetic layer (hard-magnetic layer), (ii) the model with a soft-magnetic layer of thickness 25 atomic layers (predominantly exchange-coupled system), and (iii) with 50 (weak exchange coupling) atomic layers. The effect of a soft-magnetic phase on the magnetization reversal of the magnetic bilayer and on the formation of a 1D spin spring in the magnetic bilayer has been demonstrated. An inf lection that has been detected on the arch of the hysteresis loop only for the system with weak exchange coupling is completely determined by the behavior of the soft layer in the external magnetic field. The critical fields of magnetization reversal decrease with increasing thickness of the soft phase.

Vaccination Against Dengue: Challenges and Current Developments.

PubMed

Guy, Bruno; Lang, Jean; Saville, Melanie; Jackson, Nicholas

2016-01-01

Dengue is a growing threat worldwide, and the development of a vaccine is a public health priority. The completion of the active phase of two pivotal efficacy studies conducted in Asia and Latin America by Sanofi Pasteur has constituted an important step. Several other approaches are under development, and whichever technology is used, vaccine developers face several challenges linked to the particular nature and etiology of dengue disease. We start our review by defining questions and potential issues linked to dengue pathology and presenting the main types of vaccine approaches that have explored these questions; some of these candidates are in a late stage of clinical development. In the second part of the review, we focus on the Sanofi Pasteur dengue vaccine candidate, describing the steps from research to phase III efficacy studies. Finally, we discuss what could be the next steps, before and after vaccine introduction, to ensure that the vaccine will provide the best benefit with an acceptable safety profile to the identified target populations.

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

Measuring intellectual ability in children with cerebral palsy: can we do better?

PubMed

Sherwell, Sarah; Reid, Susan M; Reddihough, Dinah S; Wrennall, Jacquie; Ong, Ben; Stargatt, Robyn

2014-10-01

Standard intelligence tests such as the WPPSI-III have limitations when testing children with motor impairment. This study aimed to determine the proportion of children with cerebral palsy with sufficient verbal and motor skills to complete the WPPSI-III, to determine their comparative ability to complete tasks with and without a significant motor component, and to investigate short forms of the WPPSI-III as alternatives. Participants were 78 of 235 eligible 4-5 year old children with cerebral palsy resident in the Australian state of Victoria. Verbal IQ (VIQ), Performance IQ (PIQ), and Full-scale IQ (FSIQ) were determined using the WPPSI-III. Initial screening for pointing and verbal abilities determined which tests were attempted. The impact of speed was investigated by comparing scores on the Block Design subtest with and without an imposed time limit. FSIQ scores were calculated from two short forms of the WPPSI-III and compared to the full form. On screening, 16 children had inadequate pointing (14) and verbal abilities (2). FSIQ was obtained in 62 (82%) children. Strong associations were seen between completion of the entire test battery and topographical pattern, level of manual ability and level of gross motor function. Scores on subtests requiring manual ability were depressed relative to other scores. Children performed better using short forms of the WPPSI-III and, for a minority, when time limits were disregarded. In summary, children with cerebral palsy often lack the fine and gross motor skills necessary to complete the WPPSI-III, scoring relatively poorly on tasks requiring a fine motor response. Using short-form estimations of FSIQ comprised of subtests without a significant fine motor component has the potential to increase a child's FSIQ by approximately 5 points. These findings have important clinical implications when assessing a child with both motor and cognitive limitations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Rational Clinical Experiment: Assessing Prior Probability and Its Impact on the Success of Phase II Clinical Trials

PubMed Central

Halperin, Daniel M.; Lee, J. Jack; Dagohoy, Cecile Gonzales; Yao, James C.

2015-01-01

Purpose Despite a robust clinical trial enterprise and encouraging phase II results, the vast minority of oncologic drugs in development receive regulatory approval. In addition, clinicians occasionally make therapeutic decisions based on phase II data. Therefore, clinicians, investigators, and regulatory agencies require improved understanding of the implications of positive phase II studies. We hypothesized that prior probability of eventual drug approval was significantly different across GI cancers, with substantial ramifications for the predictive value of phase II studies. Methods We conducted a systematic search of phase II studies conducted between 1999 and 2004 and compared studies against US Food and Drug Administration and National Cancer Institute databases of approved indications for drugs tested in those studies. Results In all, 317 phase II trials were identified and followed for a median of 12.5 years. Following completion of phase III studies, eventual new drug application approval rates varied from 0% (zero of 45) in pancreatic adenocarcinoma to 34.8% (24 of 69) for colon adenocarcinoma. The proportion of drugs eventually approved was correlated with the disease under study (P < .001). The median type I error for all published trials was 0.05, and the median type II error was 0.1, with minimal variation. By using the observed median type I error for each disease, phase II studies have positive predictive values ranging from less than 1% to 90%, depending on primary site of the cancer. Conclusion Phase II trials in different GI malignancies have distinct prior probabilities of drug approval, yielding quantitatively and qualitatively different predictive values with similar statistical designs. Incorporation of prior probability into trial design may allow for more effective design and interpretation of phase II studies. PMID:26261263

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.

Relationships between individual differences in motivation and borderline personality disorder, psychopathy, and maladjustment.

PubMed

Bernard, Larry C

2013-08-01

Two studies investigate relationships between individual differences in motivation and borderline personality disorder, psychopathy, and maladjustment. Participants completed the Brief Assessment of Individual Motives 1--Revised, a measure of 15 putative evolved motives (i.e., "traits of action"). In Study 1, N = 147 adult participants also completed the Borderline Personality Questionnaire and Self-Report Psychopathy III Questionnaire (SRP III). In Study 2, N = 135 college age participants also completed the SRP III and the Counseling Center Assessment of Psychological Symptoms-62. Regression analyses suggested that individual differences in motivational traits account for moderate amounts of variance in measures of antisocial personality disorder, psychopathy, and maladjustment. They also suggested that lower motivation to engage in cooperative behaviors (e.g., sharing resources and forming coalitions) is related to impaired interpersonal relationships and maladjustment.